Goldfrank's Toxicologic Emergencies

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HISTORICAL PRINCIPLES AND PERSPECTIVES Paul M. Wax

The term poison first appeared in the English literature around the year 1230 A.D. to describe a potion or draught that had been prepared with deadly ingredients.109,136 The history of poisons and poisoning, however, dates back thousands of years. Throughout the millennia, poisons have played an important role in human history—from political assassination in Roman times to contemporary environmental concerns. This chapter offers a perspective on the impact of poisons and poisoning on history. It also provides an historic overview of human understanding of poisons and the development of toxicology. The chapter follows the important events in the evolution of toxicology from antiquity to the present. The development of the modern poison control center, the genesis of the field of medical toxicology, and the recent increasing focus on medical errors are examined. An Antidote in Depth segment at the end of the chapter scrutinizes changes in poison management over the years, analyzing obsolete antidotes and other discarded therapeutic modalities. Chapter 2 describes poison plagues and disasters throughout history and examines the societal consequences of these unfortunate events. An appreciation of past successes and mistakes in dealing with poisons and poisoning promotes a keener insight and a more critical evaluation of present-day toxicologic issues, and helps in the assessment and management of future toxicologic problems.

Arrow and Dart Poisons The prehistoric Masai hunters of Kenya, who lived 18,000 years ago, may have utilized arrow and dart poisons to increase the lethality of their weapons.18 One of these poisons appears to have consisted of extracts of Strophanthus species, an indigenous plant that contains strophanthin, a digitalis-like substance.91 Cave paintings of arrowheads and spearheads reveal that these weapons were crafted with small depressions at the end to hold the poison.137 In fact, the term toxicology appears to be derived from the Greek terms toxikos (“bow”) and toxikon (“poison into which arrowheads are dipped”).5,137 References to arrow poisons are cited in a number of other important literary works. The ancient Indian text Rg Veda, written in the 12th century B.C., refers to the use of Aconitum species for arrow poisons.18 In the Odyssey, Homer (ca. 850 B.C.) wrote that Ulysses anointed his arrows with a variety of poisons, including extracts of Helleborus orientalis (thought to act as a heart poison) and snake venoms.106 Aristotle (384–322 B.C.) described how the Scythians prepared and used arrow poisons.138 In the Book of Job 6:04, arrow poisons are also cited: “For the arrows of the Almighty pierce men, and my spirit drinks in their poison.”17 Finally, reference to weapons poisoned with the blood of serpents can be found in the writings of Ovid (43 B.C.–A.D. 18).144 The first attempts at poison identification and classification, and the introduction of the first antidotes, took place during Greek and Roman times. An early categorization of poisons divided them into fast poisons, such as strychnine, and slow poisons, such as arsenic. In his treatise, Materia Medica, the Greek physician Dioscorides (A.D. 40–80), categorized poisons by their origin: animal, vegetable, or mineral.137 This categorization remained the standard classification for the next 1500 years.137

POISONS, POISONERS, AND ANTIDOTES OF ANTIQUITY The earliest poisons consisted of plant extracts, animal venoms, and minerals. They were used for hunting, waging war, and sanctioned and unsanctioned executions. The Ebers Papyrus, an ancient Egyptian text written about 1500 B.C., which is considered to be among the earliest medical records, describes many ancient poisons, including arsenic, antimony, lead, opium, mandrake, hemlock, aconite, wormwood, and cyanogenic glycosides.91,136 These poisons were thought to have mystical properties, and their use was surrounded by superstition and intrigue. Some agents, such as the Calabar bean from the plant Physostigma venenosum containing physostigmine, were referred to as “ordeal poisons.” Ingestion of these substances was believed to be lethal to the guilty and harmless to the innocent.91 The “penalty of the peach” involved the administration of the ordeal poison of peach pits, which contain amygdalin that is metabolized to cyanide. Magicians, sorcerers, and priests were the poison experts of antiquity. The Sumerians, in about 4500 B.C., were said to worship the deity Gula, who was known as the “mistress of charms and spells” and the “controller of noxious poisons” (Table 1–1).136

Animal Poisons Animal poisons usually referred to the venom from poisonous animals. Although the venom from poisonous snakes has always been among the most commonly feared poisons, poisons from toads, salamanders, jellyfish, stingrays, and sea hares were also of concern. Nicander of Colophon (204–135 B.C.), a Greek poet and physician, and considered to be one of the earliest toxicologists, experimented with animal poisons on condemned criminals.125 Nicander’s poem Theriaca, which along with his other toxicologic verse Alexipharmaca is considered to be the earliest extant Greek toxicologic text, described the presentations and treatment of poisonings from animal toxins.136 A notable fatality from the effects of an animal toxin was Cleopatra (69–30 B.C.), who reportedly committed suicide by deliberately falling on an African cobra.72

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TABLE 1–1.

HISTORICAL PRINCIPLES AND PERSPECTIVES

Important Early Figures in the History of Toxicology

Person

Date

Importance

Gula Shen Nung Homer Aristotle Theophrastus Socrates Nicander King Mithridates VI Sulla Cleopatra Andromachus Dioscorides Galen

ca. 4500 B.C. ca. 2000 B.C. ca. 850 B.C. 384–322 B.C. ca. 370–286 B.C. ca. 470–399 B.C. 204–135 B.C. ca. 132–63 B.C. 81 B.C. 69–30 B.C. A.D. 37–68 A.D. 40–80 ca. A.D. 129–200

Ibn Wahshiya

9th century

Moses Maimonides Petrus Abbonus

1135–1204 1250–1315

First deity associated with poisons Chinese emperor who experimented with poisons and antidotes and wrote treatise on herbal medicine Wrote how Ulysses anointed arrows with the venom of serpents Described the preparation and use of arrow poisons Referred to poisonous plants in De Historia Plantarum Executed by poison hemlock Wrote two poems that are among the earliest works on poisons: Theriaca and Alexipharmaca Fanatical fear of poisons; developed mithradatum, one of first universal antidotes Issued Lex Cornelia, first antipoisoning law Committed suicide from deliberate cobra snake envenomation Refined the mithradatum, known as the Theriac of Andromachus Wrote Materia Medica, which classified poison by animal, vegetable, and mineral Prepared “Nut Theriac” for Roman Emperiors, a remedy against bites, stings, and poisons; wrote De Antidotis I and II, which provided recipes for different antidotes, including mithradatum and panacea Famed Arabic toxicologist. Wrote toxicology treatise Book on Poisons, combining contemporary science, magic, and astrology Wrote Treatise on Poisons and Their Antidotes Wrote De Venenis, major work on poisoning

Vegetable Poisons

Poisoners of Antiquity

Theophrastus (ca. 370–286 B.C.) described vegetable poisons in his treatise De Historia Plantarum.73 Notorious poisonous plants included Aconitum species (aconite), Veratrum album (hellebore), Hyoscyamus niger (henbane), Mandragora officinarum (mandrake), Conium maculatum (hemlock), and Papaver somniferum (opium). Aconite was among the most frequently encountered poisonous plants and has been described as the “queen mother of poisons.”136 Hemlock was the official poison used by the Greeks and was employed in the execution of Socrates (ca. 470–399 B.C.) and many others.127 Poisonous plants used in India at this time included Cannabis indica (tetrahydrocannabinol), Croton tiglium (croton oil), and Strychnos nux vomica (strychnine).73

Intentional poisoning was common during Roman times. In an attempt to curtail this practice, the Roman dictator Sulla issued the first law against poisoning, entitled the Lex Cornelia, in 81 B.C. According to its provisions, if convicted of poisoning, the perpetrator was sentenced to either loss of property and exile (if the perpetrator was of high rank) or exposure to wild beasts (if the perpetrator was of low rank). During this period, members of the aristocracy employed “tasters” to shield themselves from potential poisoners, a practice that was also in vogue during the reign of Louis XIV in 16th century France.144 One of the most infamous poisoners of Ancient Rome was Locusta, who was known to experiment on slaves with poisons that included arsenic, aconite, henbane, belladonna, and poisonous fungi. In A.D. 54, Nero’s mother, Agrippina, hired Locusta to poison Claudius (Agrippina’s husband and Nero’s stepfather) and Britannicus (Nero’s stepbrother) as part of a scheme to make Nero emperor. As a result of these activities, Claudius, who was a great lover of mushrooms, died from Amanita phalloides poisoning,15 and in the next year, Britannicus also became one of Locusta’s victims. In the case of Britannicus, Locusta managed to fool the taster by preparing unusually hot soup that required additional cooling after the soup had been officially tasted. At the time of cooling, the poison was unobtrusively slipped into the soup. Almost immediately after drinking the soup prepared in this manner, Britannicus collapsed and died. The exact identity of Locusta’s choice of poison here remains debatable, but the rapidity of Britannicus’s death suggests that it was a cyanogenic substance.130

Mineral Poisons The mineral poisons of antiquity consisted of the heavy metals: lead, mercury, arsenic, and antimony. Undoubtedly the most famous of these was lead. Lead was discovered as early as 3500 B.C. Although controversy continues to this day about whether an epidemic of lead poisoning among the Roman aristocracy contributed to the fall of the Roman Empire, lead was certainly used extensively during this period.54,105 In addition to its considerable use in plumbing, lead was also utilized in the production of food and drink containers.61 It was common practice to add lead directly to wine, or to intentionally prepare the wine in a leaden kettle to improve its taste. Not surprisingly, chronic lead poisoning became widespread. Nicander is credited with describing the first case of lead poisoning in the 2nd century B.C.142 Dioscorides, writing in the 1st century A.D., noted that fortified wine was “most hurtful to the nerves.”142 Lead-induced gout (“saturnine gout”) may have also been widespread among the Roman elite.105 Although not animal, vegetable, or mineral in origin, the toxic effects of gases were also appreciated during antiquity. In the 3rd century B.C., Aristotle commented that “coal fumes (carbon monoxide) lead to a heavy head and death”70 and Cicero (106–43 B.C.) referred to the use of coal fumes in suicide and execution, a practice that continues 2000 years later.

Early Quests for the Universal Antidote The recognition, classification, and use of poisons in Ancient Greece and Rome were accompanied by an intensive search for a universal antidote. In fact, many of the physicians of this period devoted significant parts of their careers to this endeavor.136 Mystery and superstition surrounded the origin and source of these proposed antidotes. One of the earliest specific references to a protective agent can be found in Homer’s Odyssey, when Ulysses is

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advised to protect himself by taking the antidote “moli.” Recent speculation suggests that moli referred to Galanthus nivalis, a naturally occurring cholinesterase inhibitor. This agent could have been used as an antidote against poisonous plants such as Datura stramonium.113 Theriacs and the Mithradatum. The Greeks referred to the universal antidote as the alexipharmaca or theriac.136 The term alexipharmaca was derived from the words alexipharmakos (“which keeps off poison”) and antipharmakon (“antidote”). Over the years, alexipharmaca has been increasingly used to refer to a method of treatment, such as the induction of emesis by using a feather. Theriac, which originally had referred to poisonous reptiles or wild beasts, was later used to refer to the antidotes. Ingestion of the early theriacs (ca. 200 B.C.) was reputed to make people “poison-proof” against bites of all venomous animals except the asp. Their ingredients included wild thyme, apoponax, aniseed, fennel, parsley, meru, and anmi.136 The quest for the universal antidote was epitomized by the work of King Mithradates VI of Pontus (132–63 B.C.).71 After repeatedly being subjected to poisoning attempts by his enemies during his youth, Mithradates channeled his fear of being poisoned into the development of universal antidotes. To find the best antidote, he performed acute toxicity experiments on criminals and slaves. The preparation he concocted, known as the “mithradatum,” contained a minimum of 36 ingredients and was considered the best antidote in the Roman pharmacy at that time. This concoction was thought to be protective against spiders, scorpions, vipers, sea slugs, aconite, and all other poisonous substances.71 Mithradates took his concoction every day. Ironically, as an old man, Mithradates attempted suicide by poison but supposedly was unsuccessful because he had become poison-proof. Having failed at self-poisoning, Mithradates was compelled to have a soldier kill him with a sword. Galen described Mithradates’ experiences in a series of three books: De Antidotis I, De Antidotis II, and De Theriaca ad Pisonem.71,140 The Theriac of Andromachus, also known as the “Venice treacle” or “galene,” is probably the most famous theriac. According to Galen, this preparation, formulated during the 1st century A.D., was considered an improvement over the mithradatum.140 It was prepared by Andromachus (A.D. 37–68), physician to emperor Nero. Andromachus added to the mithradatum ingredients such as the flesh of vipers, squills, and generous amounts of opium.146 Other ingredients were removed. Altogether, 73 ingredients were required. It was advocated to “counteract all poisons and bites of venomous animals,” as well as a host of other medical problems, such as colic, jaundice, and dropsy, and it was used both therapeutically and prophylactically.136,140 As evidence of its efficacy, Galen demonstrated that fowl receiving poison followed by theriac had a higher survival rate than fowl receiving poison alone.136 It is likely, however, that the scientific rigor and methodology employed differed from current scientific practice. By the Middle Ages, the Theriac of Andromachus contained more than 100 ingredients. Its synthesis was quite elaborate; the initial production period lasted months, followed by an aging process that lasted years, somewhat like vintage wine.87 The final product was often more solid than liquid in consistency. Other theriac preparations were named after famous physicians (Damocrates, Nicolaus, Amando, Arnauld, and Abano) who contributed additional ingredients to the original formulation. Over the centuries certain localities were celebrated for their own pecu-

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liar brand of theriac. Notable centers of theriac production included Cairo, Venice, Florence, Genoa, Bologna, and Istanbul. At times, theriac production was accompanied by great fanfare. For example, in Bologna, the mixing of the theriac could take place only under the direction of the medical professors at the university.136 Whether these preparations truly benefited anyone is debatable. Some have suggested that the theriac may have had an antiseptic effect on the gastrointestinal tract, while others have stated that theriac’s sole benefit derived from its formulation with opium.87 Theriacs remained in vogue throughout the Middle Ages and Renaissance, and it was not until 1745 that their efficacy was finally questioned by William Heberden in Antitheriaka: An Essay on Mithradatum and Theriaca.71 Nonetheless, pharmacopeias in France, Spain, and Germany continued to list these agents until the last quarter of the 19th century and theriac was still available in Italy and Turkey into the early 20th century. 16,87 Sacred Earth. Beginning in the 5th century B.C., an adsorbent agent called terra sigillata was promoted as a universal antidote. This agent, also known as the “sacred sealed earth,” consisted of red clay that could be found on only one particular hill on the Greek island of Lemnos. Perhaps somewhat akin to the 20th-century “universal antidote,” it was advocated as effective in counteracting all poisons.136 With great ceremony, once per year, the terra sigillata was retrieved from this hill and prepared for subsequent use. According to Dioscorides, this clay was formulated with goat’s blood to make it into a paste. At one time, it was included as part of the Theriac of Andromachus. Demand for terra sigillata continued into the 15th century. Similar antidotal clays were found in Italy, Malta, Silesia, and England. Later analysis revealed these clays to be a combination of iron, aluminum, magnesium, and silicates.136 Charms. Charms, such as toadstones, snakestones, unicorn horns, and bezoar stones, were also promoted as universal antidotes. Toadstones, found in the heads of old toads, were reputed to have the capability to extract poison from the site of a venomous bite or sting. In addition, the toadstone was supposedly able to detect the mere presence of poison by producing a sensation of heat upon contact with a poisonous substance.136 Likewise, snakestones extracted from the heads of cobras (known as piedras della cobra de Capelos) were also reported to have similar magical qualities.13 The 17th-century Italian philosopher Athanasius Kircher (1602–1680) became an enthusiastic supporter of snakestone therapy for the treatment of snakebite after conducting experiments in the 1660s, demonstrating the antidotal attributes of these charms “in front of amazed spectators.” Kircher attributed the snakestone’s efficacy to the theory of “attraction of like substances,” suggesting that the snakestone attracts magnetically and sympathetically toxic spirits from the snake bite that circulate in the victim’s bloodstream. Francesco Redi (1626–1698), a court physician and contemporary of Kircher, debunked this quixotic approach. A harbinger of future experimental toxicologists, Redi was not willing to accept isolated case reports and field demonstrations as proof of the snakestone’s utility. Using a considerably more rigorous approach, provando et riprovando (by testing and retesting), Redi performed multiple experiments assessing the antidotal efficacy of snakestone on different animal species and different toxins and failed to confirm any benefit from the use of snakestone.13

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HISTORICAL PRINCIPLES AND PERSPECTIVES

Much lore has surrounded the antidotal effects of the mythical unicorn horn. Ctesias, writing in 390 B.C., was the first to chronicle the wonders of the unicorn horn, claiming that drinking water or wine from the “horn of the unicorn” would protect against poison.136 The horns were usually narwhal tusks or rhinoceros horns and were greatly valued. During the Middle Ages, the unicorn horn may have been worth as much as 10 times the price of gold. Similar to the toadstone, the unicorn horn was used both to detect poisons and to neutralize them. Supposedly a cup made of unicorn horn would sweat if a poisonous substance was placed in it.85 To give further credence to its use, a 1593 study on arsenic-poisoned dogs reportedly showed that the horn was protective.85 Bezoar stones, also touted as universal antidotes, consisted of stomach or intestinal calculi formed by the deposition of calcium phosphate around a hair, fruit pit, or gallstone. They were removed from wild goats, cows, and apes and administered orally. The Persian name for the bezoar stone was pad zahr (“expeller of poisons”). The ancient Hebrews referred to them as bel Zaard (“every cure for poisons”). Over the years, regional variations of bezoar stones were popularized, including an Asian variety from wild goat of Persia, an Occidental variety from llamas of Peru, and a European variety from chamois of the Swiss mountains.48,136

Opium, Coca, and Hallucinogens in Antiquity Although it was not until the mid-19th century that the peril of opiate addiction was first recognized, juice from the Papaver somniferum was known for its medicinal value in Egypt, at least as early as the writing of the Ebers Papyrus in 1500 B.C. Egyptian pharmacologists of that time reportedly recommended opium as a pacifier for children who exhibited incessant crying.124 In Ancient Greece, Dioscorides and Galen were early advocates of opium as a therapeutic agent. During this time, it was also used as a means of suicide. Mithradates’ lack of success in his own attempted suicide by poisoning may have been due to an opium tolerance that had developed from previous repetitive use.124 One of the earliest descriptions of the abuse potential of opium is attributed to Epistratos (304–257 B.C.), who criticized the use of opium for earache because it “dulled the sight and is a narcotic.”124 Cocaine use dates back to at least 300 B.C., when South American Indians reportedly chewed coca leaves during religious ceremonies.99 Chewing coca to increase work efficacy and to elevate mood has remained commonplace in some South American societies for thousands of years. A recent study of an Egyptian mummy from about 950 B.C. revealed significant amounts of cocaine in the stomach and liver, suggesting oral use of cocaine during this time period.103 High amounts of tetrahydrocannabinol (THC) were found in the lung and muscle of the same mummy. In another investigation of 11 Egyptian (1079 B.C.–A.D. 395) and 72 Peruvian (A.D. 200–1500) mummies, cocaine, thought to be indigenous only to South America, and hashish, thought to be indigenous only to Asia, were found in both groups.112 Other currently abused agents that were known to the ancients include peyote, hallucinogenic mushrooms, nutmeg, and cannabis. As early as 1300 B.C., Peruvian indian tribal ceremonies included the use of mescaline-containing San Pedro cacti.99 The hallucinogenic mushroom, Amanita muscaria, known as “fly agaric,” was used as a ritual drug and may have been known in India as “soma” around 2000 B.C. The use of cannabis dates back even further, to around 2700 B.C., when the Chinese used it. Known as the “liberator of sin,” cannabis use during that period may have been both

therapeutic and recreational.99 In India and Iran, it was used as an intoxicant known as bhang as early as 1000 B.C.102

Early Attempts at Gastrointestinal Decontamination Nicander’s Alexipharmaca (“Antidotes for Poisons”) recommended induction of emesis by one of several different methods: (a) ingesting warm linseed oil; (b) tickling the hypopharynx with a feather; or (c) “emptying the gullet with a small twisted and curved paper.”90 Nicander also advocated the use of suction to limit envenomation.137 The Romans referred to the feather as the “vomiting feather” or “pinna.” Most commonly, the feather was utilized after a hearty feast to avoid the gastrointestinal discomfort associated with overeating. At times, the pinna was dipped into a nauseating mixture to increase its efficacy.90

TOXICOLOGY DURING THE MEDIEVAL AND RENAISSANCE PERIODS From the fall of Rome until the Renaissance, there is relatively little documented attention to the subject of poisons. Three of the most important medieval texts were written by Ibn Wahshiya (9th century), Moses Maimonides (12th century), and Petrus Abbonus (13th century) (Table 1–1). During the 9th century, a golden age of Arab toxicology, Arab scholars, including Jabir and Ibn Wahshiya, wrote several toxicology treatises entitled Book of Poisons.82 Citing Greek, Persian, and Indian texts, Ibn Wahshiya’s work combines contemporary science, magic, and astrology. In a lengthy treatise, Ibn Wahshiya discussed poison mechanisms (as they were understood at that time), symptomatology, antidotes, including his own recommendation for a universal antidote, and prophylaxis. He categorized poisons as lethal by sight, smell, touch, and sound, as well as by drinking and eating. For victims of an aconite-containing dart arrow, Ibn Wahshiya recommended excision, followed by cauterization and topical treatment with onion and salt.82 Another significant medieval contribution to toxicology can be found in Moses Maimonides’ (1135–1204) Treatise on Poisons and Their Antidotes. In part one of this 1198 treatise, Maimonides discussed the bites of snakes and mad dogs, and the stings of bees, wasps, spiders, and scorpions.122 He also discussed the use of cupping glasses for bites (a progenitor of the modern suctioning device), and was one of the first to differentiate the hematotoxic (hot) from the neurotoxic (cold) effects of poison. In part two, he discussed mineral and vegetable poisons and their antidotes. He described belladonna poisoning as causing a “redness and a sort of excitation.”122 He suggested that emesis should be induced by hot water, anethum, and oil, followed by fresh milk, butter, and honey. Although he rejected some of the popular treatments of the day, he advocated the use of the great theriac and the mithradatum as firstand second-line agents in the treatment of snakebite.122 Petrus Abbonus (1250–1315) wrote a very comprehensive textbook on toxicology that discussed in great detail animal, vegetable, and mineral poisonings and their treatment.20 On the subject of oleander poisoning, Abbonus wrote that those who drink the juice, spines, or bark of oleander will develop anxiety, palpitations, and syncope. He described the clinical presentation of opium overdose as someone who “will be dull, lazy, and sleepy, without feeling, and he will neither understand nor feel anything,

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and if he does not receive succor, he will die.” Although this “succor” is not defined, he recommended that treatment of opium intoxication include drinking the strongest wine, rubbing the extremities with alkali and soap, and olfactory stimulation with pepper. To treat snakebite, Abbonus suggested the immediate application of a tourniquet, as well as oral suctioning of the bite wound—preferably performed by a servant. Interestingly, from a 21st-century perspective, Abbonus also suggested that St. John’s wort had the magical power to free anything from poisons and attributed this virtue to the influence of the stars.20

The Scientists Paracelsus’ (1493–1541) study on the dose-response relationship is usually considered the beginning of the scientific approach to toxicology (Table 1–2). He was the first to emphasize the chemical nature of toxic agents.110 Paracelsus stressed the need for proper observation and experimentation regarding the true response to chemicals. He underscored the need to differentiate between the therapeutic and toxic properties of chemicals when he stated in his Third Defense, “What is there that is not poison? All things are poison and nothing [is] without poison. Solely, the dose determines that a thing is not a poison.”41 Although Paracelsus is the best known Renaissance toxicologist, Ambroise Pare (1510–1590) and William Piso (1611–1678) also contributed to the field. Pare argued against the use of the unicorn horn and bezoar stone.89 He also wrote an early treatise on carbon monoxide poisoning. Piso is credited as one of the first to recognize the emetic properties of ipecacuanha.119

TABLE 1–2.

HISTORICAL PRINCIPLES AND PERSPECTIVES

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Medieval and Renaissance Poisoners Along with these advances in toxicologic knowledge, the Renaissance is mainly remembered as the age of the poisoner, a time when the art of poisoning reached new heights (Table 1–3). In fact, poisoning was so rampant during this time that King Henry VIII decreed in 1531 that convicted poisoners should be boiled alive.50 From the 15th to 17th centuries, actual schools of poisoning existed in Venice and Rome. In Venice, poisoning services were provided by a group called the Council of Ten, whose members were hired to perform murder by poison.144 Members of the infamous Borgia family were credited with many poisonings during this period. They preferred to use a poison called “La Cantarella,” a mixture of arsenic and phosphorus.138 Rodrigo Borgia (1431–1503), who became Pope Alexander VI, and his son, Cesare Borgia, were reportedly responsible for the poisoning of cardinals and kings. In the late 16th century, Catherine de Medici, wife of Henry II of France, introduced Italian poisoning techniques to France. She experimented on the poor, the sick, and the criminal. By analyzing the subsequent complaints of her victims, she is said to have learned the site of action and time of onset, the clinical signs and symptoms, and the efficacy of poisons.55 Murder by poison remained quite popular during the latter half of the 17th and the early part of the 18th centuries in Italy and France. A major center for poison practitioners was Naples, the home of the notorious Madame Giulia Toffana. She reportedly poisoned more than 600 people, preferring a particular solution of white arsenic (arsenic trioxide), better known as “aqua toffana,”

Important Figures in the Field of Toxicology from Paracelsus to the 1900s

Person

Date

Importance

Paracelsus Ambroise Pare William Piso Bernardino Ramazzini Richard Mead Percivall Pott Felice Fontana Philip Physick Baron Guillaume Dupuytren Edward Jukes M. Bertrand P. Touery A. Garrod B. Howard Rand Bonaventure Orfila Robert Christison Francois Magendie Claude Bernard O.H. Costill Theodore Wormley James Marsh Hugo Reinsch Max Gutzeit Albert Nieman Rudolf Kobert Louis Lewin

1493–1541 1510–1590 1611–1678 1633–1714 1673–1754 1714–1788 1730–1805 1767–1837 1777–1835 1820 1813 1831 1846 1848 1787–1853 1797–1882 1783–1855 1813–1878 1848 1826–1897 1794–1846 1842 1847–1915 1860 1854–1918 1850–1929

Alice Hamilton

1869–1970

Introduced dose response concept to toxicology Spoke out against unicorn horns and bezoars as antidotes First to study emetic qualities of ipecacuanha Father of occupational medicine; wrote De Morbis Artificum Diatriba Wrote English-language book dedicated to poisoning First description of occupational cancer, relating the chimney sweep occupation to scrotal cancer First scientific study of venomous snakes Early advocate of orogastric lavage to remove poisons Early advocate of orogastric lavage to remove poisons Self-experimented with orogastric lavage apparatus known as Jukes’ syringe Demonstrated charcoal’s efficacy in arsenic ingestion Demonstrated charcoal’s efficacy in strychnine ingestion First systematic study of charcoal in an animal model First study of charcoal’s efficacy in humans Father of modern toxicology; wrote Traite Des Poisons; first to isolate arsenic from humans organs Wrote Treatise on Poisons, one of the most influential texts in early 19th century Discovered emetine and studied mechanism of cyanide and strychnine Studied mechanism of toxicity of carbon monoxide and curare Wrote first book on symptoms and treatment of poisoning Wrote Micro-Chemistry of Poisons: first American book devoted exclusively to toxicology Developed reduction test for arsenic Developed qualitative test for arsenic and mercury Developed method to quantitate small amounts of arsenic Isolated cocaine alkaloid Studied digitalis and ergot alkaloids Studied many toxins, including methanol, chloroform, snake venom, carbon monoxide, lead, opioids, and hallucinogenic plants Conducted landmark investigations associating worksite chemical hazards with disease; led reform movement to improve worker safety

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TABLE 1–3.

HISTORICAL PRINCIPLES AND PERSPECTIVES

Notable Poisoners from Antiquity to the Present 130,136,138

Poisoner

Date

Victim(s)

Poison(s)

Locusta Cesare Borgia Catherine de Medici Hieronyma Spara Madame Giulia Toffana Marchioness de Brinvilliers Catherine Deshayes

54–55 A.D. 1400s 1519–1589 Died 1659 Died 1719 Died 1676 Died 1680

Claudius and Britannicus Cardinals and kings Poor, sick, criminals Taught women how to poison their husbands >600 people Hospitalized patients, husband, father >2000 infants, many husbands

Mary Blandy Anna Maria Zwanizer Marie Lefarge John Tawell William Palmer, MD Madeline Smith (acquitted) Edmond de la Pommerais, MD Edward William Pritchard, MD George Henry Lamson, MD Adelaide Bartlett (acquitted) Florence Maybrick Thomas Neville Cream, MD Johann Hoch Cordelia Botkin Roland Molineux Hawley Harvey Crippen, MD Frederick Henry Seddon Henri Girard Robert Armstrong Landru Suzanne Fazekas Sadamichi Hirasawa Christa Ambros Lehmann Nannie Doss Carl Coppolino, MD Graham Frederick Young Judias V. Buenoano Ronald Clark O’Bryan Murderer of Georgi Markov Jim Jones Harold Shipman, MD Donald Harvey “Tylenol” tamperer George Trepal Michael Swango, MD

1752 1807 1839 1845 1855 1857 1863 1865 1881 1886 1889 1891 1892–1905 1898 1898 1910 1911 1912 1921 1922 1929 1948 1954 1954 1965 1971 1971 1974 1978 1978 1974–1998 1983–1987 1982 1988 1980s–1990s

Father Random people Husband Mistress Fellow gambler Lover Patient and mistress Wife and mother-in-law Brother-in-law Husband Husband Prostitutes Serial wives Feminine rival Acquaintance Wife Boarder Acquaintances Wife Many women Supplied poison to 100 wives to kill husbands Bank employees Friend, husband, father-in-law 11 relatives including 5 husbands Wife Stepmother, coworkers Husband, son Son and neighborhood children Bulgarian diplomat 911 people in mass suicide Patients (up to 297) Patients 7 people Family members Hospitalized patients

Amanita phalloides, cyanide La Cantarella (arsenic and phosphorus) Unknown agents Mana of St. Nicholas of Bari (arsenic trioxide) Aqua toffana (arsenic trioxide) Arsenic, lead, mercury, antimony, copper La poudre de succession (arsenic mixed with aconite, belladonna, and opium) Arsenic Arsenic, antimony Arsenic (1st use of Marsh test) Cyanide Strychnine Arsenic Digitalis Antimony Aconite Chloroform Arsenic Strychnine Arsenic Arsenic (in chocolate candy) Cyanide of mercury Hyoscine Arsenic (fly paper) Amanita phalloides Arsenic (weed killer) Cyanide Arsenic Potassium cyanide E-605 (parathion) Arsenic Succinylcholine Thallium Arsenic Cyanide (in Halloween candy) Ricin Cyanide Heroin Arsenic Extra Strength Tylenol laced with cyanide Thallium Succinylcholine, potassium chloride, arsenic

and dispensed under the guise of a cosmetic. Eventually convicted of poisoning, Madame Toffana was executed in 1719.19 In France, the Marchioness de Brinvilliers (1630–1676) and Catherine Deshayes (1640–1680) were two of the most notorious poisoners.53 The Marchioness tested her poison concoctions on hospitalized patients and on her servants, and allegedly murdered her husband, father, and two siblings.130 Among the favorite poisons of the Marchioness were corrosive sublimate (mercury bichloride), arsenic, lead, copper sulfate, and tartar emetic containing antimony.138 Catherine Deshayes, a fortuneteller and sorcerer, was one of the last “poisoners for hire,” and was implicated in countless poisonings, including the killing of more than 2000 infants.55 Better known as “La Voisine,” she reportedly sold poisons to women wishing to rid themselves of their husbands. Her particular brand of poison was a concoction of arsenic, aconite, belladonna, and opium known as “la poudre de succession.”138

Ultimately, de Brinvilliers was beheaded and Deshayes was burned alive for their crimes. In an attempt to curtail these rampant poisonings, Louis XIV issued a decree in 1662 banning the sale of arsenic, mercury, and other poisons to customers not known to the apothecaries and requiring poison buyers to sign a register declaring the purpose for their purchase.130

EIGHTEENTH- AND NINETEENTHCENTURY DEVELOPMENTS IN TOXICOLOGY The development of toxicology as a distinct specialty began during the 18th and 19th centuries (see Table 1–2).111 The poison mystique—mythologic and magical—was gradually replaced by

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an increasingly rational, scientific, and experimental approach to the study of these agents. Much of the poison lore that had survived for almost 2000 years was finally debunked and discarded. The 18th-century Italian Felice Fontana was one of the first to usher in the modern age. He was an early experimental toxicologist who studied the venom of the European viper and wrote the classic text Traite sur le Venin de la Vipere in 1781.75 Through his exacting experimental study on the effects of venom, Fontana brought a scientific insight to toxicology that had previously been lacking, demonstrating that clinical symptoms are a result of the poison (venom) acting on specific target organs. During the 18th and 19th centuries, attention focused on the detection of poisons and the study of toxic effects of drugs and chemicals in animals.104 Issues relating to adverse effects of industrialization and unintentional poisoning in the workplace and home environment were raised. Also during this time, early experience and experimentation with methods of gastrointestinal decontamination took place.

Development of Analytical Toxicology and the Study of Poisons The French physician Bonaventure Orfila (1787–1853) has been called the father of modern toxicology.104 He emphasized toxicology as a distinct, scientific discipline, separate from clinical medicine and pharmacology.10 He also was an early medical-legal expert who championed the use of chemical analysis and autopsy material as evidence to prove that a poisoning had occurred. His treatise Traite des Poisons (1814)108 had five editions and was regarded as the foundation of experimental and forensic toxicology.143 This text classified poisons into six groups: astringents, corrosives, acrids, septics or putrefiants, stupefacients and narcotics, and narcoticoacrids. A number of other landmark works on poisoning also first appeared during this period. In 1829, Robert Christison (1797–1882), a professor of medical jurisprudence and Orfila’s student, wrote A Treatise on Poisons.29 This work simplified Orfila’s poison classification schema by categorizing poisons into three groups: irritants, narcotics, and narcoticoacrids. Less concerned with jurisprudence than with clinical toxicology, O.H. Costill’s A Practical Treatise on Poisons, published in 1848, was the first modern clinically oriented text to emphasize the symptoms and treatment of poisoning.34 In 1867, Theodore Wormley (1826–1897) published the first American book written exclusively on poisons. Entitled the Micro-Chemistry of Poisons,145 this pioneering American contribution also expanded on methods of poison identification.47 During this time, important breakthroughs in the chemical analysis of poisons resulted from the search for a more reliable assay for arsenic. Arsenic was widely available and was the suspected etiology of a large number of deaths. In one study of 679 homicidal poisonings, arsenic was employed 31% of the time.138 A reliable means of detecting arsenic was much needed by the courts. Until the 19th century, poisoning was mainly diagnosed by symptoms rather than by analytic tests. The first use of a chemical test as evidence in a poisoning trial occurred in the 1752 trial of Mary Blandy, who was accused of poisoning her father with arsenic.93 Although Blandy was convicted and hanged publicly, the test employed in this case was not very sensitive and depended in part on eliciting a garlic odor upon heating the gruel that the accused had fed to her father.

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7

During the 19th century, James Marsh (1794–1846), Hugo Reinsch, and Max Gutzeit (1847–1915) all worked on this problem. Assays bearing their names are important contributions to the early history of analytic toxicology.94,104 The “Marsh test” to detect arsenic was first used in a criminal case in 1839 during the trial of Marie Lefarge, who was accused of using arsenic to murder her husband.130 Orfila’s trial testimony that the victim’s viscera contained minute amounts of arsenic helped to convict the defendant although subsequent debate suggested that contamination of the forensic specimen may have also played a role. In a further attempt to curtail criminal poisoning by arsenic, the British Parliament passed the Arsenic Act in 1851. This bill, which was one of the first modern laws to regulate the sale of poisons, required that the retail sale of arsenic be confined to chemists, druggists, and apothecaries, and that a poison book be maintained to record all arsenic sales.14 Homicidal poisonings remained common during the 19th and early 20th century. Infamous poisoners of the late 19th century and early 20th century included William Palmer, Edward Pritchard, Harvey Crippen, and Frederick Seddon.138 Many of these poisoners were physicians who utilized their knowledge of medicine and pharmacology in an attempt to solve their domestic and financial difficulties by committing the “perfect” murder. Some of the poisons employed were strychnine (Palmer, Cream), antimony (Pritchard), hyoscine (Crippen), digitalis (Pommerais), aconite (Lamson, who was a classmate of Christison), cyanide (Molineux, Tawell), Amanita phalloides (Girard), as well as arsenic (Maybrick, Seddon, others) (Table 1–3).22,136,138 Systematic investigation into the underlying mechanisms of toxic substances also first took place during the 19th century. Much of this work was done in France and Germany. To cite just a few important accomplishments, Francois Magendie (1783–1855) studied the mechanisms of toxicity and sites of action of emetine, strychnine, and cyanide.45 His student, Claude Bernard (1813– 1878), the pioneering physiologist, made important contributions to the understanding of carbon monoxide and curare poisonings.81 Rudolf Kobert (1854–1918) studied digitalis and ergot alkaloids, and also authored a textbook on toxicology.106 His fellow German Louis Lewin (1850–1929) was the first person to intensively study the differences between the pharmacologic and toxicologic actions of drugs. Lewin studied chronic opium intoxication, as well as the toxicity of lead, carbon monoxide, snake venom, methanol, and chloroform. He also developed a classification system for psychoactive drugs, dividing them into euphorics, phantastics, inebriants, hypnotics, and excitants.88 Forensic investigation into suspicious deaths, including poisonings, was significantly advanced with the development of the medical examiner system that replaced the much-flawed coroner system that was subject to widespread corruption. In 1918, the first centrally controlled medical examiner system was established in New York City. Alexander Gettler, considered the father of forensic toxicology in the United States, established a toxicology laboratory within the newly created New York City Medical Examiner’s Office. Gettler pioneered new techniques for the detection of a variety of substances in biologic fluids including carbon monoxide, chloroform, heavy metals, and cyanide.46,104

The Origin of Occupational Toxicology The origins of occupational toxicology can be traced to the early 18th century and to the contributions of Bernardino Ramazzini

8

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HISTORICAL PRINCIPLES AND PERSPECTIVES

(1633–1714). Considered the father of occupational medicine, Ramazzini wrote De Morbis Artificum Diatriba (Diseases of Workers) in 1700, which was the first comprehensive text discussing the relationship between disease and workplace hazards.52 Ramazzini’s essential contribution to the care of the patient is epitomized by the addition of a question to the medical history, “What occupation does the patient follow?”49 Altogether Ramazzini described diseases associated with 54 occupations, including mercury poisoning in mirror makers, pulmonary diseases in miners, and hydrocarbon poisoning in painters. Sir Percivall Pott proposed the first association between workplace exposure and cancer in 1775 when he noticed a high incidence of scrotal cancer in English chimney sweeps. Pott’s belief that the scrotal cancer was caused by prolonged exposure to tar and soot was confirmed by other investigation in the 1920s, indicating that the polycyclic aromatic hydrocarbons contained in coal tar (including benzo[a]pyrene) are carcinogenic.68 Another pioneer in occupational toxicology, whose rigorous scientific inquiry had a profound impact on linking chemical toxins with human disease was Dr. Alice Hamilton (1869–1970). A physician, scientist, humanitarian, and social reformer, Hamilton, who would become the first female professor at Harvard University, conducted groundbreaking studies of many different occupational exposures and problems, including wrist drop in lead workers, mercury poisoning in hatters, and carbon monoxide poisoning in steelworkers. Her overriding concerns about these “dangerous trades” and her commitment to improve the health of workers would lead to extensive voluntary and regulatory reforms in the workplace.59,63

Early Advances in Gastrointestinal Decontamination Further experience with gastrointestinal decontamination also was gained during the late 18th and early 19th century. A stomach pump was first designed by Munro Secundus in 1769 to administer neutralizing substances to sheep and cattle for the treatment of bloat.23 The American surgeon Philip Physick (1768–1837) and the French surgeon Baron Guillaume Dupuytren (1777–1835) were two of the first physicians to advocate gastric lavage for the removal of poisons.23 As early as 1805, Physick demonstrated the use of a “stomach tube” for this purpose. Using brandy and water as the irrigation fluid, he performed stomach washings in twins to wash out excessive doses of tincture of opium.23 Dupuytren performed gastric emptying by first introducing warm water into the stomach via a large syringe attached to a long flexible sound and then withdrawing the “same water charged with poison.”23 Edward Jukes, a British surgeon, was another early advocate of poison removal by gastric lavage. Jukes first experimented on animals, performing gastric lavage after the oral administration of tincture of opium. Attempting to gain human experience, he experimented on himself, by first ingesting 10 drams (600 g) of tincture of opium and then performing gastric lavage using a 25-inch-long, 0.5-inch-diameter tube, which became known as Jukes’ syringe.98 Other than some nausea and a 3-hour sleep, he suffered no ill effects, and the experiment was deemed a success. The principle of using charcoal to adsorb poisons was first described by Scheele (1773) and Lowitz (1785), but the medicinal use of charcoal dates to ancient times.33 The earliest reference to the medicinal uses of charcoal is found in the Egyptian Papyrus of ~1500 B.C.33 The charcoal employed during Greek and Roman

times, referred to as wood charcoal, was used to treat anthrax, chlorosis, vertigo, and epilepsy. By the late 18th century, topical application of charcoal was recommended for gangrenous skin ulcers, and internal use of a charcoal-water suspension was recommended for use as a mouthwash and in the treatment of bilious conditions.33 The first hint that charcoal might have a role in the treatment of poisoning came from a series of heroic self-experiments in France during the early 19th century. In 1813, the French chemist M. Bertrand publicly demonstrated the antidotal properties of charcoal by surviving a 5-g ingestion of arsenic trioxide that had been mixed with charcoal.65 Eighteen years later, before the French Academy of Medicine, the pharmacist P.F. Touery survived an ingestion consisting of 10 times the lethal dose of strychnine mixed with 15 g of charcoal.65 One of the first reports of charcoal used in a poisoned patient was by the American Hort, who successfully treated a mercury bichloride–poisoned patient with large amounts of powdered charcoal in 1834.7 In the 1840s, A. Garrod performed the first controlled study of charcoal when he examined its utility on a variety of poisons in animal models.65 Garrod used dogs, cats, guinea pigs, and rabbits to demonstrate the potential benefits of charcoal in the management of strychnine poisoning. He also emphasized the importance of early utilization of charcoal and the proper ratio of charcoal to poison. Other toxic substances, such as aconite, morphine, mercury bichloride, and hemlock, were also studied during this period. The first charcoal efficacy studies in humans were performed by the American physician B. Rand in 1848.65 It was not until the early 20th century that an activation process was added to the manufacture of charcoal. In 1900, the Russian Ostrejko demonstrated that treating charcoal with superheated steam significantly enhanced its adsorbing power.33 Despite this improvement and the favorable reports mentioned, charcoal was only occasionally used in gastrointestinal decontamination until the early 1960s, when Holt and Holz repopularized its use.62

The Increasing Recognition of the Perils of Drug Abuse Opioids. Although the medical use of opium was promoted by Paracelsus in the 16th century, the popularity of this agent was given a significant boost when the distinguished British physician Thomas Sydenham (1624–1689) formulated laudanum (tincture of opium). In addition to opium, this preparation contained sherry, saffron, cinnamon, and cloves. Sydenham also formulated a different opium concoction known as “syrup of poppies.”78 A third opium preparation used during this period was designed by Sydenham’s protégé, Thomas Dover, and contained ipecac, as well as tartaric acid, saltpeter, licorice, and opium. John Jones, the author of the 1700 text The Mysteries of Opium Reveal’d, was another enthusiastic advocate of the medicinal uses of opium.78 A well-known opium user himself, Jones provided one of the earliest descriptions of opiate addiction. He insisted that opium offered many benefits if the dose was moderate, but that discontinuation or a decrease in dose, particularly after “leaving off after long and lavish use,” would result in such symptoms as sweating, itching, diarrhea, and melancholy. His recommendation for the treatment of these withdrawal symptoms included decreasing the dose of opium by 1% each day until the drug was totally withdrawn. During this period, a number of English writers became well-known opium addicts, including Samuel Taylor Co-

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leridge, Elizabeth Barrett Browning, and Thomas De Quincey. De Quincey, author of Confessions of an English Opium Eater, was an early advocate of the recreational use of opiates. The famed Coleridge poem, Kubla Khan, referred to opium as the “milk of paradise,” while De Quincey’s Confessions suggested that opium held the “key to paradise.” In many of these cases, the initiation of opium use for medical reasons led to recreational use, tolerance, and dependence.78 Although opium was first introduced to Asian societies by Arab physicians some time after the fall of the Roman Empire, the use of opium in Asian countries grew considerably during the 18th and 19th centuries. In one of the more deplorable chapters in world history, China’s growing dependence on opium was spurred on by the English desire to establish and profit from a flourishing drug trade.124 Opium was grown in India and exported east. Despite Chinese protests and edicts against this practice, the importation of opium persisted throughout the 19th century, with the British going to war twice in order to maintain their right to sell opium. Not surprisingly, by the beginning of the 20th century, opium abuse in China was endemic. In England, opium use continued to increase during the first half of the 19th century. During this period, opium was legal and freely available from the neighborhood grocer. To many, its use was considered no more problematic than alcohol.57 The Chinese usually self-administered opium by smoking, a custom that was brought to the United States in the mid-19th century by Chinese immigrants, whereas the English use of opium was more often by ingestion, that is, “opium eating.” The liberal use of opiates as infant-soothing agents was one of the most unfortunate aspects of this period of unregulated opiate use.79 Mrs. Winslow’s Soothing Syrup, Godfrey’s Cordial, Quietness, and Mother’s Friend were among the most popular of children’s opiates.83 They were advertised as producing a natural sleep and recommended for teething and bowel regulation, as well as for crying. Because of the wide availability of opiates during this period, the number of acute opiate overdoses in children was consequential and would remain problematic until these unsavory remedies were condemned and removed from the market. With the discovery of morphine in 1805 and Alexander Wood’s invention of the hypodermic syringe in 1853, parenteral administration of morphine became the preferred route of opiate administration.67 A legacy of the generous use of opium and morphine during the United States Civil War was “soldiers’ disease,” referring to a rather large veteran population that returned from the war with a lingering opiate habit.117 One hundred years later, opiate abuse and addiction would become common among US military serving in the Vietnam War. Surveys indicated that as many as 20% of American soldiers in Vietnam were addicted to opiates during the war—in part because of its widespread availability in Vietnam.121 Growing concerns about opiate abuse in England led to the passing of the Pharmacy Act of 1868, which restricted the sale of opium to registered chemists. But in 1898, the Bayer Pharmaceutical Company of Germany would synthesize heroin from opium (Bayer also introduced aspirin that same year).131 Although initially touted as a nonaddictive morphine substitute, problems with heroin use soon became evident and in the United States, the problems associated with uncontrolled use of all opiates became increasingly apparent. Cocaine. Ironically, during the later part of the 19th century, Sigmund Freud and Robert Christison, among others, were enthu-

HISTORICAL PRINCIPLES AND PERSPECTIVES

9

siastically recommending cocaine, the drug that would eventually compete with heroin for most notoriety, as a treatment for opiate addiction. After Albert Niemann’s isolation of cocaine alkaloid from coca leaf in 1860, growing enthusiasm for cocaine as a panacea ensued.74 Some of the most important medical figures of the time, including William Halsted, the famed Johns Hopkins surgeon, enthusiastically promoted the use of cocaine. In 1884, Freud wrote Uber Cocaine,25 advocating cocaine as cure for opium and morphine addiction and as a treatment for fatigue and hysteria. Halsted championed the anesthetic properties of this drug, although his own use of cocaine and subsequent morphine use in an attempt to overcome his cocaine dependency would later take a considerable toll.107 During the last third of the 19th century, cocaine was added to many popular over-the-counter tonics of the day. In 1863, a Frenchman, Angelo Mariani, introduced a new wine, “Vin Mariani,” that consisted of a mixture of cocaine and wine (6 mg of cocaine alkaloid per ounce) and was sold as a digestive aid and restorative.99 In direct competition with the French tonic was the American-made Coca-Cola, developed by J.S. Pemberton. CocaCola was originally formulated with coca and caffeine and was marketed as a headache remedy and invigorator. With the public demand for cocaine increasing, patent medication manufacturers were adding cocaine to thousands of products including products for asthma. One such asthma remedy was “Dr. Tucker’s Asthma Specific,” which contained 420 mg of cocaine per ounce and was applied directly to the nasal mucosa.74 By the end of the 19th century, the first great American cocaine epidemic was underway.101 Similar to what was occurring with opiates, the increasing use of cocaine led to a growing concern about its associated problems. In 1886, the first reports of cocaine-related cardiac arrest and stroke were published.31 Reports of cocaine habituation occurring in patients using cocaine to treat their underlying opiate addiction also began to appear. In 1902, a popular book, Eight Years in Cocaine Hell, described some of these problems. Century Magazine called cocaine “the most harmful of all habit-forming drugs,” and a report in the New York Times stated that cocaine was destroying “its victims more swiftly and surely than opium.”40 In 1910, President William Taft proclaimed cocaine Public Enemy Number 1. In an attempt to curb the increasing problems associated with drug abuse and addiction, the 1914 Harrison Narcotics Act mandated stringent control over the sale and distribution of narcotics (defined as opium, opium derivatives, and cocaine).40 It was the first federal law in the United States to criminalize the nonmedical use of drugs. The bill required doctors, pharmacists, and others who prescribed narcotics to register and to pay a tax. A similar law, the Dangerous Drugs Act, was passed in the United Kingdom in 1920.57 To help enforce these drug laws in the United States, the Narcotics Division of the Prohibition Unit of the Internal Revenue Service (a progenitor of the Drug Enforcement Agency) was established in 1920. In 1924, the Harrison Act was further strengthened with the passage of new legislation that banned the importation of opium for the purpose of manufacturing heroin, essentially outlawing the medicinal uses of heroin. With the legal venues to purchase these drugs now eliminated, users were forced to buy from illegal street dealers, creating a burgeoning black market Sedative-Hypnotics. The introduction to medical practice of the anesthetic agents nitrous oxide, ether, and chloroform during the 19th century was accompanied by the recreational use of these

10

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HISTORICAL PRINCIPLES AND PERSPECTIVES

agents and the first reports of volatile substance abuse. Chloroform “jags,” ether “frolics,” and nitrous parties became a new type of entertainment.51 Humphrey Davies was an early self-experimenter with the exhilarating effects associated with nitrous oxide inhalation.51 In certain Irish towns, especially where the temperance movement was strong, ether drinking became quite popular.96 Horace Wells, the American dentist who introduced chloroform as an anesthesic, became dependent on this volatile solvent and later committed suicide. Until the last half of the 19th century, opium, aconite, hemlock, prussic acid (cyanide), and alcohol were the primary agents used for sedation.30 During the 1860s, new, more specific sedative-hypnotics, such as chloral hydrate and potassium bromide, were introduced into medical practice. In particular, chloral hydrate was hailed as a wonder drug that was relatively safe, as compared to opium, and recommended for insomnia, anxiety, and delirium tremens, as well as for scarlet fever, asthma, and cancer. But within a few years, problems with acute toxicity of chloral hydrate, as well as its potential to produce tolerance and physical dependence, became apparent.30 Mixing chloral hydrate with ethanol was noted to produce a rather powerful “knockout” combination that would be known as a “Mickey Finn.” Abuse of chloral hydrate, as well as other new sedatives such as potassium bromide, would be a harbinger of 20th-century sedative-hypnotic abuse. Hallucinogens. American Indians used peyote in religious ceremonies at least since the 17th century. Hallucinogenic mushrooms, particularly Psilocybe mushrooms, were also used in the religious life of Native Americans. These were called “teonanacatl,” which means “God’s sacred mushrooms” or “God’s flesh.”114 Interest in the recreational use of cannabis also accelerated during the 19th century after Napoleon’s troops brought the drug back from Egypt, where its use among the lower classes was widespread at the time. In 1843, several French Romantics, including Balzac, Hugo, Baudelaire, and Gautier, formed a hashish club called “Le Club des Hachichins” in the Parisian apartment of a young French painter. Fitz Hugh Ludlow’s The Hasheesh Eater, published in 1857, was an early American text espousing the virtues of marijuana.86 Absinthe, an ethanol-containing beverage that was manufactured with an extract from wormwood (Artemisia absinthium), was very popular during the last half of the 19th century.80 This emerald-colored, very bitter drink was memorialized in the paintings of Degas, Toulouse-Lautrec, and Van Gogh, and was a staple of French society during this period.11 Thujone, a psychoactive component of wormwood, is thought to be responsible for the pleasant feelings, as well as for the hallucinogenic effects, hyperexcitability, and significant neurotoxicity associated with this drink. Given the increasing medical problems associated with its use, absinthe was banned throughout most of Europe by the early 20th century. A more recent event that would have significant impact on modern-day hallucinogen use was the synthesis of lysergic acid diethylamide (LSD) by Albert Hofmann in 1938.64 Working for Sandoz Pharmaceutical Company, Hofmann synthesized LSD while investigating the pharmacologic properties of ergot alkaloids. Subsequent self-experimentation by Hofmann led to the first description of its hallucinogenic effects and stimulated research into the use of LSD as a therapeutic agent. Hofmann is also credited with isolating psilocybin as the active ingredient in Psilocybe mexicana mushrooms in 1958.99

TWENTIETH-CENTURY EVENTS Early Regulatory Initiatives The development of the specialty of medical toxicology and the role of poison control centers began shortly after World War II. Prior to this time, serious attention to the problem of household poisonings in the United States had been limited to a few federal legislative antipoisoning initiatives (Table 1–4). The 1906 Pure Food and Drugs Act was the first federal legislation that sought to protect the public from problematic and potentially unsafe drugs and food. The driving force behind this reform was Dr. Harvey W. Wiley, the chief chemist at the Department of Agriculture. Beginning in the 1880s, Wiley investigated the problems of contaminated food. In 1902, he organized the “poison squad,” which consisted of a group of volunteers who did self-experiments with food preservatives.8 Revelations from the “poison squad,” as well as the publication of Upton Sinclair’s muckraking novel The Jungle129 in 1906, exposing unhygienic practices of the meatpacking industry, led to growing support for legislative intervention. Samuel Hopkins Adams’ reports about the patent (secret) medicine industry revealed that some drug manufacturers added opiates to soothing syrups for infants, and added to the call for reform.118 Although the 1906 regulations were mostly concerned with protecting the public from adulterated food, regulations protecting against misbranded patent medications were also included. The Federal Caustic Poison Act of 1927 was the first federal legislation to specifically address household poisoning. As early as 1859, bottles clearly demarcated “poison” were manufactured in response to a rash of unfortunate dispensing errors that occurred when oxalic acid was unintentionally substituted for a similarly appearing Epsom salts solution.26 Prior to 1927, however, “poison” warning labels were not required on chemical containers, regardless of toxicity or availability. The 1927 Caustic Act was spearheaded by the efforts of Dr. Chevalier Jackson, an otolaryngologist, who showed that unintentional exposures to household caustic agents were an increasingly frequent cause of severe gastrointestinal burns. Under this statute, for the first time, lye and acid-containing products had to clearly display a “poison” warning label.135 The most pivotal regulatory initiative in the United States prior to World War II, and perhaps the most significant American toxicologic regulation of the 20th century, was the Federal Food, Drug, and Cosmetic Act of 1938. Although the Food and Drug Administration (FDA) had been established in 1930, and legislation to strengthen the 1906 regulations had been considered by Congress beginning with President Franklin Roosevelt’s first inauguration in 1933, by 1938 proposed revisions still had not been passed. The Elixir of Sulfanilamide tragedy in 1938 (Chap. 2) claimed the lives of 105 people who ingested a prescribed liquid preparation of sulfanilamide dissolved in diethylene glycol. This event finally provided the catalyst for legislative intervention.97,141 Prior to the elixir disaster, proposed legislation called only for the banning of false and misleading drug labeling and for the outlawing of dangerous drugs without mandatory drug safety testing. After the tragedy, the enacted 1938 proposal required assessment of drug safety prior to marketing.

The Development of Poison Control Centers World War II led to the rapid proliferation of new drugs and chemicals in the marketplace and in the household.37 At the same

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11

TABLE 1–4. Protecting our Health: Important US Regulatory Initiatives Pertaining to Drugs and Toxins During the 20th Century Date

Federal Legislation

Intent

1906

Pure Food and Drugs Act

1914

Harrison Narcotics Act

1927 1930 1937 1938 1948 1951 1960 1962 1963 1966 1970

Federal Caustic Poison Act Food and Drug Administration (FDA) established Marijuana Tax Act Federal Food, Drug, and Cosmetic Act Federal Insecticide, Fungicide, and Rodenticide Act Durham-Humphrey Amendment Federal Hazardous Substances Labeling Act Kefauver-Harris Drug Amendments Clean Air Act Child Protection Act Comprehensive Drug Abuse and Control Act

1970

Poison Prevention Packaging Act

1970 1970

Environmental Protection Agency (EPA) established Occupational Safety and Health Act (OSHA)

1972 1972

Clean Water Act Consumer Product Safety Act

1972

Hazardous Material Transportation Act

1973

Drug Enforcement Administration (DEA) created

1973

Lead-based Paint Poison Prevention Act

1974 1976

Safe Drinking Water Act Resource Conservation and Recovery Act

1976

Toxic Substance Control Act

1980

1988

Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) Federal Anti-Tampering Act Superfund Amendments and Reauthorization Act (SARA) Labeling of Hazardous Art Materials Act

1994 1997

Dietary Supplement Health and Education Act FDA Modernization Act

Early regulatory initiative. Prohibits interstate commerce of misbranded and adulterated foods and drugs First federal law to criminalize the nonmedical use of drugs. Taxed and regulated distribution and sale of narcotics (opium, opium derivatives, and cocaine). It required doctors,pharmacists, and others who prescribed narcotics to register and pay a tax. Mandated labeling of concentrated caustics. Successor to the Bureau of Chemistry; promulgation of food and drug regulations. Applied controls over marijuana similar to narcotics. Required toxicity testing of pharmaceuticals prior to marketing. Provided federal control for pesticide sale, distribution, and use. Restricted many therapeutic drugs to sale by prescription only. Mandated prominent labeling warnings on hazardous household chemical products. Required drug manufacturer to demonstrate efficacy before marketing. Regulated air emissions by setting maximum pollutant standards. Banned hazardous toys where adequate label warnings could not be written. Replaced and updated all previous laws concerning narcotics and other dangerous drugs. Emphasis on law enforcement. Mandated child-resistant safety caps on certain pharmaceutical preparations to decrease unintentional childhood poisoning. Established and enforced environmental protection standards. Enacted to improve worker and workplace safety. Created NIOSH as research institution for OSHA. Regulated discharge of pollutants into US waters. Established Consumer Product Safety Commission to reduce injuries and deaths from consumer products. Authorized the Department of Transportation to develop, promulgate, and enforce regulations for the safe transportation of hazardous materials. Succeeded predecessor Bureau of Narcotics and Dangerous Drugs; charged with enforcing federal drug laws. Regulated the utilization of lead in residential paint. Lead in some paints later banned by Congress in 1978. Set safe standards for water purity. Authorized EPA to control hazardous waste from the “cradle-to-grave” including the generation, transportation, treatment, storage, and disposal of hazardous waste. Authorized EPA to track 75,000 industrial chemicals produced or imported into US. Required testing of chemicals that pose environmental or human health risk. Set controls for hazardous waste sites. Established trust fund (Superfund) to provide cleanup for these sites. Response to cyanide-Tylenol deaths. Outlawed tampering with packaged consumer products. Amendment to CERCLA. Increased funding for the research and cleanup of hazardous waste sites. Required review of all art materials to determine hazard potential and mandated warning labels for hazardous materials. Permitted dietary supplements including many herbal preparations to bypass FDA scrutiny. Accelerated FDA reviews, regulated advertising of unapproved uses of approved drugs.

1983 1986

time, suicide as a leading cause of death from these agents was recognized.134 Both of these factors led the medical community to develop a response to the serious problems of both unintentional and intentional poisonings. In Europe during the late 1940s, special toxicology wards were organized in Copenhagen and Budapest,58 and a poison information service was begun in the Netherlands (Table 1–5).139 An American Academy of Pediatrics study in 1952 revealed that more than 50% of childhood “accidents” in the United States were the result of unintentional poisonings.60 This study led to the opening of the first US poison control center in Chicago in 1953, under the leadership of Dr. Edward Press.115 Press believed that it had become extremely difficult for the individual physician to keep abreast of product information, toxicity, and treatment for the rapidly increasing number of poten-

tially poisonous household products. This initial center was organized as a cooperative effort among the departments of pediatrics at several Chicago medical schools, with the goal of collecting and disseminating product information to inquiring physicians— mainly pediatricians.115 By 1957, 17 poison control centers were operating in the United States.36 With the Chicago center serving as a model, these early centers responded to physician callers by providing ingredient and toxicity information about drug and household products, and making treatment recommendations. Records were kept of the calls, and preventive strategies were introduced into the community. As more poison control centers opened, a second important function, providing information to callers from the general public, became increasingly commonplace. The physician pioneers in poi-

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TABLE 1–5. 20th-Century Milestones in the Development of Medical Toxicology Year

Milestone

1949 1949 1952

First toxicology wards open in Budapest and Copenhagen First poison information service begins in the Netherlands American Academy of Pediatrics study shows that 5l% of children’s “accidents” are the result of the ingestion of potential poisons First US poison control center opens in Chicago National Clearinghouse for Poison Control Centers established American Association of Poison Control Centers (AAPCC) founded First Poison Prevention Week Initial call for development of regional PCCs Creation of European Association for PCCs American Academy of Clinical Toxicology (AACT) established Introduction of microfiche technology to poison information American Board of Medical Toxicology (ABMT) established AAPCC introduces standards of regional designation First examination given for Specialist in Poison Information (SPI) American Board of Applied Toxicology (ABAT) established Medical Toxicology recognized by American Board of Medical Specialties (ABMS) First ABMS examination in Medical Toxicology ACGME approval of residency training programs in Medical Toxicology

1953 1957 1958 1961 1963 1964 1968 1972 1974 1978 1983 1985 1992 1994 2000

son prevention and poison treatment were predominantly pediatricians who focused on unintentional childhood ingestions.120 During these early years in the development of poison control centers, each center had to collect its own product information, which was a laborious, and often redundant, task.36 In an effort to coordinate poison control center operations and to avoid unnecessary duplication, Surgeon General Dr. James Goddard responded to the recommendation of the American Public Health Service and established the National Clearinghouse for Poison Control Centers in 1957.95 This organization, placed under the Bureau of Product Safety of the Food and Drug Administration, disseminated 5-inch by 8-inch index cards containing poison information to each center to help standardize poison center information resources. The Clearinghouse also collected and tabulated poison data from each of the centers. Between 1953 and 1972, a rapid, uncoordinated proliferation of poison control centers occurred in the United States.92 In 1962, there were 462 poison control centers.1 By 1970, this number had risen to 590,84 and by 1978, there were 661 poison control centers in the United States, including 100 centers in the state of Illinois.126 The nature of calls to centers changed as lay public– generated calls began to outnumber physician-generated calls. Recognizing the publicity value and strong popular support associated with poison centers, some hospitals started poison control centers for public relations reasons without adequately recognizing or providing for the associated responsibilities. Unfortunately, many of these centers offered no more than a part-time telephone service located in the back of the emergency department or pharmacy, staffed by poorly trained personnel.126 Despite the growing pains of the poison control services during this period, there were many significant achievements. A dedicated group of physicians and other healthcare professionals began devoting an increasing proportion of their time to matters pertain-

ing to poisoning. In 1958, the American Association of Poison Control Centers (AAPCC) was founded to promote closer cooperation between poison centers, to establish uniform standards, and to develop educational programs for the general public and other healthcare professionals.60 Annual research meetings were held, and important legislative initiatives were stimulated by the organization’s efforts.95 Examples of such legislation include the Federal Hazardous Substances Labeling Act of 1960, which improved product labeling; the Child Protection Act of 1966, which extended labeling statutes to pesticides and other hazardous substances; and the Poison Prevention Packaging Act of 1970, which mandated safety packaging. In 1961, in an attempt to heighten public awareness of the dangers of unintentional poisoning, the third week of March was designated as National Poison Prevention Week. Another important organization, the American Academy of Clinical Toxicology (AACT), was founded in 1968 by a diverse group of toxicologists.32 This group was “interested in applying principles of rational toxicology to patient treatment” and in improving the standards of care on a national basis.123 The journal Clinical Toxicology, initially sponsored by AACT, also began publication in 1968. The first modern textbooks of clinical toxicology began to appear in the mid-1950s with the publication of Dreisbach’s Handbook of Poisoning (1955),43 Gleason, Gosselin, and Hodge’s Clinical Toxicology of Commercial Products (1957),56 and Arena’s Poisoning (1963).9 Major advancements in the storage and retrieval of poison information were instituted during these years. Information regarding consumer products initially appeared on index cards distributed regularly to poison centers by the National Clearinghouse. By 1978, more than 16,000 individual product cards had been assembled.126 The introduction of microfiche technology in 1972 enabled the storage of much larger amounts of data in much smaller spaces at the individual poison centers. Toxifile and POISINDEX, two large drug and poison databases employing microfiche technology, were introduced and gradually replaced the much more limited index card system.126 During the 1980s, POISINDEX, which had become the standard database, was made more accessible by using CD-ROM technology. Sophisticated information about the most esoteric of toxins was now instantaneously available by computer at every poison center. In 1978, the poison control center movement entered an important new stage in its development when AAPCC introduced standards for regional poison center designation.92 By defining strict criteria, AAPCC sought to upgrade poison center operations significantly and to offer a national standard of service. These criteria included employing poison specialists dedicated exclusively to operating the poison control center 24 hours per day and serving a catchment area of between 1 and 10 million people. Not surprisingly, this professionalization of the poison center movement led to a rapid consolidation of services, and the number of centers decreased to 71 by 2000. Fifty-three of the 71 centers (75%) have obtained regional certification. An AAPCC credentialing examination for poison information specialists was inaugurated in 1983 to help ensure the quality and standards of poison center staff.28 In 2000, the Poison Control Center Enhancement and Awareness Act was passed by Congress and signed into law by President William Clinton. For the first time, federal funding became available to provide assistance for poison prevention and to stabilize the funding of regional poison control centers. As of October 2001 federal assistance has permitted the establishment of a single na-

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tionwide toll-free phone number (800-222-1222) to access poison centers. A poison control center movement has also evolved in Europe over the last 35 years, but unlike the movement in the United States, from the beginning its growth focused on the development of strong centralized toxicology treatment centers. In the late 1950s, Dr. M. Gaultier in Paris developed an inpatient unit that was dedicated to the care of poisoned patients.58 In Great Britain, the National Poison Information Service was developed at Guys Hospital in 1963 under Dr. Roy Goulding.58 Dr. Henry Matthew initiated a regional poisoning treatment center in Edinburgh about the same time,116 and in 1964, the European Association for Poison Control Centers was formed at Tours, France.58

The Rise of Environmental Toxicology and Further Regulatory Protection from Toxic Substances The rise of the environmental movement during the 1960s can be traced, in part, to the publication of Rachel Carson’s Silent Spring in 1962, which revealed the perils of an increasingly toxic environment,27 and to the increasing awareness among those involved with the poison control movement of the growing menace of toxins in the home environment.24 Battery casing fume poisoning, which resulted from the burning of discarded lead battery cases, and acrodynia, which resulted from exposure to a variety of mercury-containing products,39 demonstrated that young children seemed particularly vulnerable to low-dose exposures from certain toxins. Worries about the persistence of pesticides in the ecosystem and the increasing number of chemicals introduced into the environment added to the concern that the environment was a potential source of illness, heralding a drive for additional regulatory protection. Starting with the Clean Air Act in 1963, laws were passed to help reduce the toxic burden on our environment (see Table 1–4). The establishment of the Environmental Protection Agency in 1970 spearheaded this attempt at protecting our environment, and during the next 10 years, numerous protective regulations were introduced. Among the most important initiatives were the Occupational Safety and Health Act of 1970 that established the Occupational Safety and Health Administration (OSHA). This act mandated that employers provide safe work conditions for their employees. Specific exposure limits to toxic chemicals in the workplace were promulgated. The Consumer Product Safety Commission was created in 1972 to protect the public from consumer products that posed an unreasonable risk of illness or injury. Cancer-producing substances, such as benzene, vinyl chloride, and asbestos, have been banned from consumer products as a result of these new regulations. Toxic waste disasters at Love Canal, New York, and Times Beach, Missouri, led to the passing of the Comprehensive Environmental Response, Compensation, and Liability Act (known as the Superfund) in 1980. This fund would help to pay for cleanup of hazardous substance releases that posed a potential threat to public health.

Medical Toxicology Comes of Age Over the last 25 years, the specialty of medical toxicologists has changed. The development of emergency medicine and preventive medicine as medical specialties led to the training of more physicians with a dedicated interest in toxicology. By the early 1990s, emergency physicians accounted for more than half of medical

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13

toxicologists.42 The increased diversity of medical toxicologists with primary training in emergency medicine, pediatrics, preventive medicine, or internal medicine has helped to broaden the goals of poison control centers and medical toxicologists beyond the treatment of acute unintentional childhood ingestions. The broad scope of medical toxicology now includes a much wider array of toxic exposures including acute and chronic, adult and pediatric, unintentional and intentional, occupational and environmental. The development of medical toxicology as a medical subspecialty began in 1974, when AACT established the American Board of Medical Toxicology (ABMT) to recognize physician practitioners of medical toxicology.4 From 1974 to 1992, 209 physicians obtained board certification from the ABMT. Formal subspecialty recognition of medical toxicology by the American Board of Medical Specialties (ABMS) was granted in 1992, and a conjoint board with representatives from the specialties of emergency medicine, pediatrics, and preventive medicine was created. The first ABMS-sponsored examination in medical toxicology was offered in 1994. By 2000, 254 physicians were board-certified in medical toxicology by the ABMT and/or ABMS. The American College of Medical Toxicology was founded in 1994 as an organization designed to advance clinical, educational, and research goals in medical toxicology. In 1999, the Accreditation Council of Graduate Medical Education (ACGME) in the United States formally recognized postgraduate education in Medical Toxicology, and resident program credentialing began in 2000. During the 1990s in the United States, some medical toxicologists began to work on establishing regional toxicology treatment centers. Adapting the European model, toxicology treatment centers would serve as referral centers for patients requiring advanced toxicologic evaluation and treatment. Goals of such inpatient regional centers included enhancing care of the poisoned patient, strengthening toxicology training, and facilitating research. The evaluation of the clinical efficacy and fiscal viability of such programs is ongoing. The professional maturation of nonphysicians with a primary interest in toxicology has also taken place over the past two decades. In 1985, AACT established the American Board of Applied Toxicology (ABAT), to administer a certifying examination for nonphysician practitioners of medical toxicology who meet certain rigorous standards.3 By 2000, 69 toxicologists were certified by this board, most of whom held either a PharmD degree in pharmacy or a PhD in pharmacology.

Recent Poisonings and Poisoners Although accounting for just a tiny fraction of all homicidal deaths (0.16% in the United States), notorious lethal poisonings continued throughout the 20th century (Table 1–3).2 In 1982, deliberate tampering with nonprescription acetaminophen preparations with potassium cyanide caused seven deaths in Chicago.44 Because of this tragedy, packaging of over-the-counter medications was changed to decrease the possibility of future product tampering.100 The perpetrator(s) were never apprehended, and other deaths from over-the-counter product tampering were reported in 1991.38 In England, Graham Frederick Young developed a macabre fascination with poisons.69 In 1971, at age 14 he killed his stepmother and other family members with arsenic and antimony. Sent away to a psychiatric hospital, he was released at age 24, when he was no longer considered to be a threat to society. Within months

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of his release he again engaged in lethal poisonings, killing several of his coworkers. Ultimately, he died in prison. In 1978, a Bulgarian defector living in London developed multisystem failure and died 4 days after having been stabbed by an umbrella carried by an unknown assailant. The postmortem examination revealed a pin-sized metal sphere embedded in his thigh where he had been stabbed. Investigators speculated that this sphere had most likely carried a lethal dose of ricin into the victim.35 In 1998, Judias Buenoano, known as the “black widow,” was executed for murdering her husband with arsenic in 1971 in order to collect insurance money. She was the first person executed in Florida in 150 years. The fatal poisoning remained undetected until 1983, when Buenoano was accused of trying to murder her fiancé with arsenic and by car bombing. Exhumation of the husband’s body, 12 years after he died, revealed lethal amounts of arsenic in the remains.6 Healthcare providers have also been implicated in several poisoning homicides. An epidemic of mysterious cardiopulmonary arrests at the Ann Arbor Veterans Administration Hospital in Michigan, in July and August 1975, was attributed to the homicidal use of pancuronium by two nurses.133 Intentional digoxin poisoning by hospital personnel may have explained some of the increased number of deaths on a cardiology ward of a Toronto pediatric hospital in 1981, but the exact cause of the high mortality rate was unclear.21 In 2000, an English general practitioner was convicted of murdering 15 female patients with heroin and may have murdered as many as 297 patients during his 24-year career. These recent revelations prompted calls for strengthening the death certification process, for improving preservation of case records, and for better procedures for monitoring controlled drugs.66 Also, in 2000, an American physician pleaded guilty to the charge of poisoning a number of patients under his care during his residency training. Succinylcholine, potassium chloride, and arsenic were some of the agents he used to kill his patients.132 Attention to more careful physician credentialing and to maintenance of a national physician database arose from this case because the poisonings occurred at several different hospitals across the country. By the end of the 20th century, 24 centuries after Socrates was executed by poison hemlock, the means of implementing capital punishment had come full circle. Government-sanctioned execution in the United States again favored the use of a “state” poison: this time, the combination of sodium thiopental, pancuronium, and potassium chloride.

Medical Errors In late 1999, the problem of medical errors became a highly visible issue in the United States with the publication and subsequent reaction to an Institute of Medicine (IOM) report suggesting that 44,000 to 98,000 fatalities each year were the result of medical errors.77 Many of these errors were attributed to preventable medication errors. The IOM report focused on the fact that errors usually resulted from system faults and not solely from the carelessness of individuals. Several recent, highly publicized, medication errors received considerable public attention and provided a nidus for the initiation of change in policies and systems. Ironically, all of the cases occurred at nationally preeminent university teaching hospitals. In 1984, 18-year-old Libby Zion died from severe hyperthermia soon after hospital admission. While the cause of her death was likely multifactorial, drug-drug interactions, as well as the failure to rec-

ognize and appropriately treat her agitated delirium, also contributed to her death.12 State and national guidelines for closer house staff supervision, improved working conditions, and a heightened awareness of consequential drug-drug interactions resulted from the medical, legislative, and legal issues of this case. In 1994, a prominent health journalist for the Boston Globe, Betsy Lehman, was the unfortunate victim of another preventable dosing error when she inadvertently received four times the dose of the chemotherapeutic agent cyclophosphamide as part of an experimental protocol.76 Despite treatment at a world-renowned cancer center, multiple physicians, nurses, and pharmacists failed to notice this erroneous medication order. An overhaul of the medication-ordering system was implemented after this tragic event. Another highly publicized death occurred in 1999, when 18year-old Jesse Gelsinger died after enrolling in an experimental gene-therapy study. Mr. Gelsinger, who had ornithine transcarbamylase deficiency, died from multiorgan failure 4 days after receiving, by hepatic infusion, the first dose of an engineered adenovirus containing the normal gene. While this unexpected death was not the direct result of a dosing or drug-drug interaction error, the FDA review concluded that major research violations had occurred in this case, including failure to report adverse effects with this therapy in animals and earlier clinical trials, as well as failure to properly obtain informed consent.128 Calls for additional safeguards to protect patients in research studies resulted from this case.

SUMMARY Since the dawn of recorded history, toxicology has had a great impact on human events. And although over the millennia the important poisons of the day have changed to some degree, toxic substances continue to challenge our safety. The era of poisoners for hire may have long ago reached its pinnacle, but environmental poisons confront all of us, with no end in sight to this poisoning menace. Unfortunately, knowledge acquired by one generation is often forgotten or discarded inappropriately by the next generation, leading to a cyclical historic course. The ancients were undoubtedly much more knowledgeable than many current healthcare professionals about the benefits and drawbacks of medicinal and poisonous plants, lessons that would serve us well as additional herbal concoctions flood our marketplace, leading to some of our more challenging present-day poisonings. Gastrointestinal decontamination strategies and drug-abuse trends continue to evolve. This historic review is meant to describe the past and to better prepare toxicologists and society for the future.

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102. Nahas GG: Hashish in Islam 9th to 18th century. Bull N Y Acad Med 1982;58:814–831. 103. Nerlich AG, Parsche F, Wiest I, et al: Extensive pulmonary haemorrhage in an Egyptian mummy. Virchows Arch 1995;427:423–429. 104. Niyogi SK: Historical development of forensic toxicology in America up to 1978. Am J Forensic Med Pathol 1980;1:249–264. 105. Nriagu JO: Saturnine gout among Roman aristocrats: Did lead poisoning contribute to the fall of the empire? N Engl J Med 1983;308: 660–663. 106. Oehme FW: The development of toxicology as a veterinary discipline in the United States. Clin Toxicol 1970;3:211–220. 107. Olch PD: William S. Halsted and local anesthesia. Anesthesiology 1975;42:479–486. 108. Orfila MP: Traite des Poisons. Paris, Ches Crochard, 1814. 109. Oxford English Dictionary, 2nd ed, vol 18. Oxford, Clarendon Press, 1989, p. 328. 110. Pachter HM: Paracelsus: Magic into Science. New York, Collier, 1961. 111. Pappas AA, Massoll NA, Cannon DJ: Toxicology: Past, present, future. Ann Clin Lab Sci 1999;25:253–262. 112. Parsche F, Balabanova S, Pirsig W: Drugs in ancient populations. Lancet 1993;341:503. 113. Plaitakis A, Duvoisin RC: Homer’s moly identified as Galanthus nivalis: Physiologic antidote to stramonium poisoning. Clin Neuropharmacol 1983;6:1–5. 114. Pollock SH: The psilocybin mushroom pandemic. J Psychedelic Drugs 1975;7:73–84. 115. Press E, Mellins RB: A poisoning control program. Am J Public Health 1954;44:1515–1525. 116. Proudfoot AT: Clinical toxicology: Past, present and future. Hum Toxicol 1988;7:481–487. 117. Quinones MA. Drug abuse during the Civil War (1861–1865). Int J Addictions 1975;10:1007–1020. 118. Regier CC: The struggle for federal food and drugs legislation. Law Contemp Prob 1933;1:3–15. 119. Reid DHS: Treatment of the poisoned child. Arch Dis Child 1970; 45:428–433. 120. Robertson WO: National organizations and agencies in poison control programs: A commentary. Clin Toxicol 1978;12:297–302. 121. Robins LN, Helzer JE, Davis DH: Narcotic use in Southeast Asia and afterward: An interview study of 898 Vietnam returnees. Arch Gen Psychiatry 1975;32:955–961. 122. Rosner F: Moses Maimonides’ treatise on poisons. JAMA 1968; 205: 98–100. 123. Rumack BH, Ford P, Sbarbaro J, et al: Regionalization of poison centers: A rational role mode. Clin Toxicol 1978;12:367–375. 124. Sapira JD: Speculations concerning opium abuse and world history. Perspect Biol Med 1975;18:379–398. 125. Scarborough J: Nicanders’ Toxicology. Pharm Hist 1979;21:3–34. 126. Scherz RG, Robertson WO: The history of poison control centers in the United States. Clin Toxicol 1978;12:291–296. 127. Scutchfield FD, Genovese EN: Terrible death of Socrates: Some medical and classical reflections. Pharos 1997;60:30–33. 128. Silberner J: A gene therapy death. Hastings Cent Rep 2000;30:6. 129. Sinclair U: The Jungle. New York, Doubleday, 1906. 130. Smith S: Poisons and poisoners through the ages. Med Leg J 1952:20:153–167. 131. Sneader W: The discovery of heroin. Lancet 1998;352:1697–1699. 132. Stewart JB: Blind Eye: The Terrifying Story of a Doctor Who Got Away with Murder. New York, Touchstone, 1999. 133. Stross JK, Shasby M, Harlan WR: An epidemic of mysterious cardiopulmonary arrests. N Engl J Med 1976;295:1107–1110. 134. Suicide: A leading cause of death. JAMA 1952;150:696–697. 135. Taylor HM: A preliminary survey of the effect which lye legislation has had on the incidence of esophageal stricture. Ann Otol Rhinol Laryngol 1935;44:1157–1158. 136. Thompson CJ: Poisons and Poisoners. London, Harold Shaylor, 1931.

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137. Timbrell JA: Introduction to Toxicology. London, Taylor & Francis, 1989. 138. Trestrail JH: Criminal Poisoning: Investigational Guide for Law Enforcement, Toxicologists, Forensic Scientists, and Attorneys. Totowa, NJ, Humana Press, 2000. 139. Vale JA, Meredith TJ: Poison information services. In: Vale JA, Meredith TJ, eds: Poisoning: Diagnosis and Treatment. London, Update Books, 1981: pp. 9–12 140. Watson G: Theriac and Mithradatum: A Study in Therapeutics. London, Wellcome Historical Medical Library, 1966. 141. Wax PM: Elixirs, diluents and the passage of the 1938 federal Food, Drug and Cosmetic Act. Ann Intern Med 1995;122:456–461.

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142. Wells C: Lead poisoning in the ancient world. Med Hist 1973;17: 391–397. 143. Witthaus RA, Becker TC: Medical Jurisprudence: Forensic Medicine and Toxicology, vol. 1. New York, William Wood, 1894. 144. Witthaus RA: Manual of Toxicology, 2nd ed. New York, William Wood, 1911. 145. Wormley TG: Micro-Chemistry of Poisons. New York, William Wood, 1869. 146. Wright-St. Clair RE: Poison or medicine. N Z Med J 1970;71: 224–229.

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ANTIDOTES IN DEPTH

Antiquated Antidotes Paul M. Wax While the judicious use of certain antidotes (eg, N-acetylcysteine, naloxone, pyridoxine) is critically important in the management of select poisoned patients, other antidotes do not necessarily offer a distinct clinical advantage and may create additional problems (eg, flumazenil, physostigmine). A perpetual search for better and improved antidotes features prominently in the history of toxicology. Unfortunately, many of the “antidotal breakthroughs” over the years have not lived up to their promise (Table 1–6). A number of these antidotes, such as caffeine, are ineffective. Others, such as propylene glycol, were insufficiently tested or were replaced by “safer,” more effective treatment such as paraldehyde.11 Most troubling, the use of some of these agents, such as analeptics and copper sulfate, actually worsened the clinical situation. Unfortunately, just as the various classic theriac preparations remained popular into the 20th century, the use of many of these “modern antidotes” has persisted long after scientific investigation demonstrated their ineffectiveness. An emphasis on physiologic antagonism with antidotes, such as analeptics, has often taken precedence over good supportive care. Not surprisingly, the use of modern-day theriacs, such as the “universal antidote,” persisted until quite recently, despite a lack of serious scientific support. This section highlights some of the critical changes in 20th-century poison management.

ANALEPTICS One of the most interesting changes in poison management took place during the 1940s and 1950s with regard to the use of analeptics in the treatment of barbiturate overdose.49 Analeptics are nonspecific arousal agents and include such stimulants as strychnine, camphor, caffeine, picrotoxin, pentylenetetrazol, nikethamide, amphetamine, and methylphenidate. Barbiturates, the first widely available sedative-hypnotics, were introduced in the early 20th century. Within a few years they became the most common cause of serious overdose.5 In the 1920s, barbiturate overdose management recommendations still included blood-letting techniques.34 By the next decade, as interest in principles of antagonism between stimulants and depressants became widespread, much attention was focused on the use of analeptic agents to combat the sedative effects of barbiturates. Proponents of analeptics argued that because the effects of cocaine intoxication appeared to be neutralized by barbiturates, a reciprocal approach—treating depressant overdoses with stimulants—should also be effective.34 The principal goal of analeptic therapy was to awaken the patient as soon as possible. Numerous analeptic agents have been recommended over the years. Prior to the development of the first synthetic analeptics in the late 1920s, naturally occurring stimulants, such as caffeine, lobeline, strychnine, cocaine, and camphor, were utilized for this purpose. According to Leschke’s Clinical Toxicology, a standard

textbook published in 1934, the most effective remedy for the treatment of a sedative-hypnotic overdose was the intrathecal injection of 10% camphorated oil.31 Picrotoxin, obtained from the berries of the Cocculus indicus plant, was first suggested as an antagonist to morphine in 1847.29 After a series of animal studies in the early 1930s, picrotoxin was enthusiastically endorsed as the analeptic of choice.35 Picrotoxin acts as a GABAA and GABAC receptor antagonist and as a glycine-receptor antagonist facilitating excitatory neurotransmission.18 Although picrotoxin remains one of the most powerful central nervous system (CNS) and respiratory stimulants in our pharmacopeia, it also exhibits marked convulsive activity. The subsequent introduction of synthetic analeptics, such as pentylenetetrazol (Metrazol, Cardiazol) and nikethamide (Coramine), increased the growing dependence on analeptics as the major treatment modality for barbiturate overdose.25,28,36 During his search for an effective camphor substitute, Schmidt synthesized pentylenetetrazol, the first synthetic analeptic, in 1924, and it was initially introduced as a cardiac stimulant.48 Mechanistically, it reduces GABA-ergic inhibition and interacts with picrotoxin-binding sites. It may also work by changing extraneuronal potassium permeability, thereby partially depolarizing neuronal membranes and increasing excitability. Pentylenetetrazol was employed as a CNS stimulant in the treatment of depressant overdoses from the 1930s through the 1960s,16,25 but was considered less effective than picrotoxin or strychnine. Nikethamide was also used as a cardiac and respiratory stimulant and was reputed to be helpful in overcoming the respiratory depression of morphine, sedative-hypnotics, and volatile anesthetics.36 Further experience showed that it was a less efficacious analeptic than either picrotoxin or pentylenetetrazol.20 Its exact mechanisms of enhancing excitation are unknown. Analeptic treatment strategies were often referred to as “very energetic,” because large doses of multiple analeptics were frequently utilized.38 As recently as the 1950s, newer analeptics, such as bemegride, were being introduced as the “real antidote” to barbiturate overdoses.45 During this time, methylphenidate was also used in the treatment of barbiturate overdoses. In 1967, one enthusiastic methylphenidate proponent emphasized, “Don’t let comatose patients remain comatose [after barbiturate overdose]. Methylphenidate will waken them safely.”36 Toxicology textbooks published in the 1950s and 1960s continued to recommend caffeine, picrotoxin, and nikethamide as useful analeptic agents.13,19,32 Subconvulsive electric shock therapy was also advocated as an alternative or adjunct to these chemical convulsants during this period.42 Unfortunately, many adverse effects occurred with the use of these analeptics, including hyperthermia, dysrhythmias, seizures, and psychoses.27,36,41 It gradually became evident that analeptic therapy, despite its theoretic benefits, offered no real advantage, did not reduce mortality, and, placed the patient at risk for significant iatrogenic complications.7 A different strategy was required. Beginning in the mid-1940s, a distinctive approach to barbiturate overdose was pioneered by Eric Nilsson and Carl Clemmesen at the Bispebjergs Hospital in Copenhagen, Denmark.7,39 This treat-

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TABLE 1–6.

HISTORY

19

Antiquated Antidotes

Type of Antidote

Therapeutic Agent

Uses

Adverse Effects

Analeptic

Amphetamine Bemegride Caffeine Camphorated oil Lobeline Nikethamide (Coramine) Pentylenetetrazol (Metrazol) Picrotoxin Strychnine Universal antidote Burnt toast Sodium phosphate (Phospho-Soda) Apomorphine Copper sulfate Mechanical stimulation Mustard powder Saltwater Tartar emetic Zinc sulfate Ascorbic acid Calcium bromide Ferric hydroxide/magnesium hydroxide Potassium ferrocyanide Potassium iodide Sodium formaldehyde sulfoxylate Acetazolamide Hypochlorites Potassium permanganate Propylene glycol Raw rabbit brain Calcium carbonate

Sedative overdose Sedative overdose Sedative overdose Sedative overdose Sedative overdose Sedative overdose Sedative overdose Sedative overdose Sedative overdose Gastrointestinal decontamination Gastrointestinal decontamination Iron Gastric emptying Gastric emptying Gastric emptying Gastric emptying Gastric emptying Gastric emptying Gastric emptying Lead, arsenic Lead Arsenic Copper Lead Mercury bichloride Salicylate Snakebites Alkaloids (morphine, strychnine, aconite) Phenolphthalein Amanita phalloides Acid

Seizures, hyperthermia, aspiration Seizures, hyperthermia, aspiration Seizures, hyperthermia, aspiration Seizures, hyperthermia, aspiration Seizures, hyperthermia, aspiration Seizures, hyperthermia, aspiration Seizures, hyperthermia, aspiration Seizures, hyperthermia, aspiration Seizures, hyperthermia, aspiration Ineffective; tannic acid hepatotoxicity Ineffective Hyperphosphatemia CNS depression, aspiration Caustic, increased copper load Oropharyngeal trauma; ineffective Ineffective Hypernatremia GI toxicity GI toxicity Ineffective Ineffective Ineffective Ineffective Ineffective Ineffective Acidemia; increased CNS salicylate load Ineffective Caustic

Hydrochloric acid

Alkali

Lemon juice

Alkali

Lime water

Acid

Magnesium hydroxide

Acid

Sodium bicarbonate

Acid

Vinegar

Alkali

Chloroform Digitalis Ethanol Ether Paraldehyde Sodium bromide Tribromoethanol (Avertin)

Strychnine Delirium tremens Delirium tremens Agitation/seizures Delirium tremens Delirium tremens Agitation/seizures

Adsorbent Complexing agent Emetic

Heavy metal antidote

Miscellaneous

Neutralizing agent

Sedative

ment regimen, known as the Scandinavian method, abandoned the use of analeptics in the treatment of barbiturate overdoses. Instead of primarily emphasizing the termination of coma, attention was directed at intensive supportive therapy with respiratory ventilation, oxygenation, and cardiovascular support. This strategy was analogous to the postanesthetic recovery room care provided to surgical patients. Using this “revolutionary” approach, barbiturate overdose mortality significantly dropped from about 20% with stimulation therapy to 1–2% with the Scandinavian method.7

Ineffective Exothermic reaction; gas formation; ineffective Exothermic reaction; gas formation; ineffective Exothermic reaction; gas formation; ineffective Exothermic reaction; gas formation; ineffective Exothermic reaction; gas formation; ineffective Exothermic reaction; gas formation; ineffective Exothermic reaction; gas formation; ineffective Hepatotoxin, dysrhythmias Ineffective Difficult to titrate, metabolic abnormalities Difficult to administer; irritating Acidosis; difficult to administer Difficult to use; bromism Sedation

EARLY TREATMENTS OF OPIOID OVERDOSES Prior to the 1950s, opioid overdose was treated with many of the same analeptic agents. In the early 1950s, an important development in the history of poison management occurred when two specific opioid antidotes were introduced: nalorphine (Nalline) and levallorphan (Lorfan).14 These drugs were capable of reversing the

20

CHAPTER 1

HISTORY

respiratory effects of an opioid overdose by blocking opioid receptors. Nalorphine was also routinely administered to determine the presence or absence of opioids in suspected opioid abusers. This test, known as the Nalline test, was used as a monitoring tool in drug abuse programs.22 The test was considered positive if it precipitated signs of opioid withdrawal or pupillary dilatation. Unfortunately, neither nalorphine nor levallorphan was a pure opioid antagonist. Instead, the mixed agonist/antagonist properties of these drugs significantly limited their usefulness. Respiratory depression could be potentiated, especially in opioid-free patients. This was most likely to occur when these drugs were administered to comatose patients with mild hypoventilation who had overdosed on sedative-hypnotics or ethanol. Naloxone, which was introduced in the 1970s, is a much safer drug because of its pure opioid antagonistic properties. It has completely replaced nalorphine and levallorphan in the treatment of opioid overdoses.15 Naloxone has no agonist properties, does not cause any additional respiratory depression, regardless of the ingestion, is short acting, and is safe to use for patients with coma following an undefined overdose. In addition, it is useful in treating patients with an overdose of other mixed agonist-antagonist opioids, such as pentazocine, who do not typically respond to nalorphine.

OUTDATED AND DANGEROUS EMETICS The role of emetics in poison management, both in the home and at the hospital, has undergone significant transformation over the years. The antimony salt commonly known as tartar emetic had a long history of use as an emetic, as well as a sedative, expectorant, cathartic, and diaphoretic. During the 19th century, tartar emetic was one of the three most widely prescribed drugs, along with opium and calomel (mercurous chloride).23 Tartar emetic is no longer recommended for any purpose because of its inherent toxicity and unreliability.6 Standard gastrointestinal decontamination recommendations during the 1960s included mechanical stimulation of the throat and the ingestion of saltwater emetics, or mustard water in the home, and copper sulfate, zinc sulfate, or apomorphine in the hospital.1,26 Many authorities recommended mechanical stimulation of the pharynx (finger-down-the-throat technique) as a quick-andeasy home remedy when induction of emesis was desirable.1,9 This method, however, is both ineffective and potentially traumatic, and is no longer encouraged.9 Similarly, the use of saltwater emetics was abandoned after numerous cases of severe salt poisoning resulted from their administration.3,12 Mustard powder has never been proved to be effective.6 The use of copper sulfate as an emetic26 also fell out of favor because of its caustic properties, its potential to cause acute copper poisoning, and its unreliability.24,46 Zinc sulfate also is no longer used as an emetic.6 Until the 1980s, apomorphine was advocated as an emetic.8,37 One reason for its use was the thought that it was safer and more effective than copper sulfate.24 It was supposed to be particularly useful for the combative or uncooperative patient because of its rapid onset of action and parenteral administration, and in this setting, was frequently used instead of syrup of ipecac.39 Apomorphine’s propensity to cause CNS depression, however, increased the risk of subsequent aspiration and made its use potentially very dangerous. Moreover, a sterile injectable form of apomorphine has not been available in the United States for many years. For all of

these reasons, enthusiasm for apomorphine gradually waned, leaving syrup of ipecac as the sole available emetic.33

THE UNIVERSAL ANTIDOTE Two other “antidotes” that were once commonly used for decontamination but that have since fallen into disfavor are the “universal antidote” and burnt toast. For many years the universal antidote, sold under the trade names Unidote and Res-Q, was a medical tradition40 and was advocated by many textbooks as part of the standard management of the poisoned patient.13,19,32 Commercial preparations consisted of one part magnesium oxide, one part tannic acid, and two parts activated charcoal. An alternative home recipe consisted of milk of magnesia, strong tea, and burnt toast. Combination therapy of this sort was thought to offer a broader spectrum of action than activated charcoal alone. It was theorized that the magnesium oxide would neutralize acids and the tannic acid would precipitate alkaloids and metals.32 The use of the universal antidote declined by the mid-1980s and is no longer available. Studies demonstrated that activated charcoal was superior to the universal antidote in decreasing absorption10,40 and that the decreased efficacy of the universal antidote was caused by tannic acid interfering with activated charcoal’s adsorbence of other toxins.10 Furthermore, the potential hepatotoxicity of tannic acid was increasingly recognized.40 Although burnt toast had been advocated as an activated charcoal substitute in the home,2 its use was also abandoned because of its lack of significant adsorbent activity.30

OTHER ANTIQUATED ANTIDOTES The use of drugs for the chemical restraint of agitated individuals has also undergone significant evolution during the past decades. Depressant agents, such as tribromoethanol (Avertin) and ether, are no longer used because of the availability of safer alternative agents. Likewise, paraldehyde and ethanol, which were commonly used for the treatment of alcohol withdrawal,21 have been replaced by the much safer and less toxic benzodiazepines. The use of analeptics to treat the depressive effects of ethanol has also become obsolete.47 Another change in treatment involves the abandonment of neutralizing agents for caustic ingestions. Until the 1970s, typical recommendations for the treatment of alkali ingestions included the use of vinegar (acetic acid), lemon juice, or, in some cases, dilute hydrochloric acid.32 Suggestions for neutralizing acid ingestions included the use of magnesium hydroxide, lime water, or calcium carbonate.32 Because of the extremely rapid onset of action of caustic agents, concerns arose over whether it was already too late to reverse the caustic process. Furthermore, the addition of neutralizing agents could increase the exothermic reaction and/or gas production.43 Such reactions in an already weakened hollow viscus may be poorly tolerated and lead to extension of the tissue injury or perforation. For all of these reasons, the use of neutralizing agents is no longer recommended. Other abandoned antidotes include potassium iodide, which was used to enhance lead excretion, and ferric hydroxide (antidotum arsenici), which was used in the treatment of arsenic poisoning. Acetazolamide, which was advocated for alkalinizing the urine in salicylate poisoning,44 causes a systemic acidemia that can

CHAPTER 1

worsen the salicylate toxicity, and is therefore no longer used. The use of sodium phosphate (Phospho-Soda) in the management of iron overdose in an attempt to create insoluble ferrous phosphate has also ceased because of problems with its marginal efficacy and resultant hyperphosphatemia.17 Finally, enthusiasm has waned for raw rabbit brain, which had been recommended as recently as the 1930s as a “chance of life” for patients with Amanita phalloides poisoning.31 The raw brain approach was pioneered in the early 1800s after it was observed that rabbits could eat poisonous mushrooms without ill effects.4 Postulating that rabbits had some sort of protective mechanism that neutralized the mushroom toxin, investigators formulated an antidotal concoction consisting of seven rabbit brains and three rabbit stomachs. The preparation was minced and ground into pellets and administered with a sweetener. When patients who received the rabbit brain antidote survived the mushroom poisoning, it was erroneously concluded that these uncontrolled observations provided proof of efficacy.4 Many of our current antidotes have not undergone rigorous scientific evaluation regarding efficacy and safety. In time, some of these antidotes will undoubtedly join this list of antiquated antidotes. Lessons learned from the past, such as the abandonment of analeptics, help to optimize present-day patient care and to better prepare us to investigate and evaluate the next generation of antidotes.

REFERENCES 1. Adams WC: Emetics in accidental poisoning. Pediatr Clin North Am 1961;8:351–352. 2. Arena J: Poisoning: Chemistry, Symptoms, Treatment. Springfield, IL, Charles C. Thomas, 1963. 3. Barer J, Hill L, Hill RM, Martinez WM: Fatal poisoning from salt used as an emetic. Am J Dis Child 1973;125:889–890. 4. Benjamin DR: Mushrooms: Poisons and Panaceas. New York, WH Freeman, 1995. 5. Berger FM: Drugs and suicide in the United States. Clin Pharmacol Therap 1967;8:219–223. 6. Cashman TM, Shirkey HC: Emergency management of poisoning. Pediatr Clin North Am 1970;17:525–534. 7. Clemmesen C, Nilsson E: Therapeutic trends in the treatment of barbiturate poisoning: The Scandinavian method. Clin Pharmacol Ther 1961;2:220–229. 8. Corby DG, Decker WJ, Moran MJ, Payne CE: Clinical comparison of pharmacologic emetics in children. Pediatrics 1968;42:361–364. 9. Dabbous IA, Bergman AB, Robertson WO: The ineffectiveness of mechanically induced vomiting. J Pediatr 1965; 66:952–954. 10. Daly JS, Cooney DO: Interference by tannic acid with the effectiveness of activated charcoal in “universal antidote.” Clin Toxicol 1978; 12:515–522. 11. Decker WJ: Antidotes: Some ineffective, insufficiently tested, outmoded, and potentially dangerous therapeutic agents. Vet Hum Toxicol 1983;25:10–15. 12. DeGenaro F, Nyhan WL: Salt: A dangerous “antidote.” J Pediatr 1971;78:1048–1049. 13. Deichmann WB, Gerarde HW: Signs, Symptoms and Treatment of Certain Acute Intoxications, 2nd ed. Springfield, IL, Charles C. Thomas, 1958. 14. Eckenhoff JE, Funderburg LW: Observations on the use of the opiate antagonists nalorphine and levallorphan. Am J Med Sci 1954; 228: 546–553. 15. Evans LEJ, Roscoe P, Swainson CP, Prescott LF: Treatment of drug overdosage with naloxone, a specific narcotic antagonist. Lancet 1973;1:452–455.

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16. Freund JD: Metrazol treatment of barbiturate poisoning. Psychosomatics 1968;9:172–174. 17. Geffner ME, Opas LA: Phosphate poisoning complicating treatment for iron ingestion. Am J Dis Child 1980;134:509–510. 18. Gilman AG, Goodman LS, Gilman A: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 7th ed. New York, Macmillan, 1985. 19. Gleason MN, Gosselin RE, Hodge HC: Clinical Toxicology of Commercial Products: Acute Poisoning (Home & Farm), 2nd ed. Baltimore, Williams & Wilkins, 1963. 20. Goodman LS: The Pharmacological Basis of Therapeutics. New York, Macmillan, 1941. 21. Gower WE, Kersten H: Prevention of alcohol withdrawal symptoms in surgical patients. Surg Gynecol Obstet 1980;151:382–384. 22. Halbach H, Eddy NB: Tests for addiction of morphine type. Bull World Health Organ 1963;28:139–173. 23. Haller JS: The use and abuse of tartar emetic in the 19th century materia medica. Bull Hist Med 1975;49:235–259. 24. Holtzman NA, Haslam RH: Elevation of serum copper following copper sulfate as an emetic. Pediatrics 1968;42:189–193. 25. Jones AW, Dooley J, Murphy JR: Treatment of choice in barbiturate poisoning. JAMA 1950;143:884–888. 26. Karlsson B, Noren L: Ipecacuanha and copper sulfate as emetics in intoxications in children. Acta Pediatr Scand 1965;54:331–335. 27. Klaer-Larsen J: Delirious psychosis and convulsions due to Megimide. Lancet 1956;2:967–970. 28. Koppanyi T, Fazekas JF: Acute barbiturate poisoning: Analysis and evaluation of current therapy. Am J Med Sci 1950;220:559–576. 29. Koppanyi T, Linegar CR, Dille JM: Analysis of the barbiturate-picrotoxin antagonism. J Pharmacol Exper Therap 1936;58:199–228. 30. Lehman AJ: Substitution of burned toast for activated charcoal in the “universal antidote.” Assoc Food Drug Official US Q Bull 1957;21: 210–211. 31. Leschke E: Clinical Toxicology: Modern Methods in the Diagnosis and Treatment of Poisoning. Baltimore, William Wood, 1934. 32. Lucas GH: The Symptoms and Treatment of Acute Poisoning. Toronto, Canada, Clark Irwin, 1952. 33. MacLean WC: A comparison of ipecac syrup and apomorphine in the immediate treatment of ingestion of poisons. J Pediatr 1973;82: 121–124. 34. Maloney AH, Fitch RH, Tatum AL: Picrotoxin as an antidote in acute poisoning by shorter-acting barbiturates. J Pharmacol Exp Ther 1931;41:465–482. 35. Maloney AH: A comparative study of the antidotal action of picrotoxin, strychnine and cocaine in acute intoxication by the barbiturates. J Pharmacol Exp Ther 1933;49:133–140. 36. Mark LC: Analeptics: Changing concepts, declining status. Am J Med Sci 1967:254:296–302. 37. Meester WD: Emesis and lavage. Vet Hum Toxicol 1980; 22:225– 234. 38. Nilsson E, Eyrich B: On treatment of barbiturate poisoning. Acta Med Scand 1950;137:381–389. 39. Nilsson E: On treatment of barbiturate poisoning: Modified clinical aspects. Acta Med Scand 1951;139(Suppl 253):1–127. 40. Picchioni AL, Chin L, Verhulst HL, Dieterle B: Activated charcoal vs. “universal antidote” as an antidote for poisons. Toxicol Appl Pharmacol 1966; 8:447–454. 41. Reed CE, Driggs MF, Foote CC: Acute barbiturate intoxication: Study of 300 cases based on physiologic system of classification of severity of intoxication. Ann Intern Med 1952;37:290–303. 42. Robie TR: Treatment of acute barbiturate poisoning by nonconvulsive electrostimulation. Postgrad Med J 1951;253–256. 43. Rumack BH, Burrington JD: Caustic ingestions: A rational look at diluents. Clin Toxicol 1977;11:27–34. 44. Schwartz R, Fellers F, Knapp J, Yaffe S: The renal response to administration of acetazolamide (Diamox) during salicylate intoxication. Pediatrics 1959;23:1103–1114.

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HISTORY

45. Shulman A, Shaw FH, Cass NM, Whyte HM: A new treatment of barbiturate intoxication. Br Med J 1955;1:1238–1244. 46. Stein RS, Jenkins D, Korns ME: Death after use of cupric sulfate an emetic. JAMA 1976;235:801. 47. Taberner PV: Pharmacological treatment for alcohol dependence and withdrawal—An historical perspective. Alcohol 1993;S2:259–262.

48. Wang SC, Ward JW: Analeptics. Pharmacol Therapy 1977;3: 123–165. 49. Wax PM: Analeptic use in clinical toxicology. A historical appraisal. J Toxicol Clin Toxicol 1997;35:203–209.

CHAPTER

2

TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY Paul M. Wax

Throughout history mass poisonings have caused suffering and misfortune. From the ergot epidemics of the Middle Ages to contemporary industrial disasters, these plagues have had great political, economic, social, and environmental ramifications. Particularly within the last 100 years, as the number of toxins and potential toxins has risen dramatically, toxic disasters have become an increasingly common event. The sites of some of these events—Bhopal (India), Chernobyl (Ukraine), Jonestown (Guyana), Love Canal (New York), Minamata Bay (Japan), West Bengal (India)—have come to symbolize our increasingly toxic habitat. This chapter provides an overview of some of the most consequential and historically important toxin-mediated disasters.

The release into the atmosphere of 26 tons of hydrofluoric acid at a petrochemical plant in Texas, in October 1987, resulted in 939 people seeking medical attention at nearby hospitals. Ninety-four people were hospitalized, but there were no deaths.136 More than any other single toxin, carbon monoxide has been involved with the largest number of toxic disasters. Catastrophic fires, such as the Cocoanut Grove Nightclub Fire in 1943, have caused hundreds of deaths at a time, many of them from carbon monoxide poisoning.28 The 1990 fire at the Happy Land Social Club in the Bronx, New York, claimed 87 victims, including a large number of nonburn deaths.71 Carbon monoxide poisoning was a major culprit in many of these deaths, although hydrogen cyanide gas and simple asphyxiation may also have contributed to the overall mortality. Another notable toxic gas disaster involving a fire occurred at the Cleveland Clinic in 1929, where a fire in the radiology department resulted in 125 deaths.23 The burning of nitrocellulose radiographs produced nitrogen dioxide, cyanide, and carbon monoxide gases that were thought to be responsible for many of the fatalities. Air pollution is another source of toxic gases causing significant disease and death. Known to Shakespeare, whose witches in Macbeth chant “fair is foul, and foul is fair: hover through the fog and filthy air,” complaints about smoky air date back to at least 1272, when King Edward I banned the burning of sea-coal.126 By the 19th century—the era of rapid industrialization in England— winter “fogs” became increasingly problematic. An 1873 London fog was responsible for 268 deaths from bronchitis. Excessive smog in the Meuse Valley of Belgium in 1930, and in Donora, Pennsylvania, in 1948, was also blamed for excess morbidity and mortality. Another dense sulfur dioxide–laden smog in London in 1952 was responsible for 4000 deaths.69 Both the initiation of long overdue air-pollution reform in England and Parliament’s passing of the 1956 Clean Air Act resulted from this later “fog.”

GAS DISASTERS Inhalation of toxic gases and oral ingestions resulting in food poisoning tend to subject the greatest number of people to adverse consequences of a toxic exposure. Toxic gas exposures may be the result of a natural disaster (volcanic eruption), unintentional mishap (industrial fire), chemical warfare, or intentional homicidal or genocidal endeavor (concentration camp gas chamber). Depending on the toxin, the clinical presentation may be acute, with a rapid onset of toxicity (cyanide gas), or subacute/chronic, with a gradual onset of toxicity (air pollution). Chemical toxins used in warfare include both gases (phosgene, chlorine) and liquids (mustard, organic phosphorus agents). One of the earliest recorded toxic gas disasters resulted from the eruption of Mount Vesuvius near Pompeii, Italy, in A.D. 79 (Table 2–1). Poisonous gases generated from the volcanic activity reportedly killed thousands.24 A much more recent natural disaster occurred in 1986 in Cameroon, when excessive amounts of carbon dioxide were mysteriously vented from Lake Nyos, the volcanic crater lake.6 Seventeen hundred fatalities reportedly resulted from exposure to this asphyxiant. A toxic gas leak at the Union Carbide pesticide plant in Bhopal, India, in 1984, resulted in one of the greatest civilian toxic disasters in modern history.129 An unintended exothermic reaction at this carbaryl-producing plant caused the release of over 24,000 kg of methyl isocyanate. This gas was quickly dispersed through the air over the densely populated area surrounding the factory, resulting in at least 2500 deaths and 200,000 injuries.78 The initial response to this disaster was greatly limited by a lack of pertinent information about the toxicity of this agent. A followup study 10 years later showed persistence of small-airway obstruction among survivors.19 Calls for improvement in disaster preparedness and strengthened right-to-know laws regarding potential toxic exposures resulted from this tragedy.24,129

CHEMICAL WARFARE Exposure to toxic chemicals with the deliberate intent to inflict harm has claimed an extraordinary number of victims during the 20th century (Table 2–2). During World War I, chlorine and phosgene gases and the liquid vesicant mustard were used as battlefield weapons, with mustard causing about 80% of the chemical casualties.113 Reportedly, 100,000 deaths and 1.2 million casualties were attributed to these chemical attacks during WWI.24 These toxic exposures resulted in severe airway irritation, pulmonary edema, hemorrhagic pneumonitis, skin blistering, and ocular damage. Chemical weapons were used again in the 1980s during the IranIraq war.

23

24

CHAPTER 2

TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY TABLE 2–1.

Gas Disasters

Toxin

Location

Date

Significance

Poisonous gas Smog (SO2) NO2, CO, CN

Pompeii London Cleveland Clinic, Cleveland, OH Belgium, Meuse Valley Cocoanut Grove Night Club, Boston Salerno, Italy Donora, PA London Bhopal, India Cameroon Texas Happy Land Social Club, Bronx, NY

A.D. 79 1873 1929

>2000 died from eruption of Mt. Vesuvius 268 deaths from bronchitis Fire in radiology department, 125 deaths

1930 1942

64 deaths 498 deaths from fire

1944 1948 1952 1984 1986 1987 1990

>500 deaths on train stalled in tunnel 20 deaths, thousands ill 4000 deaths attrributed to the fog/smog >2000 deaths; 200,000 injuries >1700 deaths from release of gas from Lake Nyos Atmospheric release, 94 hospitalized 87 died in fire from toxic smoke

Smog (SO2) CO, CN CO Smog (SO2) Smog (SO2) Methyl isocyanate Carbon dioxide Hydrofluoric acid CO, ? CN

The Nazis utilized poisonous gases during World War II to commit mass murder and genocide. Initially, the Nazis employed carbon monoxide to kill. To expedite the killing process, Nazi scientists developed Zyklon B gas (hydrogen cyanide gas). As many as 10,000 people per day were killed by the rapidly acting cyanide, and millions of deaths were attributed to the use of these gases. During recent wars, a variety of physical and neuropsychologic ailments were attributed to possible exposure to toxic agents.47 Agent Orange was widely used as a defoliant during the Vietnam War. This herbicide consists of a mixture of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D), as well as small amounts of a contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), better known as dioxin. Although a higher incidence of skin cancers has been found in veterans who handled Agent Orange, other possible dioxin-related adverse health effects, such as nonskin cancer, birth defects, and hepatic dysfunction, have not been observed.22 An increase in nonHodgkin lymphoma among Vietnam veterans has occurred, but this is not clearly attributable to herbicide exposure.108 Gulf War syndrome is a constellation of chronic symptoms, including fatigue, headache, muscle and joint pains, ataxia, paresthesias, diarrhea, skin rashes, sleep disturbances, impaired concentration, memory loss, and irritability, noted in thousands of Persian Gulf War veterans without a clearly identifiable cause. A number of etiologies have been advanced to explain these varied symptoms, including exposure to the smoke from burning oil wells; chemical and biologic warfare agents, including nerve agents; and TABLE 2–2.

medical prophylaxis, such as the use of pyridostigmine bromide, anthrax, and botulinum toxin vaccines.48 Other possible etiologies include pesticides such as DEET, infectious agents such as leishmaniasis, inhalation of sand contaminated with fungus, insect vectors, depleted uranium munitions, and posttraumatic stress disorder. Although organic phosphorous–induced delayed polyneuropathy may explain some of these clinical findings,39 at present, the true etiology of this illness remains unknown.30,47,49,62,125 “Emerging overlap syndromes,” such as multiple chemical sensitivity, chronic fatigue syndrome, and fibromyalgia, may also play a role in Gulf War Syndrome, making this diagnosis particularly perplexing.42,55 Mass exposure to the very potent organic phosphorus compound sarin occurred in March 1995, when terrorists released this chemical warfare agent in three separate subway lines in Tokyo.94 Eleven people were killed, and 5510 people sought emergency medical evaluation at more than 200 hospitals and clinics in the area.114 Sarin exposure also resulted in several deaths and hundreds of casualties in Matsumoto, Japan, in June 1994.83,91

FOOD DISASTERS Unintentional contamination of food and drink has led to numerous toxic disasters (Table 2–3). Ergot, produced by the fungus Claviceps purpurea, has caused a large number of deadly epidemics.80 Epidemic ergotism occurred as the result of eating

Chemical Warfare Disasters

Toxin

Location

Date

Significance

Chlorine, phosgene, mustard gas CN, CO Agent Orange (2-4D, 2-4-5-T, TCDD) Mustard gas Toxic smoke? Sarin Sarin

Ypres, Belgium

1915–1918

Europe Vietnam

1939–1945 1960s

100,000 dead and 1.2 million casualties from chemicals during WWI Millions murdered by Zyklon-B (HCN) gas Contains dioxin; excess skin cancer

Iraq-Iran Persian Gulf Matsumoto, Japan Tokyo

1982 1991 1994 1995

New cycle of war gas casualties Gulf War syndrome—possible toxic etiology First of terrorist attacks in Japan using sarin Subway exposure; 5510 people seek medical attention

CHAPTER 2

TABLE 2–3.

TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY

25

Food Disasters

Toxin

Location

Date

Significance

Ergot Ergot Lead Arsenious acid Lead

Aquitania, France Salem, Massachusetts Devonshire, England France Canada

A.D.

994 1692 1700s 1828 1846

Cadmium Hexachlorobenzene Methyl mercury Triorthocresylphosphate Methylenedianiline Polychlorinated biphenyls Methyl mercury Polybrominated biphenyls Polychlorinated biphenyls Rape seed oil (denatured) Arsenic Polychlorinated biphenyls Arsenic

Japan Turkey Minamata Bay, Japan Meknes, Morocco Epping, England Japan Iraq Michigan Taiwan Spain Buenos Aires Belgium Bangladesh and W. Bengal, India

1939–1954 1956 1950s 1959 1965 1968 1971 1973 1979 1981 1987 1999 1990s to present

40,000 died in the epidemic Bizarre behavior may be attributable to ergot Colic from production of cider 40,000 cases of polyneuropathy from contaminated wine and bread 134 men died during Franklin expedition, possibly due to contamination of food stored in lead cans Itai-itai (“ouch-ouch”) disease 4000 cases of porphyria cutanea tarda Organic mercury poisoning from fish Cooking oil adulterated with turbojet lubricant Epping jaundice Yusho (“rice oil disease”) >400 deaths from contaminated grain 97% of state contaminated through food chain Yu-Cheng (“oil disease”) Toxic oil syndrome affected 19,000 people Malicious contamination of meat; 61 people underwent chelation Contamination of meat, dairy products; no reports of illness Ground water contaminated with arsenic; millions exposed; 100,000s with symptoms; greatest mass poisoning in history

breads and cereals made from rye that had been contaminated by C. purpurea. In some epidemics, convulsive manifestations predominated, and in others, gangrenous manifestations predominated. Ergot-induced severe vasospasm was thought responsible for both types of presentations.79 In A.D. 994, 40,000 people died in Aquitania, France, in such an epidemic.67 Convulsive ergotism was initially described as a “fire which twisted the people,” and the term “St. Anthony’s fire” (ignis sacer) was used to refer to the excruciating burning pain experienced in the extremities that is an early manifestation of gangrenous ergotism. The events surrounding the Salem witchcraft trials have also been attributed to the ingestion of contaminated rye. The bizarre and psychotic behaviors exhibited by some of the individuals associated with this event may have been caused by the hallucinogenic properties of ergotamine, an LSD precursor.12,76 During the 20th century, unintentional mass poisoning from food and drink contaminated with toxic chemicals has become all too common. One of the more unusual poisonings occurred in 1956, in Turkey, when wheat seed treated with the fungicide hexachlorobenzene and intended for planting was inadvertently used for human consumption. Four thousand cases of porphyria cutanea tarda were attributed to the ingestion of this wheat seed.106 Another example of chemical food poisoning took place in Epping, England, in 1965. In this incident, a sack of flour became contaminated with methylenedianiline when the chemical unintentionally spilled onto the flour during transport to a bakery. Subsequent ingestion of bread baked with the contaminated flour produced hepatitis in 84 people. This outbreak of toxic hepatitis became known as Epping jaundice.58 The manufacture of polybromated biphenyls (PBBs) in a factory that also produced food supplements for livestock resulted in the unintentional contamination of a large amount of livestock feed in Michigan in 1973.13 Significant morbidity and mortality among the livestock population resulted. Increased human tissue levels of PBBs were reported,137 although human toxicity seemed limited to vague constitutional symptoms and abnormal liver function tests.2

The chemical contamination of a particular lot of rice oil in Japan in 1968 caused an illness called Yusho (“rice oil disease”). This occurred when heat-exchange fluid containing polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) leaked from a heating pipe into the rice oil. More than 1600 people developed this new illness. Manifestations included chloracne, hyperpigmentation, increased incidence of liver cancer, and adverse reproductive effects. A similar illness after exposure to another batch of PCB-contaminated rice oil affected 2000 people in Taiwan in 1979. This latter epidemic was referred to as Yu-Cheng (“oil disease”).51 In 1999, toxic amounts of PCBs and dioxin were found in Belgian meat (particularly poultry), eggs, and other dairy products, as a result of the consumption of animal feed deliberately contaminated with motor oils.9 The PCB/dioxin burden was considerably less than that found in the Yushu incident and no human illnesses linked to the contaminated feed were reported. In another oil contamination epidemic, consumption of an illegally marketed cooking oil in Spain, in 1981, was responsible for a mysterious poisoning epidemic that affected more than 19,000 people and resulted in at least 340 deaths. Exposed patients developed a multisystem disorder referred to as toxic oil syndrome (or toxic epidemic syndrome), which was characterized by pneumonitis, eosinophilia, pulmonary hypertension, scleroderma-like features, and neuromuscular changes. Although this syndrome was associated with the consumption of rapeseed oil denatured with 2% aniline, the exact etiologic agent was never definitively identified.54,123 In 1999, an outbreak of Coca-Cola–related health complaints occurred in Belgium, when about 100 people, mostly children, complained of gastrointestinal symptoms, malaise, headaches, and palpitations, after consuming Coca-Cola. Many of those affected complained of an off taste or bad odor to the soft drink. Millions of cans and bottles were removed from the market at a cost of $900 million. Although a toxicologic cause was never identified in the drink, a hydrocarbon was found on the outside of the containers and it remains unclear whether the complaints should be solely attributable to mass sociogenic illness.92,127

26

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TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY

Epidemics of heavy metal poisoning from contaminated food and drink have also occurred throughout history. Epidemic lead poisoning has been associated with many different vehicles of transmission, including leaden bowls, kettles, and pipes. A famous 18th-century epidemic was known as the Devonshire colic. Although the exact etiology of this disorder was unknown for many years, later evidence suggested that the ingestion of lead-contaminated cider was responsible.130 A more recent incident involving multiple cases of heavymetal poisoning occurred in Buenos Aires in 1987, when vandals broke into a butcher’s shop and poured an unknown amount of acaricide (45% sodium arsenite solution) over 200 kg of partly minced meat.102 The contaminated meat was purchased by 718 people. Of 307 meat purchasers who submitted to urine sampling, 49 had urine arsenic levels of 76–500 µg/dL, and 12 had urine arsenic levels above 500 µg/dL. At the end of the 20th century and into the 21st century, what some observers call the greatest mass poisoning in history is occurring in Bangladesh and the West Bengal State of India.21,85,118 In Bangladesh alone, 60 million people are regularly drinking arsenic-contaminated ground water. At least 220,000 inhabitants of India’s West Bengal have been diagnosed with symptoms of arsenic poisoning.84 Reported symptoms include melanosis, depigmentation, hyperkeratosis, hepatomegaly, splenomegaly, squamous cell carcinoma, intraepidermal carcinoma, and gangrene.21 In a country that was long plagued with dysentery, attempts to clean up the water supply led to the drilling of millions of wells into the superficial water table. Unbeknownst to the engineers, this water was naturally contaminated with arsenic leaving several thousand tube wells with extremely high concentrations of arsenic—up to 40 times the acceptable concentration. Although toxicity from arsenic-contaminated groundwater was previously reported from other areas of the world, including Argentina, China, Mexico, Taiwan (Black Foot’s Disease), and Thailand, the number of people at risk in Bangladesh and West Bengal is by far the largest. Methyl mercury, an organic mercurial, has been the etiologic agent for several recent poisoning epidemics. During the 1950s, a Japanese chemical factory that manufactured vinyl chloride and acetaldehyde routinely discharged mercury into Minamata Bay, resulting in contamination of the aquatic food chain. An epidemic of methyl mercury poisoning followed after the local people ate the poisoned fish.100,124 Chronic brain damage, tunnel vision, deafness, and severe congenital defects were associated with this outbreak.100 Another mass epidemic of methyl mercury poisoning occurred in Iraq in 1971, when the local population consumed homemade bread prepared from wheat seed treated with a methyl mercury fungicide.4 Six thousand hospital admissions and more than 400 hospital deaths were associated with this disaster. As with the hexachlorobenzene exposure in Turkey 25 years previously, the treated grain, intended for use as seed, was instead used as food. Contamination of the local water supply with the wastewater runoff from a zinc-lead-cadmium mine in Japan, from 1939 to 1954, was believed responsible for causing itai-itai (“ouch-ouch”) disease, an unusual chronic syndrome manifested by extreme bone pain and osteomalacia. The local water was used for drinking and irrigation of the rice fields. Approximately 200 people who lived along the banks of the Jintsu River developed these peculiar symptoms, which were thought most likely to be due to the cadmium.10

THERAPEUTIC DRUG DISASTERS Illness and death as a consequence of therapeutic drug use occur as sporadic events, usually affecting individual patients, or as mass disasters, affecting multiple (sometimes hundreds or thousands) patients. Sporadic single-patient medication-induced tragedies usually result from errors (Chap. 1) or unforeseen idiosyncratic reactions. Mass therapeutic drug disasters have generally occurred secondary to poor safety testing, a lack of understanding of diluents and excipients, drug contamination, or problems with unanticipated drug-drug interactions or drug toxicity (Table 2–4). In September and October 1937, more than 100 deaths were associated with the use of one of the early sulfa preparations— elixir of sulfanilamide-Massengill—that contained 72% diethylene glycol as the vehicle for drug delivery. Little was known about diethylene glycol toxicity at the time, and many cases of renal failure and death occurred.33 As a result of this catastrophe, animal drug testing was mandated by the Food, Drug, and Cosmetic Act of 1938 to avoid similar tragedies in the future.131 Unfortunately, diethylene glycol continued to be sporadically used in other countries as a medicinal diluent, resulting in additional deaths in South Africa (1969), India (1986), Nigeria (1990), Bangladesh (1990– 1992), and Haiti (1995–1996).132 In the most recent disaster in Haiti at least 88 children died (case fatality rate 98% for those who remained in Haiti) after ingesting an acetaminophen elixir formulated with diethylene glycol–contaminated glycerin.93,105 A lesser-known drug manufacturing disaster, also involving an early sulfa antimicrobial, occurred in 1940–1941, when at least 82 people died from the therapeutic use of sulfathiazole that had been contaminated with phenobarbital (Luminal).119 The responsible pharmaceutical company, Winthrop Chemical, produced both sulfathiazole and phenobarbital, and the contamination likely occurred during the tabletting process, because the tabletting machines for the two medications were adjacent to each other and were used interchangeably. Each contaminated sulfathiazole tablet contained about 350 mg of phenobarbital (and no sulfathiazole), and the typical sulfathiazole dosing regimen was several tablets within the first few hours of therapy. Twenty-nine percent of the production lot was contaminated. FDA intervention was required to assist with the recovery of the suspect sulfathiazole, although 22,000 contaminated tablets were never found.119 In the early 1960s, one of the greatest modern-day drug catastrophes occurred with the release of thalidomide as an antiemetic and sedative-hypnotic.20 Its use as a sedative-hypnotic by pregnant women resulted in about 5000 babies born with severe congenital anomalies.80 This tragedy was largely confined to Europe, Australia, and Canada, where the drug was initially marketed. Only the length of time required for review and the rigorous scrutiny of new drug applications by the FDA in the United States prevented a concurrent disaster here.77 Another major therapeutic drug misadventure that did occur in the United States involved the widespread use of diethylstilbestrol (DES) for the treatment of threatened and habitual abortions. Despite the lack of convincing efficacy data, as many as 10 million Americans received DES during pregnancy, or in utero, during a 30-year period, until use of the drug in pregnancy was prohibited in 1971. Adverse health effects associated with DES use include increased risk for breast cancer in “DES mothers” and increased risk of a rare form of vaginal cancer, reproductive tract anomalies, and premature births in “DES daughters.”35,41

CHAPTER 2

TABLE 2–4.

TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY

27

Therapeutic Drug Disasters

Toxin

Location

Date

Significance

Thallium Tubercle bacilli

US Germany

1920s–1930s 1930

Diethylene glycol Thorotrast Phenobarbital

US US US

1937 1930s–1950s 1940–1941

Hepatitis virus

US

1942

Diethylstilbestrol Stalinon Clioquinol

US, Europe France Japan

1940s–1950s 1954 1955–1970

Thalidomide

Europe

1960

Pentachlorophenol

US

1967

HIV

US

1970s–1980s

Benzyl alcohol Acetaminophen-cyanide Tryptophan Diethylene glycol

US Chicago US Haiti

1981 1982 1989 1996

Fenfluramine/dexfenfluramine

US

1997

Phenylpropanolamine (PPA)

US

2000

Used for ringworm; 31 deaths Tubercle bacilli given to neonates instead of BCG; 72 deaths Elixir of sulfanilamide; renal failure Hepatic angiosarcoma Sulfathiazole contaminated with phenobarbital; 82 deaths Yellow fever vaccine contamination; 28,000 military develop hepatitis Vaginal adenocarcinoma in daughters Severe neurotoxicity from triethyltin Subacute myelooptico neuropathy (SMON); 10,000 symptomatic 5000 cases of phocomelia (limb deformaties) Used in hospital laundry; 9 neonates ill, 2 deaths Cryoprecipitate contaminated with HIV; 90% hemophilia A population seroconverted Gasping syndrome Tampering incident resulted in 7 homicides Eosinophilia-myalgia syndrome Acetaminophen elixir contaminated; renal failure; >88 pediatric deaths Fen-phen diet regimen associated with valvular heart disease OTC cold remedy removed from market due to association with hemorrhagic stroke

Drug disasters that have affected the greatest number of individuals have often occurred from infectious contamination of vaccines or other drug treatments. After the American entrance into World War II, 3 million troops received yellow fever immunization. It was the practice at the time to add human serum to the vaccine to preserve the attenuated yellow fever virus. In the spring of 1942, 28,000 cases of hepatitis and 62 deaths resulted from the yellow fever vaccination. Subsequent investigation traced this outbreak to viral hepatitis contamination of 9 of the 177 lots of vaccine administered.104 Another vaccine-related disaster occurred in 1930, when 207 of 251 newborn babies in Lubeck, Germany, who were given oral bacillus Calmette-Guérin (BCG) vaccination to prevent tuberculosis, ended up developing clinical tuberculosis; 72 newborns died. This tragedy occurred because a preparation containing nonattenuated human tubercle bacilli had been carelessly substituted for the nonvirulent BCG vaccine .61 A more recent infectious disaster attributed to medication has been the calamitous development of HIV infection in hemophiliacs who had received concentrated cryoprecipitate preparations. Approximately 90% of patients with hemophilia A seroconverted after receiving factor replacement treatments in the late 1970s and early 1980s. By the time HIV was first identified as the causative agent of AIDS, and routine screening for HIV on blood products was implemented, a profound impact on the hemophiliac community had already occurred. Thorotrast (thorium dioxide 25%) is an intravenous radiologic contrast medium that was widely used between 1928 and 1955. Its

use was associated with the delayed development of hepatic angiosarcomas, as well as skeletal sarcomas, leukemia, and “thorotrastomas”—malignancies at the site of extravasated thorotrast.117,133 The use of thallium to treat innocuous ringworm infections in the 1920s and 1930s also led to needless morbidity and mortality.36 Understanding that thallium caused alopecia, dermatologists and other physicians prescribed thallium acetate, both as pills and as a topical ointment (Koremlu), to remove the infected hair. A 1934 study found 692 cases of thallium toxicity after oral and topical application and 31 deaths after oral use.87 Medicinal thallium was subsequently taken off the market. The “Stalinon affair” in France, in 1954, was another major toxicologic disaster that involved the unintentional contamination of a therapeutic agent. Stalinon was a proprietary oral medication that was marketed for the treatment of staphylococcal skin infections, osteomyelitis, and anthrax. Although it was supposed to contain diethyltin diiodide and linoleic acid, triethyltin, a potent neurotoxin and the most toxic of organotin compounds, and trimethyltin were present as impurities. Of the approximately 1000 people who received this medication, 217 patients developed symptoms, and 102 patients died.5,116 An unusual syndrome, featuring a constellation of abdominal symptoms (pain and diarrhea), followed by neurologic symptoms (peripheral neuropathy and visual disturbances including blindness), was experienced by approximately 10,000 Japanese between 1955 and 1970, resulting in several hundred deaths.61 This presentation, subsequently labeled subacute myelo-opticoneuropa-

28

CHAPTER 2

TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY

thy (SMON), was associated with the use of the gastrointestinal disinfectant clioquinol, known in the West as Entero-Vioform and most often used for the prevention of travelers’ diarrhea.90 In Japan, this drug was referred to as “sei-cho-zai” (“active in normalizing intestinal function”). It was incorporated into more than 100 nonprescription proprietary medications and was used by millions of people, often for weeks or months. The exact mechanism of toxicity has not been determined, but recent investigators theorize that clioquinol may enhance the cellular uptake of certain heavy metals, particularly zinc, and that the clioquinol-zinc chelate may act as a mitochondrial toxin causing this syndrome.3 New cases declined rapidly when clioquinol was banned in Japan. In 1981, a number of premature neonates died with a “gasping syndrome,” manifested by severe metabolic acidosis, respiratory depression with gasping, and encephalopathy.34 Prior to the development of these findings, they had all received multiple injections of heparinized bacteriostatic sodium chloride solution (to flush their indwelling catheters) and bacteriostatic water (to mix medications), both of which contained 0.9% benzyl alcohol. Accumulation of large amounts of benzyl alcohol and its metabolite benzoic acid in the blood was thought responsible for this syndrome.34 A previous nursery mass poisoning occurred in 1967, when nine neonates developed extreme diaphoresis, fever, and tachypnea, without rash or cyanosis. Two fatalities resulted, although the others responded dramatically to exchange transfusion. The illness was traced to sodium pentachlorophenate that had been used as an antimildew agent in the hospital laundry.97 In 1989 and 1990, eosinophilia-myalgia syndrome, a debilitating syndrome somewhat similar to toxic oil syndrome, developed in more than 1500 people who had taken the dietary supplement Ltryptophan.53,128 These patients presented with disabling myalgias and eosinophilia, often accompanied by extremity edema, dyspnea, and arthralgias. Skin changes, neuropathy, and weight loss sometimes developed. Intensive investigation revealed that all affected patients had ingested tryptophan produced by a single manufacturer, who had recently introduced a new process involving genetically altered bacteria to improve tryptophan production. A contaminant produced by this process probably is responsible for this syndrome.7 The banning of L-tryptophan by the FDA set in motion the passage of the Dietary Supplement Health and Educa-

TABLE 2–5.

tion Act of 1994 that facilitated industry marketing of dietary supplements bypassing FDA scrutiny. During the 1990s a growing number of therapeutic drugs, previously approved by the FDA, were withdrawn from the market because of concern about health risks. In a number of cases, the drugs that were withdrawn had been responsible for causing serious drug-drug interactions (astemizole, cisapride, mibefradil, terfenadine).86 Other drugs were withdrawn because of a propensity to cause hepatotoxicity (troglitazone), anaphylaxis (bromfenac sodium), valvular heart disease (fenfluramine, dexfenfluramine), and hemorrhagic stroke (phenylpropanolamine). One of the most disconcerting drug problems to arise was the development of cardiac valvulopathy and pulmonary hypertension in patients taking the weight loss drug combination fenfluramine and phentermine (fen-phen) or dexfenfluramine.17,112 The histopathologic features observed with this condition were similar to the valvular lesions associated with ergotamine and carcinoid. Interestingly, appetite suppressant medications, as well as ergotamine and carcinoid all increase available serotonin. While many of these withdrawals involved drugs that had only recently been approved, the withdrawal of phenylpropanolamine in 2000 removed an omnipresent over-the-counter agent that for several decades had continually been consumed as a component of many cough and cold remedies. Despite the accumulation over the years of increasing numbers of case reports and case series of medical problems associated with phenylpropanolamine use, drug production was only halted after a well-designed case-control study demonstrated that phenylpropanolamine use was an independent risk factor for hemorrhagic stroke.52

ALCOHOL AND ILLICIT DRUG DISASTERS Unintended toxic disasters have also resulted from the use of alcohol and other drugs of abuse (Table 2–5). Arsenical neuropathy developed in an estimated 40,000 people in France in 1828, when wine and bread were unintentionally contaminated by arsenious acid.75 The use of arsenic-contaminated sugar in the production of beer in England in 1900 resulted in at least 6000 cases of peripheral neuropathy and 70 deaths (Staffordshire beer epidemic).31

Alcohol and Illicit Drug Disasters

Toxin

Location

Date

Significance

Arsenic Triorthocresyl-phosphate Methanol Cobalt Methanol MPTP 3-Methyl fentanyl Methanol Fentanyl Methanol Methanol Scopolamine Methanol

Staffordshire, England US Atlanta, GA Quebec City, Canada Jackson, MI San Jose, CA Pittsburgh, PA Baroda, India New York, NY New Delhi, India Cuttack, India US East Coast Cambodia

1900 1930–1931 1951 1960s 1979 1982 1988 1989 1990 1991 1992 1995–1996 1998

Arsenic-contaminated sugar used in beer production Jamaica ginger paralysis Epidemic from ingesting bootleg whiskey Cobalt beer cardiomyopathy Occurred in a prison Drug-induced parkinsonism “China-white” epidemic Moonshine contamination; 100 deaths “Tango and Cash” epidemic Antidiarrheal medication contaminated with methanol; >200 deaths Methanol-tainted liquor; 162 deaths 325 cases of anticholinergic poisoning in heroin users >60 deaths

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Another toxin-induced disorder, also associated with beer drinking, involved the addition of cobalt, as a foam stabilizer, to several brands of beer in the 1960s. Certain local breweries in Quebec City, Canada, Minneapolis, Minnesota, Omaha, Nebraska, and Louvain, Belgium, added 0.5–5.5 ppm cobalt to their beer. This resulted in epidemics of fulminant heart failure among heavy beer drinkers in these locales (cobalt-beer cardiomyopathy).1,82 During the early 20th century, and particularly during prohibition, the ethanolic extract of Jamaican ginger (sold as “the Jake”) was a popular ethanol substitute in the southern and midwestern United States.81 It was sold legally because it was considered a medical supplement to treat headaches and aid digestion and was not subject to prohibition. For years, the Jake was sold adulterated with castor oil, but in 1930, as the price of castor oil rose, the Jake was reformulated with an alternative adulterant, triorthocresylphosphate (TOCP). Little was previously known about the toxicity of this compound, but TOCP proved to be a potent neurotoxin. At least 50,000 people who drank the Jake developed TOCP poisoning from 1930 to 1931, which was manifested by upper and lower extremity weakness (“ginger Jake paralysis”) and gait impairment (“Jake walk” or “Jake leg”).81 Thirty years later, in Morocco, the dilution of cooking oil with a turbojet lubricant containing TOCP caused an additional 10,000 cases of TOCP-induced paralysis.115 Epidemic methanol poisoning among those seeking ethanol and other inebriants has also been well described. In one such incident in Atlanta, in 1951, the ingestion of methanol-contaminated bootleg whiskey caused 323 cases of methanol poisoning, resulting in 41 deaths.8 In another epidemic in 1979, 46 prisoners became ill after ingesting a methanol-containing diluent used in photocopy machines.120 In recent years, major mass methanol poisonings have continued to occur in third-world countries where store-bought alcohol is often prohibitively expensive. In the eastern Indian city of Baroda, in 1989, at least 100 people died and another 200 became ill after drinking a homemade liquor that was contaminated with methanol.27 In New Delhi, India, in 1991, an inexpensive antidiarrheal medicine, advertised as containing large amounts of ethanol, was contaminated with methanol, and caused more than 200 deaths.16 The following year, in Cuttack, India, 162 people died and an additional 448 were hospitalized after drinking methanoltainted liquor.121 More recently, a major epidemic of methanol poisoning occurred in Cambodia, in 1998, when rice wine was contaminated with methanol.11 At least 60 deaths and 400 cases of illness were attributed to the methanol. Fomepizole was exported to Cambodia on an emergent basis to treat some of the victims. So-called “designer drugs” are responsible for several toxicologic disasters. In 1982, several intravenous drug abusers living in San Jose, California, who had been using meperidine analog MPPP (1-methyl-4-phenyl-4-propionoxy-piperidine), developed a peculiar irreversible neurologic disease closely resembling parkinsonism.64 Investigation revealed that these patients had unknowingly injected trace amounts of MPTP (1-methyl-4-phenyl1,2,3,6-tetrahydropyridine), present as an inadvertent product of the clandestine MPPP synthesis. The subsequent metabolism of MPTP to MPP+ resulted in a toxic moiety that selectively destroyed cells in the substantia nigra, causing severe irreversible parkinsonism. A result of the vigorous pursuit of the cause of this disaster was a better understanding of the pathophysiology of parkinsonism and the development of possible future treatment modalities.

29

Another example of a “designer-drug” mass poisoning occurred in the New York metropolitan area in 1991, when a sudden epidemic of opioid overdoses occurred among heroin abusers who bought envelopes labeled “Tango and Cash.”29 Expecting to receive a new brand of heroin, the drug abusers instead purchased the much more potent fentanyl. Increased toxicity from fentanyl resulted from the inability of the dealer to adjust (“cut”) the dose properly. Some purchasers presumably received little or no fentanyl, while others received potentially lethal doses. A similar epidemic involving 3-methylfentanyl occurred in Pittsburgh in 1988.73 At least 325 cases of anticholinergic poisoning occurred among heroin users in New York City, Newark, Philadelphia, and Baltimore from 1995 to 1996.107 The “street drug” used in these cases was contaminated with scopolamine. Whereas naloxone treatment was associated with increased agitation and hallucinations, physostigmine administration resulted in resolution of symptoms. Why the heroin was contaminated was unknown, although the use of an opiate-scopolamine mixture was reminiscent of the morphine/scopolamine combination therapy known as “twilight sleep” that was heavily used in obstetric anesthesia during the early 20th century.98 Another unexpected complication of heroin abuse was observed in the Netherlands in the 1980s, when 47 heroin abusers developed spongiform leukoencephalopathy, manifested by mutism and spastic quadriparesis.138 In these cases, as well as in subsequent cases in Europe and the United States, the users inhaled heroin vapors after the heroin powder had been heated on aluminum foil, a drug administration technique known as “chasing the dragon.”59,138 The exact toxic mechanism has not been elucidated.

OCCUPATIONAL TOXIN EPIDEMICS Unfortunately, occupation-related toxic epidemics have become increasingly common (Table 2–6). These poisoning syndromes tend to have an insidious onset and may not be recognized clinically until years after the exposure. A specific toxin may cause a myriad of problems; among the most worrisome being the carcinogenic and mutagenic potentials. While the 18th-century observations of Ramazzini and Pott introduced the concept that certain diseases were a direct result of toxic exposures in the workplace, it was not until the height of the 19th-century industrial revolution that the problems associated with the increasingly hazardous workplace became apparent.46 During the 1860s, a peculiar disorder, attributed to the effects of inhaling mercury vapor, was described among manufacturers of felt hats in New Jersey.134 Mercury nitrate was used as an essential part of the felting process at the time. “Hatter’s shakes” refers to the tremor that developed in an estimated 10–60% of hatters surveyed.134 Extreme shyness, another manifestation of mercurialism, was also seen in many hatters in later studies. Five percent of hatters during this period died from renal failure. Other notable 19th-century and early 20th-century occupational tragedies included an increased incidence of mandibular necrosis (phossy jaw) among workers in the match-making industry who were exposed to white phosphorus,44 an increased incidence of bladder tumors among synthetic dye makers who used
-naphthylamine,37 and an increased incidence of aplastic anemia

30

CHAPTER 2

TABLE 2–6.

TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY

Occupational Disasters

Toxin

Location

Date

Significance

Polycyclic aromatic hydrocarbons

England

1700s

Mercury White phosphorus β-Naphthylamine Benzene Asbestos Vinyl chloride

New Jersey Europe Worldwide Newark, New Jersey Worldwide Louisville, Kentucky

Mid- to late 1800s Mid- to late 1800s Early 1900s 1916–1928 20th century 1960s–1970s

Chlordecone

James River, Virginia

1973–1975

1,2-Dibromo-chloropropane

California

1974

High incidence of scrotal cancer among chimney sweeps; first description of occupational cancer Outbreak of mercurialism in hatters Phossy jaw in matchmakers Increased bladder cancer in dye makers Aplastic anemia among artificial leather manufacturers Millions at risk for asbestos-related disease Increased cases of hepatic angiosarcoma among polyvinyl chloride polymerization workers Increased incidence of neurologic abnormalities among insecticide workers Infertility among pesticide makers

among artificial leather manufacturers who used benzene.111 The epidemic of phossy jaw among match makers had an induction period of 5 years and a mortality rate of 20% and has been called the “greatest tragedy in the whole story of occupational disease.”14 The problem continued in the United States until Congress passed the White Phosphorus Match Act in 1912, which established a prohibitive tax on white phosphorus matches.89 Since antiquity, occupational lead poisoning has been a constant threat. Workplace exposure to lead was particularly problematic during the 19th century and early 20th century, because of the large number of industries that relied heavily on lead. One of the most notorious of the “lead trades” was the actual production of white lead and lead oxides. Palsies, encephalopathy, and death from severe poisoning were reported by Alice Hamilton from every worksite.40 Other occupations that entailed dangerous lead exposures included pottery glazing, rubber industry, pigment manufacturing, painting, printing, and plumbing.72 Given the increasing awareness of harm suffered in the workplace, the British Factory and Workshop Act was enacted in 1895, which required the notification of occupational diseases caused by lead, arsenic, and phosphorus poisoning, as well as of occupational diseases caused by anthrax.66 Exposure to asbestos during the 20th century has become one of the most consequential occupational and environmental disasters in recent memory.18,88 Despite the fact that the first case of asbestosis was reported in 1907, asbestos was heavily utilized in the shipbuilding industries in the 1940s as an insulating and fireproofing material. Since the early 1940s, 8–11 million individuals were

TABLE 2–7.

occupationally exposed to asbestos,68 including 4.5 million individuals who worked in the shipyards. Asbestos-related diseases include mesothelioma, lung cancer, and pulmonary fibrosis (asbestosis). A 3-fold excess of cancer deaths has been attributed to asbestos-exposed insulation workers, primarily as a consequence of excess lung cancer deaths.109 Other more recent occupational poisonings involve exposure to a variety of newly synthesized chemicals. In Louisville, Kentucky, in 1974, an increased incidence of angiosarcoma of the liver was first noticed among polyvinyl chloride polymerization workers who were exposed to vinyl chloride monomer.26 In 1975, chemical factory workers exposed to the organochlorine insecticide chlordecone (Kepone) experienced a high incidence of neurologic abnormalities, including tremor and chaotic eye movements.122 An increased incidence of infertility among male Californian pesticide workers exposed to dibromochloropropane (DBCP) was noted in 1977.135

ENVIRONMENTAL DISASTERS Although the incidence of significant human toxicity from dioxin (2,3,7,8-tetrachlorodibenzodioxin) and other similar polychlorinated compounds remains controversial, the lethality of this agent in an animal model has caused considerable concern for acute and latent injury from human exposure to this and other environmental toxins (Table 2–7). The release of a dioxin-containing chemical

Environmental and Radiation Disasters

Toxin

Location

Date

Significance

Radium Radium Radiation Dioxin Toxic waste Toxic waste Radiation Cesium Radiation Cyanide

Orange, New Jersey United States Hiroshima and Nagasaki, Japan Seveso, Italy Times Beach, Missouri Love Canal, New York Chernobyl, Belarus and Ukraine Goiania, Brazil Japan Romania

1910s–1920s 1920s 1945 1976 1975 1978 1986 1987 1999 2000

Increase in bone cancer in dial-painting workers “Radithor” (radioactive water) sold as radium-containing patent medication First atomic bombs dropped at end of WWII; clinical effects still evident today Unintentional release of dioxin into environment; chloracne Public alarmed by dioxin-containing toxic waste Further concern and intense debate regarding toxic waste Increase in childhood thyroid cancer; increase in other cancers anticipated Acute radiation sickness and radiation burns Nuclear event at a uranium processing plant; 2 deaths Cyanide contaminated Danube River, killing wildlife for hundreds of miles

CHAPTER 2

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cloud into the atmosphere from an explosion at a hexachlorophene production factory in Seveso, Italy, in 1976, resulted in one of the most serious exposures to dioxin.43 Chloracne was the only significant clinical finding related to the dioxin exposure at 5-year followup.110 Large-scale toxic disasters have also increased because of mass exposure to toxic waste dumps. Previously inhabited, but now deserted sites, such as Times Beach, Missouri, and Love Canal, New York, conjure up the very worst consequences of our toxic environment. Although little scientific evidence has been offered to confirm adverse health effects from the Love Canal toxic dump, this event directed attention to the problems of how best to deal with environmental poisons and their disposal.50,96 A recent environmental disaster, called the greatest environmental catastrophe since Chernobyl, occurred in February 2000, when a gold mine in western Romania disgorged 100,000 gallons of cyanide-contaminated water into the Tisza River.57 Within a few days the contaminated water flowed into the Danube River as well. The chemical spill eradicated all animal life for 250 miles along the rivers, resulting in 200 tons of dead fish. Adverse human health effects from this chemical spill were not reported.

RADIATION DISASTERS A discussion of mass poisonings is incomplete without mention of a growing number of radiation disasters that have occurred during the 20th century (Table 2–7). The first significant mass exposure to radiation occurred among several thousand teenage girls and young women employed in the dial-painting industry.15 These workers painted luminous numbers on watch and instrument dials with paint that contained radium. Exposure occurred by licking the paint brushes and inhaling radium-laden dust. Studies showed an increase in bone-related cancers, as well as aplastic anemia and leukemia, in exposed workers.74,99 At the time of the “watch” disaster, radium was also being sold as a nostrum touted to cure all sorts of ailments, including rheumatism, syphilis, multiple sclerosis, and sexual dysfunction. Referred to as “mild radium therapy,” in order to differentiate it from the higher-dose radium that was used in the treatment of cancer at that time, such -particle-emitting isotopes were hailed as a powerful natural elixir that acted as a metabolic catalyst by delivering direct energy transfusions.70 During the 1920s, dozens of patent medications contained small doses of radium and were sold as radioactive tablets, liniments, or liquids. One of the most infamous preparations was Radithor. Each half-ounce bottle contained slightly more than 1 µCi of radium 228 and radium 226. This radioactive water was sold all over the world “as harmless in every respect” and was heavily promoted as a sexual stimulant and aphrodisiac, taking on the glamour of a recreational drug for the wealthy.70 More than 400,000 bottles were sold. The 1932 death of a prominent socialite and Radithor connoisseur from chronic radiation poisoning drew increased public and governmental scrutiny to this unregulated radium industry and helped end the era of radioactive patent medications.70 Concerns about the health effects of radiation have continued to escalate since the dawn of the nuclear age in 1945. Long-term followup studies 50 years after the atomic bombings at Hiroshima and Nagasaki show an increased incidence of leukemia, other cancers, radiation cataracts, hyperparathyroidism, delayed growth and development, and chromosomal anomalies in exposed individuals.56

31

The unintentional nuclear disaster at Chernobyl, Ukraine, in April 1986, again forced us to confront the medical consequences of 20th-century scientific advances that brought us the atomic age.32 The release of radioactive material resulted in the hospitalization of more than 200 people for acute radiation sickness and 31 deaths. In some areas with heavy contamination, the increase in childhood thyroid cancer has increased 100-fold.103 In the long term, many more people will undoubtedly be affected, and the total number of Chernobyl-associated cancer cases is likely to be high. Another serious radiation event occurred in Goiania, Brazil, in 1987. When an abandoned radiotherapy unit was opened in a junkyard, 244 people were exposed to cesium-137. Of those people exposed to cesium-137, 104 showed evidence of internal contamination, 28 had local radiation injuries, and 8 developed acute radiation syndrome. There were at least 4 deaths.95,101 In September 1999, a nuclear event at a uranium processing plant in Japan set off an uncontrolled chain reaction exposing 49 people to radiation.25,60 Radiation measured outside the facility reached 4000 times the normal ambient level. Two workers died from the effects of the radiation.

MASS SUICIDE BY POISON Toxic disasters have also manifested themselves as events of mass suicide. In 1978, in Jonestown, Guyana, 911 members of the Peoples Temple died when they ingested a beverage to which cyanide had been added.38 Although the majority of these deaths may have been by suicide, some of them do not appear to have been voluntary.65 More recently, in 1997, phenobarbital and ethanol (sometimes assisted by physical asphyxiation) was the suicidal method favored by 39 members of the Heavens Gate cult in Rancho Santa Fe, California. This means of suicide was recommended in the book Final Exit.45 Apparently the cult members committed suicide in order to shed their bodies in hopes of hopping aboard an alien spaceship they believed was in the wake of Comet Hale-Bopp.63

SUMMARY Unfortunately, toxicologic plagues and disasters have had an all too prominent role in our history. An understanding of the pathogenesis of these toxic plagues (eg, issues pertaining to drug, food, and occupational safety) is critically important if future disasters are to be prevented. Given the practical and ethical limitations in studying the effects of many specific toxins in humans, lessons from these unfortunate tragedies must be fully mastered and retained for future generations.

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64. Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983;219:979–980. 65. Layton D: Seductive Poison: A Jonestown Survivor’s Story of Live and Death in the Peoples Temple. New York, Anchor, 1998. 66. Lee WR: The history of the statutory control of mercury poisoning in Great Britain. Brit J Indust Med 1968;25:52–62. 67. Leschke E: Clinical Toxicology: Modern Methods in the Diagnosis and Treatment of Poisoning. Baltimore, William Wood, 1934. 68. Levin SM, Kann PE, Lax MB: Medical examination for asbestosrelated disease. Am J Indust Med 2000;37:6–22. 69. Logan WPD: Mortality in the London fog incident, 1952. Lancet 1953;1:336–338. 70. Macklis RM: Radithor and the era of mild radium therapy. JAMA 1990;262:614–618. 71. Magnuson E: The devil made him do it. Time, April 9, 1990, p. 38. 72. Markowitz G, Rosner D: “Cater to the children”: The role of the lead industry in a public health tragedy, 1900–1955. Am J Pub Health 2000:90:36–46. 73. Martin M, Hecker J, Clark R, et al: China white epidemic: An eastern United States emergency department experience. Ann Emerg Med 1991;20:158–164. 74. Martland HS: Occupational poisoning in manufacture of luminous watch dials. JAMA 1929;92:466-473, 552–559. 75. Massey EW, Wold D, Heyman A: Arsenic: Homicidal intoxication. South Med J 1984;77:848–851. 76. Matossian MK: Ergot and the Salem witchcraft affair. Am Sci 1982; 70:355–357. 77. McFadyen RE: Thalidomide in America: A brush with tragedy. Clin Med 1976;11:79–93. 78. Mehta PS, Mehta AS, Mehta SJ, Makjijani AB: Bhopal tragedy’s health effects: A review of methyl isocyanate toxicity. JAMA 1990; 264:2781–2787. 79. Merhoff GC, Porter JM: Ergot intoxication: Historical review and description of unusual clinical manifestations. Ann Surg 1974;180: 773–779. 80. Modell W: Mass drug catastrophes and the roles of science and technology. Science 1967;156:346–351. 81. Morgan JP: The Jamaica ginger paralysis. JAMA 1982;248: 1864–1867. 82. Morin YL, Foley AR, Martineau G, Roussel J: Quebec beerdrinkers’ cardiomyopathy: Forty-eight cases. Can Med Assoc J 1967;97:881–883. 83. Morita H, Yanagisawa N, Nakajima T, et al: Sarin poisoning in Matsumoto, Japan. Lancet 1995;346:290–293. 84. Mudur G: Arsenic poisons 220,000 in India. BMJ 1996;313:9. 85. Mudur G: Half of Bangladesh population at risk of arsenic poisoning [news]. BMJ 2000;320:822. 86. Mullins ME, Horowitz BZ, Linden DHJ, et al: Life-threatening interaction of mibefradil and beta blockers with dihydropyridine calcium channel blockers. JAMA 1998;280;157–158. 87. Munch JC: Human thallotoxicosis. JAMA 1934;102:1929–1934. 88. Murray R: Asbestos: A chronology of its origins and health effects. Br J Indust Med 1990;47:361–365. 89. Myers ML, McGlothin JD: Matchmakers “phossy jaw” eradicated. AIHAJ 1996;57:330–332. 90. Nakae K, Yamamoto A, Shigematsu I, et al: Relation between subacute myelo-optic neuropathy (S.M.O.M.) and clioquinol: Nationwide survey. Lancet 1973;1;171–173. 91. Nakajima T, Ohta S, Morita H, et al: Epidemiological study of sarin poisoning in Matsumoto City, Japan. J Epidemiol 1998;8:33–41. 92. Nemery B, Fischler B, Boogaerts M, Lison D: Dioxins, Coca-Cola, and mass sociogenic illness in Belgium [letter]. Lancet 1999;354:77. 93. O’Brien KL, Selanikio JD, Heedivert C, for the Acute Renal Failure Investigation Team: Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. JAMA 1998;279: 1175–1180.

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94. Okumura T, Takasu N, Ishimatsu S, et al: Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med 1996;28:129–135. 95. Oliveira AR, Hunt JG, Valverde NJL, et al: Medical and related aspects of the Goiania accident: An overview. Health Physics 1991; 60:17–24. 96. Paigen B: Controversy at Love Canal. Hastings Cent Rep 1982; 12:29–37. 97. Pentachlorophenol poisoning in newborn infants—St Louis Missouri, April-August 1967. MMWR Morb Mortal Wkly Rep 1996; 45:545–549. 98. Pitcock CD, Clark RB: From Fanny to Fernand: The development of consumerism in pain control during the birth process. Am J Obstet Gynecol 1992;167:581–587. 99. Polednak AP, Stehney AF, Rowland RE: Mortality among women first employed before 1930 in the U.S. radium dial-painting industry. Am J Epidemiol 1978;107:179–195. 100. Powell PP: Minimata disease: A story of mercury’s malevolence. South Med J 1991;84:1352–1358. 101. Roberts L: Radiation accident grips Goiania. Science 1987;238: 1028–1031. 102. Roses OE, Fernandez JCG, Villaamil ED, et al: Mass poisoning by sodium arsenite. J Toxicol Clin Toxicol 1991;29:209–213. 103. Rytomaa T: Ten years after Chernobyl. Ann Med 1996;28:83–87. 104. Sawyer WA, Meyer KF, Eaton MD, et al: Jaundice in army personnel in the western region of the United Sates and its relation to vaccination against yellow fever. Am J Hygiene 1944;39:337–432. 105. Scalzo AJ: Diethylene glycol toxicity revisited: The 1996 Haitian epidemic. J Toxicol Clin Toxicol 1996;34:513–516. 106. Schmid R: Cutaneous porphyria in Turkey. N Engl J Med 1960;263: 397–398. 107. Scopolamine poisoning among heroin users—New York City, Newark, Philadelphia, and Baltimore, 1995 and 1996. MMWR Morb Mortal Wkly Rep 1996;45:457–460. 108. Selected Cancers Cooperative Study Group: The association of selected cancers with service in the U.S. military in Vietnam, I: nonHodgkin’s lymphoma. Arch Intern Med 1990;150:2473–2483. 109. Selikoff IJ, Hammond EC, Seidman H: Mortality experience of insulation workers in the United States and Canada, 1943–1976. Ann N Y Acad Sci 1979;330:91–116. 110. Seveso after five years. Lancet 1981;2:731–732. 111. Sharpe WD: Benzene, artifical leather and aplastic anemia: Newark, 1916–1928. Bull N Y Acad Med 1993;69:47–60. 112. Shively BK, Roldan CA, Gill EA, et al: Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine. Circulation 1999;100:2161–2167. 113. Sidell FR, Takafuji ET, Franz DR, eds: Medical Aspects of Chemical and Biological Warfare. Washington, DC, Office of the Surgeon General, 1997. 114. Sidell FR: Chemical agent terrorism. Ann Emerg Med 1996;28: 223–224. 115. Smith HV, Spalding JM: Outbreak of paralysis in Morocco due to ortho-cresyl phosphate poisoning. Lancet 1959;2:1019–1021. 116. Stalinon: A therapeutic disaster. Br Med J 1958;1:515. 117. Stover BJ: Effects of thorotrast in humans. Health Physics 1983; 44(S1):253–257. 118. Subramanian KS, Kosnett MJ: Human exposures to arsenic from consumption of well water in West Bengal, India. Int J Occup Environ Health 1998;4:217–230. 119. Swann JP: The 1941 sulfathiazole disaster and the birth of good manufacturing practices. PDA J Pharm Sci Technol 1999;53: 148–153. 120. Swartz RD, Millman RP, Billi JE, et al: Epidemic methanol poisoning: Clinical and biochemical analysis of a recent episode. Medicine (Baltimore) 1981;60:373–382. 121. Tainted liquor kills 162, sickens 228. Los Angeles Times, May 10, 1992. 122. Taylor JR, Selhorst JB, Houff SA, Martinez AJ: Chlordecone intoxication in man. Neurology 1978;28:626–630.

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123. Toxic Epidemic Syndrome Study Group: Toxic epidemic syndrome, Spain, 1981. Lancet 1982;2:697–702. 124. Tsuchiya K: The discovery of the causal agent of Minamata disease. Am J Indust Med 1992;21:275–280. 125. Unwin C, Blatchley N, Coker W, et al: Health of UK servicemen who served in Persian Gulf War. Lancet 1999;353:169–178. 126. Urbinato D: London’s historic “pea-soupers.” EPA J 1994, p. 59 (Summer). 127. Van Loock F, Gallay A, Demarest S, et al: Outbreak of Coca-Colarelated illness in Belgium: A true association [letter]. Lancet 1999; 354:680–681. 128. Vargas J, Uitto J, Jimenez SA: The cause and pathogenesis of the eosinophilia-myalgia syndrome. Ann Intern Med 1992;116:140–147. 129. Varma DR, Guest I: The Bhopal accident and methyl isocyanate toxicity. J Toxicol Environ Health 1993;40:513–529. 130. Waldron HA: The Devonshire colic. J Hist Med 1970;25:383-413. 131. Wax PM: Elixirs, diluents and the passage of the 1938 federal Food, Drug and Cosmetic Act. Ann Intern Med 1995;122:456–461.

132. Wax PM: It’s happening again—another diethylene glycol mass poisoning. J Toxicol Clin Toxicol 1996;34:513–516. 133. Weber E, Laarbai F, Michel L, Donckier J: Abdominal pain: Do not forget Thorotrast! Postgrad Med J 1995;7:367–369. 134. Wedeen RP: Were the hatters of New Jersey “mad?” Am J Indust Med 1989;16:225–233. 135. Whorton MD, Krauss RM, Marshall S, Milby TH: Infertility in male pesticide workers. Lancet 1977;2:1259–1261. 136. Wing JS, Sanderson LM, Brender JD, et al: Acute health effects in a community after a release of hydrofluoric acid. Arch Environ Health 1991;46:155–160. 137. Wolff MS, Anderson HA, Selikoff IJ: Human tissue burdens of halogenated aromatic chemicals in Michigan. JAMA 1982;247: 2112–2116. 138. Wolters ED, van Wijngaarden GK, Stam FC: Leucoencephalopathy after inhaling “heroin” pyrolysate. Lancet 1982;2:1233–1237.

PART

GENERAL APPROACH TO MEDICAL TOXICOLOGY

A

CHAPTER

3

PRINCIPLES OF MANAGING THE POISONED OR OVERDOSED PATIENT:AN OVERVIEW Lewis R. Goldfrank / Neal E. Flomenbaum / Neal A. Lewin / Mary Ann Howland / Robert S. Hoffman / Lewis S. Nelson

While focusing on probable or possible toxicologic etiologies, nontoxicologic conditions that may have similar presentations must be excluded. The physical examination, therefore, should include a careful search for any external signs of head, neck, or blunt abdominal trauma; abnormal or focal neurologic findings; abnormal pupillary responses; unusual breath or skin odors (Table 28–1); abnormal respiratory or cardiac sounds; as well as toxicologic syndromes or “toxidromes.” Toxicologic etiologies of abnormal vital signs and physical findings are summarized in Tables 17–1 to 17–7. Toxidromes are summarized in Table 17–2 and other details of the physical assessment are provided in Chapter 31. With stabilization of the patient’s condition, attention can be addressed to the issues of gastrointestinal decontamination. A detailed discussion of these issues is found in Chapter 5. The indications, contraindications, precautions, and adverse effects associated with orogastric lavage, whole-bowel irrigation, administration of single- or multiple-dose activated charcoal, (MDAC), cathartics, and (in the conscious patient) emesis utilizing syrup of ipecac are summarized in Tables 31–1 to 31–5. Fully referenced descriptions of whole-bowel irrigation, activated charcoal, cathartics, and syrup of ipecac may be found in the respective Antidotes in Depth sections immediately following Chapter 31. At the next stage in the management of a poisoned or overdosed patient, it is appropriate to consider various methods of eliminating absorbed toxins. Currently, available methods range from raising urinary pH (also known as “ion trapping”) and MDAC to hemodialysis, hemoperfusion, hemofiltration, and exchange transfusion. All are described in Chapter 6. Although the vast majority of toxicologic emergencies result from ingestion, injection, or inhalation, the eyes and skin are occasionally the route of systemic absorption or are the organs at risk. The management of toxic cutaneous and ophthalmic exposures are described along with a more detailed management approach to the unknown or suspected overdose in Chapters 27, 29, and 31. Typically, in managing patients with toxicologic emergencies, there is both a necessity and an opportunity to obtain various diagnostic studies and ancillary tests interspersed with stabilizing the patient’s condition (when establishing intravenous access, for example), obtaining the history, and performing the physical examination. Chapters 7 through 9 discuss the timing and indications for qualitative and quantitative diagnostic laboratory studies, the use and interpretation of the electrocardiogram, and radiologic and imaging procedures in diagnosing and managing the poisoned or overdosed patient. A recommended stock list of antidotes and therapeutic agents for the treatment of poisonings and overdoses appears in Table 3–1.

For almost four decades, medical toxicologists and information specialists at poison centers have utilized a clinical approach to the poisoned or overdosed patient that emphasizes treating the patient rather than treating the poison. Too often in the past, patients were initially all but neglected while attention was focused on the list of ingredients on the container of the product(s). Although the astute clinician must always be prepared to administer a specific antidote immediately in those uncommon instances when nothing else will save a patient, all poisoned or overdosed patients will benefit from an organized, rapid clinical management plan (Fig. 3–1). The initial management of all seriously ill patients begins with attention to the ABCs: airway compromise, breathing difficulties, and circulatory problems. When a patient’s mental status is abnormal, metabolic derangements, such as glucose and electrolyte abnormalities, and the possibilities of head and cervical spine trauma must be considered. In such cases, the cervical spine may need to be protected until injury can either be excluded or diagnosed and treated. The bedside assessment of the adequacy of respirations (frequency and depth) and a decision on the necessity of early intubation is followed by a determination of all of the vital signs and identification and treatment of life-threatening conditions such as hypotension, hypertension, bradycardia, tachycardia, dysrhythmias, hyperthermia, and hypothermia (Chap. 17). Accurate identification and treatment of conduction disturbances and dysrhythmias necessitate obtaining a 12-lead ECG and cardiac monitoring (Chap. 9). Similarly, an arterial blood gas analysis may be indicated to more accurately assess ventilation, oxygenation, some toxic-metabolic etiologies of altered mental status such as a wide anion gap metabolic acidosis, and, when appropriate, carbon monoxide poisoning (by cooximetry). With the initiation of an IV infusion, blood samples can also be sent as indicated. If the patient has an altered mental status, there may be specific indications to test for CNS depressants and/or “drugs of abuse,” but these tests rarely provide useful information. For the potentially suicidal patient, an acetaminophen level should routinely be requested along with tests affecting the management of any specific drug or toxin such as lithium, theophylline, iron, salicylates, and digoxin, as suggested by the history, physical examination, or bedside diagnostic tests. Early treatment of a patient with a suspected toxicologic exposure and an altered mental status should typically include consideration or administration of (a) hypertonic dextrose, 0.5–1.0 g/kg as D50W for an adult or D10–20W for a child; (b) thiamine, 100 mg IV for an adult; (c) naloxone, 0.4–2 mg IV bolus for adults and children with respiratory compromise; and (d) oxygen, 100% at 8–10 L/min. Dextrose administration should be omitted when hypoglycemia can be definitely excluded, but hypoglycemia may be the sole or contributing cause of coma even when the patient manifests focal findings.

37

Is the patient having difficulty breathing? Yes

No

Obtain control of the airway, ventilation, and oxygenation while stabilizing the cervical spine

Assess and stabilize the cervical spine if indicated

Obtain vital signs; are life-threatening abnormalities present? Yes 1. 2. 3. 4.

No

Attach the patient to a cardiac monitor, obtain a 12-lead ECG Obtain an ABG and give supplemental oxygen if not already done Start an intravenous line Send blood for glucose, electrolytes, and save blood for other studies

Consider empiric administration of: 1. Hypertonic dextrose 2. Thiamine 3. Naloxone

Consider the use of emergent therapies for seizures, significant psychomotor agitation, cardiac dysrhythmias, or severe metabolic abnormalities

Perform a rapid physical examination

Can a specific toxidrome be identified? Yes

No

Treat the toxidrome

Obtain a thorough history Reassess and complete the physical examination Send bloods: electrolytes, glucose, CBC, ABG, acetaminophen, as indicated Obtain an ECG if not already done

Consider gastric emptying: 1. Emesis with syrup of ipecac 2. Orogastric lavage

Consider prevention of toxin absorption: 1. Activated charcoal 2. Cathartic 3. Whole-bowel irrigation

Evaluate for enhanced elimination: 1. Multiple-dose activated charcoal 2. Ion trapping 3. Extracorporeal drug removal

Evaluate for ICU admission, continued emergency department management, psychiatric status, and social services needs prior to discharge, as indicated

Figure 3–1. This algorithm is a basic guide to management of poisoned patients. A more detailed description of the steps in management may be found in the accompanying text and in Chapter 31. This algorithm is only a guide to actual management, which must, of course, consider the patient’s clinical status.

38

CHAPTER 3

TABLE 3–1.

PRINCIPLES OF MANAGING THE POISONED OR OVERDOSED PATIENT: AN OVERVIEW

39

Antidotes and Therapeutic Agents for the Treatment of Poisonings and Overdoses*

Therapeutic Agent**

Uses

Activated charcoal (p. 469) Antivenom (Crotalinae) (p. 1568) Polyvalent Antivenom (Latrodectus mactans) (p. 1589) Antivenom (Elapidae) (p. 1568) Atropine (p. 1353)

Adsorbs toxin or drug in GI tract Crotaline snake envenomations Black widow spider envenomations Coral snake envenomations Bradydysrhythmias, cholinesterase inhibitors (organic phosphorus agents, physostigmine) poisonings, muscarinic mushrooms (Clitocybe, Inocybe) ingestions Botulism (available from local health department or Centers for Disease Control) Oxalates, fluoride, hydrofluoric acid, ethylene glycol, calcium channel blockers, hypomagnesemia,
-adrenergic antagonists Valproic acid Cyanide poisoning Iron ingestions Hypoglycemia due to a variety of agents, to Dx or Rx patients with altered mental status Seizures, severe agitation, stimulants, sedative-hyponotic withdrawal Digoxin, digitoxin, and digoxin-like cardiac glycosides of any origin (pharmaceuticals, plants, animals) Arsenic, mercury, gold, and lead poisoning Extrapyramidal drug reactions, allergic reactions Lead, and other selected metal poisonings

Botulinum antitoxin (ABE-Trivalent) (p. 1112) Calcium chloride, calcium gluconate (p. 1341) Carnitine (p. 621) Cyanide kit (amyl nitrite, sodium nitrite, sodium thiosulfate) (p. 1511) Deferoxamine mesylate (Desferal) (p. 558) Dextrose in water (50% adults; 20% pediatrics; 10% neonates) (p. 606) Diazepam (Valium) or lorazepam (Ativan) (p. 1011) Digoxin-specific antibody fragments (Digibind) (p. 735) Dimercaprol (BAL, British Anti-Lewisite) (p. 1196) Diphenhydramine (p. 879) Edetate calcium disodium (Calcium disodium versenate, CaNa2 EDTA) (p. 1235) Ethanol oral and parenteral dosage forms (p. 995) Flumazenil (Romazicon) (p. 946) Folinic acid (p. 991) Fomepizole (Antizole) (p. 999) Glucagon (p. 758) Ipecac, syrup of (p. 465) Magnesium sulfate or magnesium citrate (p. 475) Magnesium sulfate injection (p. 732) Methylene blue (1% solution) (p. 1450) N-Acetylcysteine (Mucomyst) (p. 502) Naloxone hydrochloride (Narcan) (p. 924) Norepinephrine (Levarterenol) (p. 858) Octreotide (Sandostatin) (p. 611) Oxygen (oxygen, hyperbaric) (p. 1492) D-Penicillamine (Cuprimine) (p. 1268) Phenobarbital (p. 1063) Phentolamine (p. 1011) Physostigmine salicylate (Antilirium) (p. 544) Polyethylene glycol electrolyte solution (p. 478) Pralidoxime chloride (2-PAM-chloride) (Protopam) (p. 1361) Protamine sulfate (p. 651) Pyridoxine hydrochloride (Vitamin B6) (p. 667) Sodium bicarbonate (p. 519)

Sorbitol (p. 475) Starch (p. 1285) Succimer (Chemet) (p. 1228) Thiamine hydrochloride (p. 966) Vitamin K1 (Aquamephyton) (p. 647)

Methanol and ethylene glycol poisoning Pure benzodiazepine poisoning in a non-benzodiazepine-dependent patient Methotrexate toxicity, methanol poisoning Ethylene glycol, methanol poisoning β-adrenergic antagonist and calcium channel blocker overdoses Induces emesis Induces catharsis Cardiac glycoside overdoses, hydrofluoric acid exposures, hypomagnesemia, ethanol withdrawal, torsades de pointes Methemoglobinemia Acetaminophen overdoses, and other causes of liver failure Opioid overdoses, clonidine overdoses Hypotension (preferred for cyclic antidepressants), α-adrenergic antagonist overdoses Oral hypoglycemic agent-induced hypoglycemia Carbon monoxide, cyanide, hydrogen sulfide poisoning Copper, lead poisoning Seizures, agitation, stimulants, sedative-hypnotic withdrawal MAOI interactions; cocaine; epinephrine and ergot alkaloid overdoses Anticholinergic toxicity Decontaminates GI tract Acetylcholinesterase inhibitor (organic phosphorus agents and carbamates) poisoning Heparin anticoagulation (agent reverses anticoagulation) Ethylene glycol poisoning, isoniazid overdoses, gyromitrin-containing mushroom ingestions Ethylene glycol and methanol poisoning; salicylate, cyclic antidepressant, methotrexate, phenobarbital, quinidine, and chlorpropamide overdoses, drugs with type I antidysrhythmic toxicity; chlorphenoxy herbicide poisoning Induces catharsis Iodine poisoning Lead, mercury, arsenic poisoning Thiamine deficiency, ethylene glycol poisoning, chronic ethanol consumption (“alcoholism”) Warfarin or rodenticide anticoagulant

*Each emergency department should have all the above agents readily available to its staff. Some of these antidotes may be stored in the pharmacy, and others may be available from the Centers for Disease Control and Prevention, but the precise mechanism for locating each one must be known by each staff member. **A detailed analysis of each of these agents is found in the text, in the Antidotes in Depth section on the page cited to the right of each therapeutic agent listed.

CHAPTER

4

PRINCIPLES AND TECHNIQUES TO IDENTIFY THE NONTOXIC EXPOSURE Richard Weisman

A large number of calls received by physicians and poison centers throughout the United States are for nontoxic exposures. During the past 5 years, greater than 40% of the exposures reported to the American Association of Poison Centers were judged by poison information specialists to be nontoxic exposures (Chap. 116 has further details). One of the most important skills that an emergency physician, poison information specialist, or medical toxicologist can develop is the ability to identify and appropriately triage exposures that are not likely to result in toxicity. This may prevent an unnecessary visit to the emergency department (or physician’s office), or if the patient is in the emergency department, it may prevent unnecessary testing. Allowing patients with nontoxic exposures to be evaluated, observed, and followed up outside of the emergency department or physician’s private office is cost effective, and a major justification for governmental funding for poison centers. Poison centers also render a substantial public health service in that they relieve the overcrowding common to many large inner-city emergency departments by keeping patients at home who do not require medical evaluation or interventions. The patient with a potentially nontoxic exposure who telephones an emergency department, paramedic base station, or a poison center requires extensive evaluation by a healthcare provider with specialized training in toxicology. The analysis of nontoxic exposures can be divided into two major categories. The first and least problematic category is an exposure to products unlikely to result in toxicity at any dose by a particular route of administration. In such a situation, the physician or poison information specialist must only establish, by history, an absolute identity of the product and the route of administration. A product that is harmless at any dose by a particular route of exposure may nevertheless be toxic by another route. For example, pure talcum powder never causes a problem when applied dermally. If, however, during intentional ingestion or substantial inhalation the patient aspirates the powder, severe pulmonary complications or death may occur.9 The second type of nontoxic exposure is exposure to a nontoxic quantity of a product that is potentially toxic, for example, a patient with a 50-mg/kg exposure to acetaminophen.11

fore an exposure should be considered nontoxic, all of the criteria discussed below and listed in Table 4–1 should be met.6–8

WHEN CAN AN EXPOSURE BE CONSIDERED NONTOXIC?

4.

PRODUCT IDENTIFICATION For an exposure to be categorized as nontoxic, the product must be absolutely and completely identified. The product name, manufacturer, ingredients, quantities, concentrations, and production date are all essential in assessing the toxicity of the product. Manufacturers often change product ingredients (both active and inactive) without changing the product name. If there are any inconsistencies or missing information in the patient’s exposure history, the ingestion cannot be classified as nontoxic. Patients often transfer medications into different containers. When unexplained symptoms occur, a manufacturing or labeling error or product tampering must be considered. In 1996, more than 70 Haitian children developed acute renal failure and neurologic toxicity when diethylene glycol was used instead of propylene glycol as the vehicle in acetaminophen syrup.13

SINGLE-PRODUCT EXPOSURE Usually, for an exposure to be considered nontoxic, only a single product should be involved. Often, exposure to two nontoxic products will also be nontoxic. Synergistic or additional toxicity and/or toxic interactions may occur if multiple substances are involved and additional care must therefore be used in trying to assess this type of exposure. Nontoxic amounts of aspirin, ibuprofen, and iron ingested together would likely result in gastrointestinal toxicity. When evaluating patients who have ingested multiple substances, the most prudent plan is for the patient to be examined at either the TABLE 4–1. General Guidelines for an Exposure to be Considered Nontoxic 1. 2. 3.

5.

An exposure is considered nontoxic when a sufficient history regarding the exposure can be obtained, when the information is considered reliable, and when the exposure would still be considered nontoxic if the quantity was significantly underestimated. Be-

6. 7. 8.

40

Identification of the product and its ingredients is possible. Usually only one product is involved with the exposure. The exposure was unintentional. The patient is not suicidal or the victim of abuse or neglect. The CPSC “signal words” CAUTION, WARNING, or DANGER do not appear on the product label. The history permits a reliable approximation of the quantity involved with the exposure. The history permits the routes of exposure to be determined. The patient is asymptomatic. Followup consultation with the patient or care provider is possible.

CHAPTER 4

PRINCIPLES AND TECHNIQUES TO IDENTIFY THE NONTOXIC EXPOSURE

physician’s office or at an emergency department. Unintentional exposures, particularly in children, typically involve small amounts of a single product. Concurrent exposure to multiple products should alert the physician to the possibility of an intentional ingestion, abuse, or neglect.6,12 An ingestion that is not the patient’s first “unintentional” poisoning may be a clue to a psychiatric disorder in the case of a child or a compromised adult, or to neglect or abuse.

UNINTENTIONAL EXPOSURE An adult who has intentionally ingested a drug or toxin almost always requires evaluation in a healthcare facility. With the exception of therapeutic errors and mistakes from confusion, or mental, linguistic, or visual impairment, most ingestions in adults result from misuse, abuse, or suicidal intent. Identifying over the telephone adults who may require psychiatric or social interventions is not possible. Unintentional toxic exposures in adults may result from therapeutic errors and drug interactions, occupational or environmental exposures, and food poisonings. Suicidal ingestions and ingestions by drug and alcohol users comprise the largest proportion (>90%) of intentional exposures. Both groups of patients may be difficult to adequately assess over the telephone; they give the least-accurate histories and are most likely to have a life-threatening exposure. Every effort should be made to expedite their transfer to a healthcare facility capable of providing medical, psychiatric, and social assistance. The emergency physician should be extremely reluctant to categorize an adult exposure as unintentional and nontoxic without a complete evaluation.

CONSUMER PRODUCT SAFETY COMMISSION SIGNAL WORDS To be considered a nontoxic exposure, the product label must not contain a Consumer Product Safety Commission “signal word. ” These signal words include Caution, Warning, and Danger.1 Patients who have been exposed to a product containing a signal word require assessment by a healthcare provider knowledgeable in toxicology and capable of providing both basic and advanced poison management.

AMOUNT OF EXPOSURE A reliable approximation of the amount of product or toxin ingested must be possible in order to establish whether an exposure is nontoxic. The detail required in the history of the amount ingested is directly related to the potential toxicity of the product. A much more precise history will be required for the patient who unintentionally ingests digoxin tablets than for the patient who unintentionally ingests oral contraceptives. The margin of error acceptable in quantifying the amount ingested is inversely related to the toxicity of the product. Several logical conclusions can be reached from the magnitude of the ingestion: The patient who ingests 4 ounces of automotive motor oil may require psychiatric evaluation and counseling, whereas the patient who unintentionally takes a sip of the same motor oil may not require any care.

41

Although the 4-ounce ingestion will probably not result in significantly greater toxicity than the sip, one is unintentional and the other may be representative of either a grave psychiatric impairment or of suicidal intent. The likelihood is also greater that other substances have been concurrently ingested with the larger ingestion. The larger ingestion requires referral to an emergency department or healthcare facility for immediate evaluation, including psychiatric assessment. Little, if any, poison management would be required for either ingestion unless aspiration occurred. If it can be established that an ingestion is unintentional, the amount ingested can often be used to calculate the nontoxic nature of the exposure. For example, if a 3-year-old (15-kg) child drank liquid acetaminophen (160 mg/5 mL) from a bottle containing 60 mL, an accurate analysis can be made of the maximum possible exposure based upon knowledge of the quantity of acetaminophen remaining.10 In this example, knowing that 30 mL remains of a 60 mL bottle containing 32 mg/mL of acetaminophen enables the healthcare provider to determine that a total of 960 mg of acetaminophen was ingested. A dose-per-body-weight-exposure calculation (mg/kg) enables the determination of an ingestion of 64 mg/kg of acetaminophen. Because the toxicity data for acetaminophen poisonings predict that an acute ingestion of less than 150 mg/kg is not associated with hepatotoxicity,11 the clinician can confidently categorize this ingestion as nontoxic. To ensure that no toxicity ensues, it is also necessary to determine that the child has not received any other acetaminophen during the previous 12–24 hours. If these questions can be answered with confidence, the administration of activated charcoal would not be necessary, nor would a visit to a healthcare facility for an acetaminophen blood level be necessary. The child would have had to ingest approximately 2.5 times the amount reported by history to reach the predicted threshold for hepatotoxicity. The clinician’s or poison information specialist’s only intervention should be to counsel the child’s parents about the basic skills necessary to poison-proof the child’s environment. The assessment of an exposure or ingestion cannot be quantitative when two children simultaneously share exposure to a toxin. It is also difficult to assess the actual amount ingested when a large amount of a liquid product has been partially ingested and partially spilled on or around the child. In both of these situations, the only safe approach is to develop a worstcase scenario. When it is possible to determine exactly how much of the product is unaccounted for, it is necessary to assume that each child ingested the entire amount that is missing. In the situation in which a product has been partially spilled and partially ingested, it is again necessary to assume that the entire missing amount was ingested. It is extremely difficult to estimate how much liquid the child’s clothing absorbed or how much liquid is present in a puddle on the bathroom or kitchen floor. If the product is well absorbed through the skin, the contribution it may play in a combined ingestion and dermal exposure is impossible to predict. The problem can be further complicated if the product contains highly volatile substances such as acetone, ethyl acetate, or ethyl or isopropyl alcohol, which may lead to toxicity not only by gastric absorption, but also by dermal absorption and inhalation.4 In summary, if an accurate estimate of the amount of the ingestion cannot be established, the prudent approach is to assume the worst-case scenario and to provide a higher level of care and surveillance than might initially appear necessary.

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ROUTE OF EXPOSURE The route(s) of exposure can often be accurately assessed from the available history. Determination of the amount of toxicity that is likely to occur from an exposure is largely dependent on how the patient was exposed.5 Household products such as bleach, laundry detergents, ammonia, or rubber cement are generally nontoxic following a dermal exposure, minimally toxic following an oral exposure, but can cause considerable morbidity following inhalation or upon ophthalmic exposure. As in the case of most other products, if such household products are aspirated, the consequences may be significant. A routine part of assessing a patient for a nontoxic exposure should include careful questioning to exclude the possibility of multiple routes of exposure.

AN ABSENCE OF CLINICAL EFFECTS The presence of symptoms (related to the exposure) is a clue that some toxic effect is occurring and that further assessment may be warranted. If symptoms are present, the exposure cannot be considered nontoxic, but this does not necessarily mean that a patient must be evaluated in a healthcare facility. If the symptoms are minor in severity and unlikely to result in further illness or complications, further medical evaluation may not be needed. The ingestion of products such as household bleach (2–5% sodium hypochlorite) is usually not associated with significant toxicity such as burns of the skin, oropharynx, or esophagus.3 Following an ingestion of household bleach, the patient should not have pain, dysphagia, drooling, or dyspnea (Chap. 87), but it is common for a patient to vomit once following the ingestion of household bleach. If the child continues to vomit or shows any involvement of the respiratory tract such as coughing, shortness of breath, or any other difficulty in breathing, immediate medical care is needed. If the caller cannot reliably perform this assessment, the patient should be evaluated in an emergency department or by a physician.

FOLLOWUP CONSULTATION Most triage decisions are based on the premise that followup consultation is possible and that the parent or guardian is reliable. Care must be taken in establishing that an exposure is nontoxic or minimally toxic. There is always the possibility that an error in judgment can occur. The option of care in the home is only possible if the poison center, physician’s office, or emergency department is capable of making a followup call to ascertain that the victim has remained asymptomatic or that minor symptoms are resolving. A parent, guardian, or other responsible adult (not the victim) must be capable of recontacting the healthcare provider when there is either a change in the history or a change in the patient’s clinical condition. At the time of the initial contact, it is extremely important to assess the reliability and capacity to understand and comply with the directions needed to monitor the exposed individual. Whenever a failure in communications occurs, or when there is a high probability of a communications breakdown, the patient should be brought into the healthcare environment. A list of household items that generally do not result in toxicity appears in Table 4–2.2 The list specifically applies to oral exposures, not to ophthalmic, cutaneous, or inhalational exposures.

TABLE 4–2. Household Items Generally Regarded as Nontoxic Following Oral Exposure Personal-Use Items Toys Antiperspirants Bathtub toys Baby soaps Etch-a-Sketch Baby lotion (without alcohol) Mylar balloons Baby shampoo Play-Doh Baby wipes (without alcohol) Silly-Putty Bar soap Teething rings Bath oils (beads) Toy cosmetics Body conditioners Bubble bath Medications Chewing gum Antacids Cologne (low alcohol content) Antibiotics (with exceptions Cosmetics such as Chloramphenicol, Deodorants Isoniazid, Penicillin) Eye makeup Antibiotic ointment Fingernail polish (dry) Calamine lotion Hair products (dyes, sprays, tonics) Carboxymethyl cellulose Hand lotion Clotrimazole cream Hand soap Corticosteroids Lipstick Glycerol Lip balm Lactaid Mascara Lanolin Petroleum jelly Oral contraceptives Rouge Titanium oxide Shampoo (small amounts) Zinc oxide Shaving cream Shoe polish (white) Miscellaneous Suntan lotion Abrasives Sunscreen products Air fresheners Thermometer (elemental mercury Hand dish-washing liquid soaps not toxic if ingested) (not electric dishwashing Toothpaste (without fluoride) type) Vitamins (without fluoride, iron, Aluminum foil and niacin) Ashes, wood/fireplace Book matches (one book) Art Supplies Candles (paraffin wax) Acacia Charcoal briquettes Ballpoint pen ink (blue and black) Cigarette ashes Chalk Dehumidifying packets (silica or Charcoal charcoal) Clay Grease, motor oil Crayons (marked A.P., C.P.) Gypsum Cyanoacrylate Incense Erasers Latex paint Felt-tip pens (waterbase) Lubricant Glow stick/jewelry Lubricating oils Ink (without aniline dyes) Newspaper Pencils (graphite) Putty Photographs Rust Plaster Sachets (essential oils, powder) Starch Sesame oil Styrofoam Sheet rock Water colors Silica gel Wax Soil White glue, paste Spackle Stick-em Glue Traps Sweetening agents (saccharin, cyclamate) Wallboard Tallow

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Any of those routes of exposure may lead to significant morbidity and even mortality. The products can be conveniently divided into five major categories: personal-use items, art supplies, toys, medications, and miscellaneous household items.

REFERENCES 1. Craft AW, Lawson CR, Williams H, Sibert JR: Accidental childhood poisoning with household products. Br Med J 1984;288:682. 2. Done AK: Poisoning from common household products. Pediatr Clin North Am 1970;17:569–581. 3. Edwards JN, Jenkins, HL, Volans GN: Hazards of household cleaning products. Hum Toxicol 1982;1:403–409. 4. Litovitz TL: The alcohols: Ethanol, methanol, isopropanol, ethylene glycol. Pediatr Clin North Am 1986;33:311–323. 5. Lovejoy FH JR, Flowers J, McGuigan MA: The epidemiology of poisoning from household products. Vet Hum Toxicol 1979; 21(Suppl):33–34.

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6. McGuigan MA: Poisoning in childhood. Emerg Med Clin North Am 1983;1:187–200. 7. Mofenson HC, Greensher J, Caraccio TR: Ingestions considered nontoxic. Emerg Med Clin North Am 1984;2:159–174. 8. Mofenson HC, Greensher J: The nontoxic ingestion. Pediatr Clin North Am 1970;17:583–590. 9. Motomatsu K, Adachi H, Uno T: Two infant deaths after inhaling baby powder. Chest 1979;75:448–450. 10. Osborne SC, Garrettson LK: Perception of toxicity and dose by 3- and 4-year-old children. Am J Dis Child 1985;139:790–792. 11. Peterson RG, Rumack BH: Toxicity of acetaminophen overdose. JACEP 1978;7:202–205. 12. Rogers J: Recurrent childhood poisoning as a family problem. J Fam Pract 1981;13:337–340. 13. Scalzo AJ: Diethylene glycol toxicity revisited: The 1996 Haitian epidemic. J Toxicol Clin Toxicol 1996;34:513–516.

CHAPTER

5

TECHNIQUES USED TO PREVENT GASTROINTESTINAL ABSORPTION OF TOXIC COMPOUNDS Martin J. Smilkstein

Several factors must be considered: (a) the risk or potential danger to the patient caused by the ingestion; (b) the likelihood that gastric emptying will remove a clinically significant amount of the ingestion; (c) the benefits of removing that amount of agent; (d) the risks of gastric emptying; and (e) the availability and utility of alternative methods to limit absorption or effectively treat the poisoning.

Limiting ongoing absorption of toxic compounds is a core principle of care for poisoned patients. Gastrointestinal decontamination is the most common issue considered and the topic of this chapter; however, an understanding of dermal, ophthalmic, and respiratory decontamination is also important. Dermal decontamination is discussed in Chapter 29, decontamination of the eye in Chapter 27, and considerations for inhalation exposures in Chapter 95. Although gastrointestinal decontamination has been a critical and familiar part of therapy of the poisoned patient for some time, no other area of medical toxicology has generated as much recent and continuing controversy. 15,37,78,90,152,154 The controversy arises because the results of clinically relevant studies of gastric emptying, activated charcoal, and cathartics challenge many of the assumptions on which previous therapy was based. Studies of gastric emptying fail to show benefit, or find benefit only in limited circumstances.4,91,108,128 Activated charcoal appears to be more effective than gastric emptying in many cases,44,115 and often may enhance drug elimination in addition to decreasing absorption.19,20,38 These findings are among many that have radically changed concepts about gastrointestinal decontamination.70,78 Despite these ongoing controversies, a great deal of information is available that can form the basis for a rational approach to gastrointestinal decontamination. For specific information on dosages and technical aspects of delivering gastrointestinal decontamination modalities, see Chapters 3 and 31 and these Antidotes in Depth: Syrup of Ipecac, Activated Charcoal, Cathartics, and Whole-Bowel Irrigation. This chapter discusses a conceptual approach to the use of those modalities that can be modified, as new data become available. Because of variations in patient age, agent ingested, severity of symptoms, time since ingestion, presence of coingestants, and numerous other factors, it is inappropriate to create simplistic gastrointestinal decontamination guidelines. A single strategy may not always be logical, even in treating the same type of ingestion in two different patients. It is more useful to understand each intervention and its limitations, and then to consider each clinical situation individually using a logical approach. The first consideration is often whether or not to empty the stomach.

What Factors Indicate That Ongoing Absorption May Be Dangerous? An assessment of the risk to the patient includes a consideration of the amount and type of agent ingested and the clinical course since ingestion. If the clinician is confident that the ingestion was of a nontoxic agent or of a nontoxic amount of a potentially toxic agent, then obviously gastric emptying is not indicated. If the history obtained suggests a toxic ingestion but the clinical course excludes toxicity, then gastric emptying is inappropriate. For example, consider an asymptomatic patient with a history of ingesting several diazepam tablets 6 hours earlier, with no access to other agents, and observed by family members to be asymptomatic throughout that 6-hour period. Regardless of the amount reportedly ingested, such a patient does not require gastric emptying. The absorption and onset of the clinical effects of diazepam occur rapidly, and the clinical course effectively excludes the ingestion. Such decisions require familiarity with the agent involved: 6 hours without symptoms is adequate to exclude significant iron poisoning, but it is inadequate to exclude poisoning by sustained-release verapamil or diltiazem, a sulfonylurea, or a monoamine oxidase inhibitor, each of which may cause delayed life-threatening symptoms. Such an approach is appropriate only when other ingestants can be excluded. Because this is often not the case, many patients should be managed as though they have either a more recent, larger, or different (and potentially toxic) ingestion than that described to the healthcare practitioner. Another exception should be made for ingestions of extraordinarily high potential risk. Although the benefit of gastric emptying remains unproved for the majority of these highpotential-risk ingestions, patients with high-risk ingestions are either not specifically studied or are expressly excluded, and as is discussed later, some data suggest evidence of gastric emptying benefit in this group. Therefore, the safest course at this time is to perform gastric emptying on patients with undefined, potentially lethal ingestions or with recognized high-risk ingestions (eg, cyanide, colchicine, chloroquine, aspirin, cyclic antidepressants, verapamil), sometimes even if the patient is asymptomatic beyond the time that onset of toxicity would be expected by history.

WHAT CONSIDERATIONS GUIDE APPROPRIATE GASTRIC EMPTYING DECISIONS? The decision to utilize or forgo gastric emptying should be based on whether it is reasonable to expect that a beneficial amount of drug removal can be safely accomplished by gastric emptying.

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Can Gastric Emptying Remove a Clinically Significant Amount of the Agent Ingested? The likelihood that gastric emptying will effectively remove a clinically significant amount of the agent depends on whether any of the agent remains in the stomach and whether the gastric emptying technique chosen can in fact remove it. Absorption of many agents (eg, alcohols, most acetaminophen formulations) is so rapid that essentially no toxin remains in the stomach after a few hours,22 and gastric emptying is therefore not indicated. Even for the many toxins that are more slowly absorbed, the yield of delayed gastric emptying is often unimpressive.42 Uncontrolled clinical studies41,42 suggest that other than anticholinergics, sedative-hypnotics, and opioids (drugs that slow gastrointestinal motility), drugs are unlikely to be recoverable by gastric emptying more than 2–4 hours after ingestion. These results, as in the case of other gastric emptying research, suggest little potential value of gastric emptying in most cases, but fail to resolve the question of benefit to the subset of individuals at very high risk. Drugs with or without the ability to slow gut motility can also remain in the stomach if they tend to form adherent masses. Aspirin (especially enteric-coated),21 iron,58 meprobamate,75 and phenobarbital77 serve as examples of this phenomenon, although this may also occur following massive ingestion of many agents. Drugs such as aspirin that may cause pylorospasm also cause prolonged gastric retention. Clinical anecdotes including postmortem information clearly show that, in some cases, large amounts of drug can remain in the stomach for hours to days. Even rapidly absorbed drugs may remain in the stomach for unusually long periods under certain clinical conditions.145 These observations continue to stimulate the use of delayed gastric emptying despite the lack of proven clinical efficacy. The occurrence of antecedent spontaneous vomiting is often considered another determinant of whether or not an agent remains in the stomach. Although it is true that some drug may remain in the stomach after repeated episodes of spontaneous vomiting, it is unlikely that either lavage or emesis can subsequently remove a significant amount. To induce further emesis or to perform orogastric lavage is not only futile, it may increase the risk of complications, and in the case of the use of syrup of ipecac, makes subsequent administration of activated charcoal more difficult.44 Any attempt to determine how much antecedent vomiting is sufficient to obviate gastric emptying is clearly speculative and a matter of clinical judgment. As is true for most issues related to gastrointestinal decontamination, the degree of risk to the patient from the ingestion must be considered along with the complications from the procedure. For example, it is logical to forego gastric emptying after a codeine ingestion if the patient has vomited two or three times, but orogastric lavage might be appropriate after the same amount of vomiting following a massive colchicine overdose.

What Clinical Benefits of Gastric Emptying Have Been Demonstrated? Gastric emptying can result in removal of drug from the stomach of poisoned patients,13,24,41 and volunteer studies demonstrate that drug absorption can be decreased,144 but neither of these observations proves clinical benefit. Although a difficult issue to study, clinical benefit from gastric emptying is, to date, demonstrable only in patients with serious overdoses when gastric emptying is

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accomplished within 1 hour of the ingestion.91 Other authors are unable to describe a benefit at all.108,128 New guidelines emphasize these studies and conclude that gastric emptying should be entirely abandoned, or used only in extraordinary situations.15,37,90,152,154 While these studies do demonstrate that the majority of patients can be treated effectively with activated charcoal alone, they clearly do not prove that either timely or delayed gastric emptying is ineffective in all cases. It is worthwhile to examine how the limitations of these studies should affect their interpretation. The decision to perform gastric emptying should be largely based on speculation that the ingestion may lead to a clinically unstable, life-threatening condition for which even a small decrease in toxic exposure may be critical. The impact of gastric emptying on the clinical outcome of patients with the most dangerous exposures is therefore of greatest interest. Studies thus far include patients with a wide variety of overdoses and possible exposures, the vast majority of whom are expected to do well with supportive care alone. This is particularly true of those patients who had no actual exposure, but who were included in the study because of the technical difficulties in confirming most suspected poisonings. Clearly, it is difficult to show any therapeutic benefit in this situation, and study of this heterogeneous group of cases does not resolve the question in the most important subset. Understandably, no controlled study to date has included enough patients with confirmed life-threatening ingestions to adequately compare outcome with and without gastric emptying. It is also important to consider certain other drug subsets, such as sustained-release formulations, drugs likely to form aggregations or to cause pylorospasm, amounts of drug large enough to exceed the adsorptive capacity of activated charcoal, and agents not well adsorbed to activated charcoal. Although gastric emptying would seem most logical after these ingestions, either they were not studied separately or they were excluded from study altogether.91,108 In one study, in which the author concludes that gastric emptying is futile, the results actually appear to suggest benefit to gastric emptying in the highest-risk patients.128 In 8 of 10 analyses of groups subdivided by severity or time to presentation and compared with regard to incidence of improvement and deterioration, results were better in the groups undergoing gastric emptying. Despite small subgroup size, these differences approached or achieved statistical significance in four of these analyses. The authors discount these observations as either a consequence of other factors or as not statistically significant. Power analysis indicated that the group size of the “severely” intoxicated group was only large enough to detect a 50% reduction in poor outcome from gastric emptying. Very few medical interventions provide such dramatic results, and lesser degrees of benefit may be important, particularly in patients very close to life-threatening thresholds of toxicity. An earlier study demonstrated benefit to gastric emptying among the most ill, despite the fact that seven critically ill patients were excluded from the study.91 Within any large sample of poisoned patients, the incidence of serious toxicity is low, and the ability to demonstrate benefit despite exclusion of a significant portion of the sickest patients is noteworthy. In combination with the above-mentioned recent data, such observations suggest that gastric emptying will continue to benefit a small, but critically important subset of patients. An example of an analogous consideration is thrombolytic therapy for acute myocardial infarction. If thrombolytic therapy is assessed among all patients with chest pain, there is no evidence

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of benefit, and it is likely that harm will be evident because of treatment. If, instead, appropriate criteria are selected to define the patients at highest risk for consequential myocardial infarction and the conditions most likely to be associated with benefit, thrombolysis is an extraordinarily effective therapy. This effect, sometimes called the Pollyanna phenomenon, similarly explains why, as in the above studies, no benefit is identified from gastric emptying if all patients with actual or potential overdose are considered. What remains to be done is to define the characteristics of patients with overdoses most likely to benefit from gastric emptying, and to study those cases. It is unlikely that gastric emptying decisions will ever be amenable to strict predetermined criteria. Instead, a case-by-case analysis considering the factors that make gastric emptying more or less logical is appropriate (Table 5–1). In most cases, gastric emptying is only suggested for patients with ingestions matching several of the listed features. In some cases, however, the potential lethality of the ingestion is so great that a single feature might appropriately prompt orogastric lavage. Until these issues are better evaluated, the value of gastric emptying will remain controversial. Studies clearly support the use of a selective approach and result in decreased patient discomfort, complications, and cost from unnecessary gastric emptying. Nonetheless, it is inappropriate to generalize these findings to include patients at highest risk. Based on current studies, it is neither scientifically nor logically sound to withhold gastric emptying from patients with overdoses of cyanide, colchicine, cyclic antidepressants, and many other potentially lethal ingestions; or after large ingestions of aspirin,
-adrenergic antagonists, or calcium channel blockers and other agents with delayed and prolonged toxicity; or ingestions of lithium, iron, or other less adsorbable agents (see individual chapters for expanded discussion). To establish the appropriate indications for gastric emptying in the context of these observations, it is critical to consider the possible risks. As the benefits of other modes of gastrointestinal decontamination are identified, they may supplant or complement those of

TABLE 5–1. Factors that Cumulatively Increase the Appropriateness of Gastric Emptying* • Substantial risk of consequential toxicity: eg, ingestion of aspirin, chloroquine, colchicine, cyclic antidepressants, calcium channel blockers • Evidence of consequential toxicity: eg, repeated seizures, hypotension, cardiac dysrhythmias, apnea, acid-base or other metabolic disturbances • Antidotal or adjunctive therapy ineffective or nonexistent: eg, colchicine, paraquat • Recent ingestion (100 mg/kg of pills such as aspirin, sustained-release verapamil, sustained-release theophylline • Ingested agent not adsorbed by activated charcoal: eg, iron, lithium • Ingested agent likely to form durable mass after overdose: eg, large amounts of aspirin, enteric-coated agents, iron, meprobamate • Ingestions of extended or sustained-release formulations: eg, calcium channel blockers, theophylline • No antecedent vomiting • Gastric tube placement required for activated charcoal administration • No contraindications to gastric emptying *The explanations and examples that follow each factor are meant only to illustrate the concepts, and are not intended to be comprehensive. See text for further discussion.

gastric emptying. For example, whole-bowel irrigation has essentially displaced gastric emptying for patients with consequential sustained-release tablet ingestions.

What Are the Potential Complications of Gastric Emptying? Gastric emptying is usually safe but can cause significant morbidity. Complications are very rare, and most are preventable by appropriate patient selection and the use of appropriate techniques (Chaps. 3 and 31). Orogastric lavage can cause esophageal tears or perforation.91,161 In addition, following lavage, nasal, oral, and pharyngeal injury, pyriform sinus and gastric perforation, and tracheal aspiration can occur.103 Other complications described following nasogastric tube placement in settings other than poisoning management, such as tracheal intubation, pulmonary hemorrhage, pneumothorax, and empyema, are all potential complications of orogastric lavage. Therapeutic use of syrup of ipecac may result in aspiration,91,127 protracted vomiting,35 Mallory-Weiss tears,143 intracerebral hemorrhage,87 pneumomediastinum and pneumoretroperitoneum,159 and diaphragmatic rupture.131 Attempts at gastric emptying may also propel ingested material beyond the pylorus, where many drugs are more readily absorbed.134 Perhaps the most common avoidable morbidity occurs in the somewhat combative patient who resists attempts at gastric emptying. If patient movement cannot be well controlled, alternatives to orogastric lavage must be considered. In the majority of such cases, there is little evidence for efficacy of gastric emptying, good evidence that activated charcoal will be effective (discussed later), and significant risk for injury to the patient or staff during the procedure. In the unusual case in which gastric emptying is deemed to be very important, persistent attempts at lavage may be indicated. Although the use of sedation or neuromuscular paralysis is common prior to orogastric lavage,48 except to obtain airway control such measures are almost never indicated. Except in vanishingly rare circumstances, the risks of sedation and paralysis far outweigh the benefits of gastric emptying, and orogastric lavage can be avoided or delayed until clinical findings permit the procedure without additional risk. Contraindications to gastric emptying include any situation when it is unnecessary or ineffective (see the earlier discussion) or potentially dangerous. For example, gastric emptying is illogical after ingestion of alkaline caustics (Chap. 87), which cause consequential local injury but carry little risk from systemic absorption. Gastric emptying cannot be safely undertaken in these cases, and would not be expected to be of any value. The advisability of gastric emptying is more controversial after ingestion of agents such as phenols and acids, which, although caustic, can also cause systemic toxicity by absorption (Chap. 87). With some caustic agents, such as mercuric chloride, the potential systemic toxicity is so great that gastric emptying seems clearly warranted despite the presence of probable gastric injury.

What Are the Appropriate Alternatives to Gastric Emptying? Assessment of the risk/benefit ratio of gastric emptying should consider alternative treatments. Some authors suggest the use of no gastrointestinal decontamination at all;108 however, the most important alternative to gastric emptying is the use of activated charcoal alone. In volunteer studies following small ingestions of agents well adsorbed to activated charcoal, activated charcoal is

CHAPTER 5

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more effective in preventing drug absorption than is gastric emptying.44,106,116,149 Studies of actual drug overdoses find gastric emptying followed by activated charcoal to be no more effective than activated charcoal alone for the majority of poisoned patients.91,108,128 Because the activated charcoal–to-drug ratio is one of the most important determinants of activated charcoal efficacy,122 the amount of drug ingested may determine whether activated charcoal alone is likely to be adequate. For patients with small ingestions of agents well adsorbed to activated charcoal, there is good support for the use of activated charcoal alone. An activated charcoal–to-drug ratio of 10:1 can serve to illustrate this important concept. This commonly mentioned ratio is a midrange value from in vitro studies7 of uncertain clinical value, because ideal ratios vary by agent and GI conditions, but it serves as a useful conceptual guide. Using lorazepam as an example, to achieve a 10:1 activated charcoal–to-drug ratio in a patient who has ingested 100 tablets of 2 mg each requires only 2 g of activated charcoal. In an adult, a typical activated charcoal dose of 1 g/kg of body weight is likely to be effective in reducing further drug absorption. From another perspective, 2 g of activated charcoal theoretically treats an ingestion of one thousand 0.2-mg clonidine tablets (200 mg total), whereas even 100 g of activated charcoal is ineffective after an ingestion of only fifty 300-mg theophylline tablets (15 g total). Activated charcoal is still a critical part of management of patients with large ingestions, but gastric emptying may take on greater importance as an adjunct in these situations. The availability of an antidote or adjunctive therapy may also affect the decision to forego gastric emptying. When there is no clear indication for gastric emptying, the risk of subsequent unexpected gastrointestinal absorption is more acceptable if there is a very effective treatment or antidote available. Antidotal therapy obviously should not replace gastric emptying if gastric emptying is clearly effective, but this is not usually the case. Consider a patient who reportedly ingested 25 tablets of acetaminophen with codeine 4.5 hours earlier. Absorption would probably be complete even if slowed by codeine. Because there is probably little or no benefit of gastric emptying at this point, and because there are effective antidotes for both acetaminophen (N-acetylcysteine) and codeine (naloxone), it is appropriate to forego gastric emptying.

Summary: Gastric Emptying The use of gastric emptying should be a selective (Table 5–1), not a routine procedure. Gastric emptying is largely an unproved therapy that is, nevertheless, useful in some situations when it can be accomplished safely. The method chosen should consider the nature of the poison and the current and projected clinical status of the patient. Rarely, if ever, should the patient be placed at additional serious risk to empty the stomach.

WHEN GASTRIC EMPTYING IS INDICATED, WHICH TECHNIQUE SHOULD BE USED? Until 1985, syrup of ipecac was routinely administered after ingestions unless the patient was comatose, or convulsing, or had lost the gag reflex; under these circumstances, orogastric lavage was recommended. Comparing the risks and benefits of these two methods, it became apparent that this approach was far too sim-

47

plistic. While earlier debate focused primarily on which method removed more drug,l,11,25 more recent work attempts to view these modalities in the context of the whole patient. Determining relative benefit includes consideration of the amount of drug removed, whether that removal is consequential, comparison of the potential complications of each gastric emptying technique, and the impact of each upon the use of other important treatment methods such as activated charcoal and oral antidotes. In most circumstances, comparison of induced emesis and orogastric lavage is only of historical interest; however, the analysis is instructive.

Is Either Emesis or Orogastric Lavage Superior in Prevention of Toxin Absorption? Attempts to determine conclusively whether emesis or lavage removes more drug fail partly because of study design but more importantly because there may be no single correct answer. With respect to study design, studies of emesis or lavage recovery of liquid barium from puppiesl or magnesium hydroxide solution from children43 performed soon after ingestion may have little or no bearing on the potential to recover solid pill fragments 2–3 hours after overdose. Similarly, studies of lavage utilizing smallbore nasogastric tubes25 do not provide useful information about the efficacy of lavage as practiced, using large-bore orogastric tubes. Other study design issues are evident in the literature and have led to a variety of conflicting and inaccurate conclusions. Currently, no adequately controlled study shows either emesis or lavage as clearly superior in drug removal.133 Both are probably equivalent overall, but in the clinical setting of an actual specific ingestion, the overall results are not relevant. The results of several gastric emptying studies emphasize this fact. Although children given a standard dose of a magnesium hydroxide marker immediately before syrup of ipecac–induced emesis vomited an average of 28% of the marker, the range was 0 to 78%.43 In another study, syrup of ipecac and lavage each resulted in average removal of about half of the ingested material, but the range of retained material in the gastrointestinal tract was 0 to 100%.134 Similar variability is noted in other controlled studies,11 and the actual overdose setting certainly offers substantially more variables than these studies.

What Substances Will Pass Through an Orogastric Lavage Tube? Another factor in considering whether emesis or lavage is preferable for a patient with a particular ingestion is the formulation of the substance (eg, liquid, tablet, capsule, enteric coating, size, shape) as it relates to the tube lumen size and the mechanics of orogastric lavage. Large drug packets, pills, or pill fragments (particularly enteric coated and sustained release), adherent masses of pills, and plant or mushroom fragments will not pass through even a 40-French lavage tube.2 If gastric emptying is appropriate, ipecac-induced emesis may be more logical for this group of ingestions. This issue is even more important when the patient is a small child. Passing a very large-bore tube in an infant is impossible, and a 24-French tube is probably the largest that can safely be used. As a result, substances that might be effectively removed by lavage in an adult cannot be lavaged from a child. In many cases, however, although lavage may not return a substantial amount of solid material, syrup of ipecac–induced emesis may be contraindicated. In such cases, lavage should be considered for the removal

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of dissolved drug and small fragments as well as for the administration of activated charcoal.

When Is Emesis Contraindicated? Deciding between syrup of ipecac–induced emesis and lavage is more often based on a consideration of potential risks than on efficacy. The most important of these risks is the aspiration of stomach contents into the tracheobronchial tree. Any patient who initially lacks the ability to protect his or her airway, or who is likely to lose airway-protective reflexes during the duration of action of syrup of ipecac, must not have emesis induced. Instead, if gastric emptying is indicated, such a patient should be lavaged after endotracheal intubation. An ingestion of any substance causing or capable of rapidly causing a decreased level of consciousness, seizure, cardiovascular collapse, or neuromuscular paralysis should be managed in this manner. Examples of substances that may preclude the use of syrup of ipecac are camphor, cyclic antidepressants, isoniazid, propoxyphene, and propranolol; but many, if not most, serious overdoses may fit this description. The limited potential benefit offered by emesis does not justify placing the patient at risk for aspiration. Induction of emesis is also contraindicated following ingestions of foreign bodies likely to cause mechanical injury or upper airway obstruction and in patients with certain structural lesions or bleeding diatheses. Contraindications to emesis are summarized in Table 31–4 and should be considered in addition to contraindications to gastric emptying in general.

How Does the Anticipated Use of Activated Charcoal or Other Oral Antidotes Impact the Choice of Gastric Emptying Method? The increasing appreciation of the efficacy of activated charcoal also has a profound effect on the approach to gastric emptying. In addition to replacing gastric emptying in many settings, activated charcoal is useful following gastric emptying in the vast majority of ingestions and is absolutely essential in some (see Antidotes in Depth: Activated Charcoal). Orogastric lavage can usually be accomplished rapidly and then followed quickly by administration of activated charcoal via the lavage tube. Syrup of ipecac results in significant delays in charcoal administration, as a consequence of the combination of delay to its onset of effect and a period of repeated emesis and subsequent nausea during recovery. Because delayed administration of activated charcoal decreases its efficacy, emesis has been largely abandoned or replaced by lavage in cases involving ingestions of toxic substances well adsorbed to activated charcoal. The effective use of oral N-acetylcysteine and other oral agents can also be delayed by the use of syrup of ipecac. Patients poisoned with acetaminophen are often nauseated from the ingestion itself, making the effective use of oral N-acetylcysteine difficult. Using syrup of ipecac in this situation will increase their tendency to vomit, further preventing or delaying effective use of N-acetylcysteine. In summary, if N-acetylcysteine or other oral agents are needed within 2–3 hours and gastric emptying is indicated, orogastric lavage is the preferred method.

Are There Other Unique Considerations? The at-home use of syrup of ipecac for children who are not subsequently treated at a healthcare facility, as often recommended by

poison information specialists, represents an important clinical issue. Thus far, activated charcoal is not a widely available or a practical alternative in the home,32,47,50,69,88,94,121 and studies of gastric emptying efficacy are largely irrelevant in the assessment of this form of intervention. Because of the nature of such exposures, the potential benefit of emesis in this setting would likely be avoidance of an emergency department visit, rather than avoidance of consequential clinical deterioration. Without the use of ipecac, would symptoms occur from the exposure that are not dangerous, but that are noticeable enough to prompt medical evaluation? Are other symptoms masked by, or misattributed to, ipecac-induced emesis? Does the induction of emesis provide reassurance to parents or poison center staff, facilitating home observation? Given the high incidence of minor, unintentional pediatric exposures (Chap. 106), these questions are extraordinarily important to resolve. A much rarer gastric emptying challenge is the “body stuffer” (Chap. 67). Body stuffers are people who spontaneously, and without antecedent preparation, ingest packets containing illicit drugs, generally in an attempt to conceal evidence of drug possession. The amount ingested is often unclear, there is significant risk of drug container leakage, and there is no reliable early test to confirm and quantify the ingestion.71 The drugs involved, typically cocaine or heroin, may cause abrupt clinical deterioration, but in the overwhelming majority of cases no identifiable toxicity occurs. Lavage is ineffective because of the size of the drug packages; syrup of ipecac-induced emesis is potentially dangerous because of the possibility of clinical deterioration before or during emesis; and observation alone means a lengthy hospitalization that is most often unnecessary and for which there is no clear endpoint. Some authors believe that ipecac-induced emesis deserves consideration if the ingestion involves a small amount of drug; if there is no evidence of drug leakage or drug effect by history or physical examination; if the drug containers are crack vials or sealed waterresistant bags that are less likely to result in early massive leakage; and if there is no contraindication to emesis. There is certainly no consensus on the management of these patients, but in our opinion, there is no role for syrup of ipecac–induced emesis in these cases. We feel that the risk of subsequent deterioration can never be predicted and thus favor the use of activated charcoal and whole-bowel irrigation (described later in this chapter). Some sustained-release pharmaceutical preparations present a special problem because the bulk of the pill matrix remains largely intact even as the active drug is released. These dissolution characteristics result in a pill that persists for many hours, too large to pass through a lavage tube.2 In this case, lavage is ineffective and emesis will significantly complicate effective activated-charcoal delivery, but such ingestions are often very serious and may be too massive to rely on activated charcoal alone. In many such cases, use of whole-bowel irrigation is logical, but questions related to gastric emptying may be pertinent. For example, consider a patient who presents within an hour of a massive ingestion of persistentmatrix theophylline or verapamil, without antecedent vomiting. Is induction of emesis a logical intervention? Apomorphine is a morphine derivative with diminished analgesic action and potent emetic effects mediated by stimulation of the chemoreceptor trigger zone and possibly the vestibular apparatus.100 It generally induces emesis within 3–5 minutes of a single subcutaneous dose. However, it produces concomitant central nervous system and respiratory depression, and holds the potential for severe or protracted vomiting. It is also currently unavailable in a

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premixed parenteral form. Although there are data to suggest that naloxone may reverse vomiting and at least some of the adverse effects associated with apomorphine,23 it is unlikely that it will ever be used for this clinical indication. A related, more practical issue is the capability of newer potent antiemetics to reverse the emetic effects of syrup of ipecac.109 Although these potential therapies are mentioned, they remain only areas of investigation and there are no data to support their use at this time.

Summary: Emesis versus Orogastric Lavage In summary, when gastric emptying is indicated in a hospital, orogastric lavage is almost always preferable to syrup of ipecac–induced emesis. Emesis continues to be important following the ingestion of large pills that do not disintegrate, ingestions by infants and small children in whom large-bore tubes cannot be used safely, very recent ingestion of lithium or other agents that are not adsorbed by activated charcoal, and for home use. These guidelines are not absolute and always must be considered on an individual basis, recognizing potential contraindications and alternatives for a particular patient and a particular poison.

WHAT IS THE ROLE OF ACTIVATED CHARCOAL? There is no question that activated charcoal is important in the management of toxicologic emergencies, but its role is still being defined. Like other treatment modalities, the appropriate use of activated charcoal should be determined by analysis of the relative risks and benefits of its use. Adverse effects are rare despite its widespread use, but in the absence of well-controlled studies in poisoned patients it is difficult to accurately assess its clinical benefit.

How Beneficial Is Activated Charcoal? It is necessary to consider separately the two potential benefits of activated charcoal: preventing the absorption of toxic agents from the gastrointestinal tract and enhancing the elimination of agents already absorbed. For activated charcoal to prevent systemic absorption of toxic substances from the gastrointestinal tract effectively, the substance must be adsorbed by activated charcoal and still be present in the gastrointestinal tract at the time of activated charcoal administration. When both of these conditions are met, there is no doubt that activated charcoal results in diminished absorption, lower peak serum concentration, and decreased area under the concentration versus time curve. Activated charcoal has been studied with hundreds of substances in vitro, in animals, in human volunteers, and in patients with actual overdoses.26,38,118,126 Although controlled studies showing clinical benefit are not available, these other data are convincing enough to warrant the use of activated charcoal soon after most ingestions. Even substances not well adsorbed qualitatively to activated charcoal may nevertheless be adequately adsorbed from a quantitative perspective, and thus activated charcoal may be beneficial even following these exposures. For example, based on in vitro studies, cyanide is considered to be poorly adsorbed by activated charcoal, because 1 g of activated charcoal binds only 35 mg of potassium cyanide, far less than other toxic agents studied.7 If the same ratio were to hold in an actual patient, then delivery of 60 g

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of activated charcoal could adsorb 2.1 g of potassium cyanide, well above the expected lethal dose. In vivo efficacy of activated charcoal in the treatment of cyanide poisoning was demonstrated in an animal model,93 suggesting that this logic is valid and that it may apply to other potentially lethal agents as well. As the amount ingested increases and the binding affinity decreases, the stoichiometric advantage is lost and this approach clearly becomes less effective. Typical ingestions of ethanol, lithium, or iron, for example, involve several grams of drug; thus, the very limited adsorption of each to activated charcoal makes this modality clinically insignificant. In fact, of all commonly ingested substances, ethanol, lithium, and iron are the only ones for which activated charcoal is documented to be completely ineffective.119 There are other substances described in qualitative terms as being poorly adsorbed to activated charcoal that are nevertheless adsorbed to an extent that may justify the adminstration of activated charcoal. Hydrocarbons are said to be poorly adsorbed, yet activated charcoal decreased gastrointestinal absorption of kerosene, benzene, and dichloroethane in rats.92 Metals are similarly described as poorly adsorbed, but significant activated charcoal adsorption of mercuric chloride was first noted in the 1940s,7 and its therapeutic use in mercury poisoning dates to the 19th century. For many agents, only in vitro data are available, which may or may not be applicable. Regardless of the ingestion history, administration of activated charcoal may be appropriate due to the likelihood of inaccurate information or unrecognized coingestion of agents that are well adsorbed. For substances that are well adsorbed, activated charcoal decreases drug absorption from the gastrointestinal tract and enhances elimination of drug already absorbed; thus, its use is often appropriate regardless of the interval since ingestion. An initial dose of activated charcoal should be administered in nearly all cases of potentially toxic ingestions unless contraindicated. Because of concerns that orogastric lavage might delay activated charcoal administration, or might increase drug absorption by dissolving a drug or pushing it out of the stomach into the small intestine, some have suggested that activated charcoal be administered prior to or during lavage.30,134 Although theoretically appealing, this approach has obvious practical disadvantages and its true value remains to be determined. Although one volunteer study found that lavage forced marker past the pylorus,134 another did not.135 In addition, proper patient positioning156 and proper lavage technique should limit drug passage beyond the pylorus. As a result, activated charcoal prior to or during lavage is rarely indicated, but it may be appropriate after particularly massive or dangerous ingestions. Multiple-dose activated charcoal (MDAC) may also be indicated to prevent absorption in several circumstances when a significant amount of the agent is likely to remain in the gastrointestinal tract. Some ingestions are too massive to be effectively adsorbed by a single dose of activated charcoal. In other cases, the continuous release of drug from a sustained-release formulation or from concretion makes repeated doses of activated charcoal a logical choice. Only a few agents probably lead to formation of true concretions, but persistence of large quantities of undissolved drug in any form has similar clinical implications. Many substances slow gastrointestinal motility and are thus particularly likely to remain in the gastrointestinal tract, especially following large ingestions. Although cyclic antidepressants, calcium channel blockers, phenothiazines, anticholinergics, opioids, and sedative-hypnotics are usually associated with delayed gastrointestinal passage, many

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other substances are also capable of effectively delaying gastrointestinal passage directly or indirectly by altering electrolytes, changing blood pressure, causing mechanical obstruction or pylorospasm, or by other mechanisms. As a result, MDAC is often appropriate regardless of whether or not the ingested substance is known to slow motility or cause concretions. MDAC is far more controversial as a method of enhancing elimination of toxic substances (see Antidotes in Depth: Activated Charcoal).33,38,119,126,150 For it to be effective in enhancing elimination of a given substance, the substance must either undergo enterohepatic recirculation or, more often, be present to a significant extent in circulating blood (enteroenteric recirculation, or “gut dialysis”) and be well adsorbed to activated charcoal. For some substances, such as theophylline, there is good evidence that MDAC substantially limits absorption and enhances elimination. For many other substances, MDAC alters drug kinetics favorably, but the change is small. In still other cases, despite in vitro adsorption, no effect is noted in volunteers. Applying the results of these studies to the overdose setting remains difficult. There are profound differences between drug pharmacokinetics at doses used in therapeutic or volunteer studies and toxicokinetics in poisoned patients. Depending on whether the drug is likely to persist in the gastrointestinal tract and whether the elimination of the drug is zero-order, first-order, or MichaelisMenten, the effect of activated charcoal in overdose may be less than, equal to, or more than that reported at a low drug dosage.39 There is also uncertainty as to how much effect on drug kinetics is required to produce a clinical benefit.150 For example, many authors argue that MDAC is not useful for treating salicylate overdose because it either has no effect76 or only slightly augments salicylate elimination.85,105 On the other hand, proponents of MDAC in this setting speculate that a small reduction in the area under the concentration versus time curve80 might be enough to prevent some component of delayed clinical deterioration. On the basis of current information, utilization of MDAC is appropriate in many such potentially serious ingestions, when it can be accomplished safely.

Can Activated Charcoal Harm the Patient? Is It Ever Contraindicated? Activated charcoal is generally safe and has few contraindications. Most patients with caustic ingestions who require endoscopy should not receive activated charcoal, because activated charcoal does not effectively adsorb most caustics. In addition, activated charcoal obscures the endoscopist’s view. Although most patients tolerate activated charcoal well, at least some patients do vomit after receiving it. As a result, it is also contraindicated in patients with ingestions of pure petroleum distillates and other agents that are not well adsorbed to activated charcoal but that do carry a high risk of pulmonary aspiration. It should be noted that other toxic hydrocarbons (eg, benzene) and agents found in combination with hydrocarbons (eg, pesticides) are not well studied and may be at least partially adsorbed by activated charcoal, making its administration appropriate. Minor adverse effects of activated charcoal, including nausea, vomiting, and constipation, are common.1,5,119 Pulmonary aspiration is the most serious complication that may occur in the overdose setting. Activated charcoal is occasionally noted in the respiratory tract, and several cases of aspiration, including fatalities,18,51,68,107 are described.45,63,67,127 It is inappropriate to consider

these cases the result of activated charcoal use; instead, they illustrate failure to secure adequate airway protection or direct instillation of activated charcoal into the trachea after improper nasogastric or orogastric tube placement. In addition to massive consequential aspiration, trivial charcoal aspiration is very common. An endotracheal tube cuff does not provide a perfect seal, and small amounts of black-tinged secretions are occasionally suctioned from intubated patients with properly protected airways.111 There is no evidence that the administration of oral activated charcoal increases the risk of aspiration in patients with intact airway protective reflexes. Although it increases lung microvascular permeability, causing acute lung injury in animal models,12 there is no evidence that it causes more severe sequellae than equivalent aspiration of gastric contents without activated charcoal. In summary, if appropriate standards of airway protection and activated charcoal administration techniques are observed, there appears to be no increased risk of consequential pulmonary aspiration as a result of activated charcoal. This concern is therefore an inappropriate reason to forgo activated charcoal therapy. Although there are few credible reports of other serious complications from a single dose of activated charcoal, cases of bowel obstruction or pseudo-obstruction are described following MDAC.27,57,65,66,99,129,158 Although extraordinarily rare, these cases deserve consideration. Most cases involve the administration of repeated activated charcoal dosing at 3–6-hour intervals for 36–120 hours. As experience with MDAC continues, other cases may be reported. This rare but serious risk should be weighed against the potential benefits. In a patient with decreased gastrointestinal motility, MDAC might be continued despite the risk if there were good evidence of enhanced toxin elimination (eg, massive phenobarbital or theophylline overdose). On the other hand, if ileus is present, MDAC might not be warranted when there is little reason to expect much yield (eg, cyclic antidepressant overdose). Most reports of serious complications after MDAC are actually the result of multiple cathartic doses. Because so many commercial preparations combine both agents, it is of critical importance to specify activated charcoal without cathartic when ordering MDAC for a patient (cathartics are discussed later in this chapter).

Activated Charcoal: How Much, How Many Times, How Often? There is no single correct dose of activated charcoal. As discussed earlier, in some cases, the expenditure of time, effort, and cost in administering large amounts or repeated doses of activated charcoal is not justifiable, but in other cases (eg, theophylline overdose), it should be considered a life-saving therapeutic maneuver of the highest priority. The maximum amount of activated charcoal that can be safely and successfully given is unknown and certainly varies with the patient. For example, to treat a severe theophylline overdose in an adult, as much as 100 g initially, followed by a continuous nasogastric tube infusion of 100 g/h, may be appropriate. It is unusual for both patient and staff to tolerate such a regimen. It is certainly unnecessary and unreasonable to give most patients the maximum possible dosage; although complications are rare, such dosing likely increases the risks. Although dosage is largely dictated by convention or packaging, a more rational approach is possible. It is certainly necessary to consider the age and size of the patient when determining activated charcoal dosage, but it is also critical to consider the type of agent involved and the amount ingested.

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The optimum activated charcoal dose theoretically is the minimum dose that completely adsorbs the ingested toxic agent and, if relevant, that maximizes enhanced elimination. Because of variables such as the physical properties of the drug formulation ingested, the volume and pH of gastric and intestinal fluid, and the presence of other agents or foods adsorbed by activated charcoal,8,9,101,117,121 the optimum dose cannot be known with certainty in any given patient. It is possible, however, to develop a logical approach to dosing based on available data. The results of in vitro studies show that ideal activated charcoal–to-drug ratios vary widely, but that 10:1 is a representative value for many typical drugs and is therefore useful in theoretical consideration of optimal activated charcoal dosing.7,122 As noted, achieving a large activated charcoal–to-drug ratio is often quite feasible for ingestions of drugs dispensed in small formulations, such as digoxin (0.25 mg), clonidine (0.2 mg), or levothyroxine (0.025–0.3 mg), but impossible for agents such as adult aspirin (325 mg), sustained-release theophylline (200–400 mg), or sustained-release verapamil (up to 240 mg). This should not be interpreted to mean that activated charcoal dosage should be decreased significantly for small ingestions; it seems logical to use the largest dose that can be easily and safely given (0.5– 1 g/kg). Activated charcoal dosage should, however, be increased to treat certain ingestions. Maximal initial dosing (1.5–2 g/kg) is appropriate after massive ingestions of dangerous substances that are well adsorbed to activated charcoal (eg, theophylline, aspirin, sustained-release verapamil). Maximal activated charcoal dosing should also be used after ingestion of some lethal substances, even if they are poorly adsorbed, if a limited amount of adsorption to activated charcoal might be of significant clinical benefit (eg, cyanide). Thus, it is the total quantitative adsorption to activated charcoal relative to the amount of drug ingested and not the qualitative characteristics of the drug adsorption that determines the optimal dosing of activated charcoal. The amount and frequency of MDAC dosing should vary based on considerations of risks and benefits as discussed. For cases less likely to benefit significantly from multiple doses, such as exposure to low-risk, rapidly absorbed, widely distributed substances, a low dose of MDAC, such as 0.5–1 g/kg every 4–6 hours, may be appropriate. More seriously poisoned patients should receive larger doses of activated charcoal, and patients for whom MDAC is critical, as in life-threatening overdoses of sustained-release theophylline, should be given as high a dose as they can tolerate, 1 g/kg or more per hour. Some patients tolerate “miniboluses” or continuous nasogastric infusions better than large intermittent doses. In many cases, antiemetics are necessary to accomplish aggressive activated charcoal dosing. Some drugs or agents, particularly the phenothiazines, possess the undesirable effects of decreasing gastrointestinal motility and, possibly, of lowering the seizure threshold. For this reason, metoclopramide or a serotonin agonist, such as ondansetron, may be most advantageous in poisoned patients. The appropriate endpoint for MDAC is also unstudied and may vary with the agent involved. The pharmacokinetics, toxicokinetics, and amount of the agent ingested all must be considered. In some cases, altered mental status or another toxic effect will persist long after the role of activated charcoal’s has become minimal; in these cases multiple-dose therapy may be discontinued prior to clinical resolution. A number of studies suggest that activated charcoal may unbind a drug in the gastrointestinal tract, a process known as desorption. This drug then becomes available for systemic absorption.14,56,117 If desorp-

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tion from activated charcoal is likely, such as after massive salicylate ingestion, it may be appropriate to continue MDAC even after clinical improvement is evident. In most cases, significant clinical improvement and the passage of activated charcoal stools are adequate criteria for termination of MDAC.

Summary: Activated Charcoal A single dose of activated charcoal is appropriate after nearly all suspected toxic ingestions. Exceptions include confirmed, singlesubstance ingestions of lithium, iron, ethanol, simple hydrocarbons, or acid or alkali caustics. With adequate airway protection, there is no serious risk associated with single-dose therapy. MDAC is warranted if there is evidence of a large amount of residual substance in the gastrointestinal tract, or to enhance the elimination of a drug or toxin already absorbed. Strong clinical evidence supporting the use of MDAC exists for only a few types of drug overdoses, but its use is often appropriate even in unproved circumstances. In most instances, 0.5–1 g/kg is an appropriate initial dose of activated charcoal; doses of 1.5–2 g/kg should be used following particularly massive or dangerous ingestions. Dosing varies when using MDAC. To treat exposures to substances for which there are less data or rationale to support MDAC, 0.5 g/kg once or twice is probably adequate. When multiple-dose therapy is thought to be critical, activated charcoal doses as high as 1.5 g/kg/h may be justified. Other exposures warrant dosing between these extreme values, based on the factors discussed.

SHOULD A CATHARTIC BE USED? Are Cathartics Beneficial? Although cathartics are routinely used in the treatment of the poisoned patient, their efficacy remains unproved. Cathartics are used to increase gastrointestinal transit speed, and thus cathartics, theoretically, decrease the transit time during which drug absorption may occur. Cathartics may also counteract the constipating effect of activated charcoal. Another proposed reason to use cathartics is to promote rapid passage through the gastrointestinal tract to decrease time available for systemic absorption of a drug that has “desorbed” from activated charcoal. Despite these theoretical advantages of cathartic use, it has been impossible to prove any consistent benefit. In fact, one study even suggests that use of cathartics alone may be deleterious, perhaps by increasing drug dissolution.3 Most studies examine the possible effects of cathartics on the efficacy of activated charcoal. The addition of cathartic to activated charcoal is occasionally beneficial,36,62,64,82,124 usually ineffective,49,60,118,136 and infrequently alleged to reduce the efficacy of activated charcoal.59,155 Many cathartics are available, although only magnesium citrate, magnesium sulfate, and sorbitol are generally considered for use (Table 31–3). All are effective cathartics and, although sorbitol may produce a bowel movement more rapidly, none appears to be clinically superior or better tolerated.89,141 Another clinically useful method of comparing cathartics is to investigate how different cathartics affect adsorption of a drug to activated charcoal. The results of such studies thus far offer conflicting results and no single cathartic significantly affects drug absorption. Although study design issues hinder direct comparison of the cathartics, some

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studies suggest that sorbitol is the most effective cathartic74,89 (see Antidotes in Depth: Cathartics).

Do Cathartics Harm the Patient? Are Cathartics Ever Contraindicated? In appropriate doses, and when contraindications to their use are excluded, there is no evidence that a single dose of cathartic is harmful. Following inadvertent overdosing or the use of repetitive, and therefore inappropriate, dosing, cathartics may have the potential for significant morbidity and mortality. Use of sodium sulfate and sodium phosphate (Phospho-Soda) is associated with serious fluid and electrolyte disturbances.46,104 The relative safety of magnesium cathartics may be a result of the limited absorption of magnesium ions compared to those of sodium.l Although no reports exist of magnesium toxicity following appropriate single-dose cathartic therapy in patients with normal renal function, cathartic-induced hypermagnesemia can occur, even in patients with normal renal function, after acute overdose or following multiple “appropriate” doses.55,110,137,138 All cathartics can cause dehydration from water loss in the stool or intraluminal “third-spacing.” For example, although sorbitol is not significantly absorbed, severe fluid and electrolyte derangements, intravascular volume depletion, hypernatremia, shock, and acidosis are reported following excessive dosing. Although these abnormalities can occur in adults,5 children, presumably because of their size, are at a particular risk.54 Because sorbitol fermentation by gut flora results in gas production, it may also cause abdominal distension. Although this is usually without serious result, massive distension sufficient to result in respiratory embarrassment and death is reported.10,53 Distension appears to be most common and problematic when there is decreased gut motility. The incidence of all cathartic-induced fluid and electrolyte disturbances is probably increased by slow gastrointestinal transit; thus, obstruction and ileus should be considered at least relative contraindications to cathartic use. Conversely, the use of cathartics in patients with preexisting diarrhea is obviously also unnecessary and therefore contraindicated. Volume depletion should always be corrected before catharsis, and cathartic use should be minimized in infants because of the risk of causing significant fluid and electrolyte disorders. To avoid precipitating hypermagnesemia, magnesium-containing cathartics should not be used in patients with renal failure or decreased glomerular filtration rates from any cause, because of resultant impaired renal magnesium excretion.142 Table 31–3 summarizes these contraindications.

What Is an Appropriate Cathartic Dose? Cathartic dosing is largely empirical with the goal of safely speeding the passage of stool. An initial dose of sorbitol, 1 g/kg, is reasonable in adults receiving activated charcoal. Cathartic administration, however, should not be considered obligatory for all adult patients. Furthermore, given the lack of proven benefit and potential for increased risk in children, cathartics are relatively contraindicated for infants and young children with low-risk ingestions. For those with potentially serious ingestions in whom cathartic administration is desired, a single dose of 0.5 g/kg of sorbitol may be acceptable. Repetitive cathartic administration is speculative and only rarely indicated. An adult patient who is receiving MDAC occa-

sionally requires a second sorbitol dose of 0.5 g/kg if laxity does not occur and no ileus is present. More than one additional dose of cathartic is probably inappropriate and dangerous. Children should never receive additional cathartic doses, and if done inadvertently, they should have meticulous monitoring of their vital signs, their intravascular volume status, and their electrolytes. Inadvertent administration of multiple doses of cathartic during MDAC therapy is a frequent occurrence because premixed preparations combining activated charcoal and sorbitol are widely available.

Summary: Cathartics Single doses of cathartics are generally safe and appropriate for adults, despite a lack of convincing evidence of efficacy. Although more than one dose of cathartic may sometimes seem logical, using multiple doses of any cathartic can cause significant toxicity, particularly in children. Repeat cathartic dosing should not be routine. If indicated in adults, repeat doses of cathartics should only be used if frequent fluid and electrolyte monitoring can be provided.

WHEN SHOULD WHOLE-BOWEL IRRIGATION BE USED? Because cathartic administration is limited by the risk of serious fluid and electrolyte disturbances, other methods of gastrointestinal decontamination are gaining favor. One clinical advance is the use of whole-bowel irrigation by using isotonic polyethylene glycol electrolyte lavage solutions (PEG-ELS).1,6,146 These solutions were originally introduced for preoperative bowel preparations, and were adapted for the management of poisoned or overdosed patients over the past 15 years. The components of these solutions are not absorbed, and because they are isotonic, there is no significant fluid shift into or out of the gastrointestinal tract. As a result, large volumes of PEG-ELS can be safely administered to patients with normal gastrointestinal function to “flush the gastrointestinal tract.” Huge volumes over long durations are routinely used without any significant change in volume status, electrolytes, or other laboratory parameters.72,79 Rather than inducing diarrhea by drawing water into the stool or directly stimulating motility, the large volume of fluid administered during whole-bowel irrigation mechanically washes bowel contents through the gastrointestinal tract. The first successful use of whole-bowel irrigation for poisoning management occurred in patients with iron overdoses who had radiographic evidence of residual iron in their gastrointestinal tract.151 Subsequently, studies of both human volunteers and animals show that whole-bowel irrigation reduces drug absorption after ingestion of ampicillin,148 lithium,139 and enteric-coated aspirin.84 Other studies, however, have not found beneficial effects for whole-bowel irrigation.29,127,132,142 Although case reports provide visually impressive radiographic or bedside evidence of gastrointestinal passage of arsenic,96 iron,52 lead,112,130 or sustained-release calcium channel blockers,28 they provide little useful data regarding either the clinical benefits achieved with the procedure or the outcome without it. The apparent safety and efficacy of whole-bowel irrigation make it an intriguing tool, but its role is yet to be fully defined. Delivering and retrieving the large volumes of solution required can present significant problems and is certainly not warranted routinely. The greatest utility of whole-bowel irrigation probably

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is in the management of life-threatening ingestions of agents that are poorly adsorbed to activated charcoal (eg, iron, lithium), too massive for activated charcoal alone (eg, sustained-release calcium channel blockers, theophylline), or ostensibly foreign bodies (eg, in body packers and stuffers) that are impossible to remove safely and effectively by other means. Other than practical issues related to the administration of whole-bowel irrigation, the most important concerns raised are about its effect on the adsorptive capacity of activated charcoal. Several in vitro studies demonstrate that PEG-ELS may interfere with activated charcoal efficacy.73,86,102,132 Whether the magnitude of benefit from whole-bowel irrigation outweighs the risk from slightly decreased activated charcoal adsorption remains to be shown. In patients with massive ingestions of sustained-release drugs such as theophylline or verapamil, where whole-bowel irrigation may be of benefit and MDAC is essential, the potential for decreased efficiency of activated charcoal becomes an extremely important consideration. Perhaps simply increasing the amount, frequency, or duration of activated charcoal administration would effectively compensate for any decreased adsorption. Other important considerations for study include effects of whole-bowel irrigation–induced pH, intestinal fluid volume, and mechanical action on drug dissolution in massive overdose models. An additional, related concern involves the institution of whole-bowel irrigation in patients who are already receiving oral activated charcoal. This is most consequential following overdose with sustained-release products, such as calcium channel blockers, under circumstances in which there is delayed recognition of the utility of whole-bowel irrigation. These patients may have large amounts of drug already adsorbed to the activated charcoal, which may be displaced by PEG-ELS. The liberated drug is available for subsequent absorption and may lead to acute decompensation of the patient.

Summary: Whole-Bowel Irrigation Whole-bowel irrigation can reduce absorption and augment removal of toxic agents in the gastrointestinal tract, although, like many other modalities, its actual clinical benefit remains undefined and unproved. Until the clinical benefit and potential adverse effects are better understood, its use should be limited to patients who have ingested sustained-release pills or drug packets, or who have gastrointestinal drug bezoars.

ARE THERE OTHER GASTROINTESTINAL DECONTAMINATION MODALITIES TO CONSIDER? What Other Binding Agents May Be Used? In rare cases, oral or enteral administration of binding resins may be useful. Cholestyramine adsorbs organochlorine pesticides such as chlordecone (Kepone) and lindane, and may limit their absorption or enhance their fecal elimination,40,61,81 but it is not known whether this is clinically beneficial. Elimination of digoxin and digitoxin is also enhanced by use of cholestyramine31,125 or colestipol,16,83 but the availability of the far more effective digoxin-specific antibodies and activated charcoal probably makes these other forms of therapy unnecessary. The possible efficacy of sodium polystyrene sulfonate (Kayexalate) to prevent gastroin-

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testinal absorption and to increase elimination of lithium is demonstrated in human volunteer and animal studies,17,97,153 but several study design issues limit the applicability of these results to poisoned patients. The resin-to-lithium ratios in these studies, which are very large, suggest that its value after actual poisoning will ultimately prove to be quite limited. In addition, the development of hypokalemia may prove problematic.98 Gastrointestinal administration of Prussian blue (potassium ferricyanoferrate) is advocated to exchange potassium for thallium, thus enhancing fecal thallium excretion (Chap. 83). Fuller’s earth adsorbs paraquat and diquat, but there appears to be no reason to advocate its use over activated charcoal. Oral starch can be utilized both diagnostically and therapeutically after ingestion of concentrated iodine solutions.

When Should Endoscopic Removal Be Used? Endoscopic removal of gastric contents is often considered but is rarely of practical value.113 Endoscopic removal is logical when a substance remains in the stomach, is a significant threat to the patient, cannot be removed by another less invasive means, and can be safely removed in this manner. Unfortunately, on a practical basis, many of the agents likely to be considered for endoscopic removal do not meet these criteria. Drug masses due to iron, enteric aspirin, meprobamate, and others, despite their solid appearance on radiographs, cannot be effectively grasped through an endoscope. When life-threatening deterioration is likely or evident, it remains unresolved whether these masses are best left untreated, treated with whole-bowel irrigation, broken up, or surgically removed. There are no clinically relevant data regarding the use of these methods or others of theoretical value (eg, lithotripsy). In body packers and body stuffers (Chap. 67) only the most durable drug packets may be safely grasped in this manner;72 others may rupture during removal, limiting the usefulness of endoscopy. In addition, removing multiple objects with an endoscope requires repeated passage of the endoscope and thus increases potential complications. Procedural complications, such as perforation, are expected to occur, but unexpected complications, such as gastrointestinal bleeding, are reported.95 Nonetheless, in rare circumstances meeting the criteria given, endoscopic removal may be of value.

When Is Surgery Indicated? Although exceptional, there are a few indications for surgical gastrointestinal decontamination. In rare instances, patients who ingest packets containing illicit drugs may require their surgical removal. Specifically, mechanical bowel obstruction, or bowel ischemia because of release of cocaine from drug packets, is an indication for surgery.34 Rupture of the packets and resultant toxicity may be managed medically if the amount of drug is small, the agent is not potentially lethal (marijuana), or an effective antidote is available (opioids). However, if packets containing a large amount of cocaine rupture, immediate surgical removal of remaining drug is warranted following appropriate stabilization.140 Other agents that cause toxicity and that form large masses or that adhere to the gastrointestinal tract wall and are not removed by gastric emptying, activated charcoal, and cathartic or wholebowel irrigation might require surgical removal. Although many agents are described as resulting in bezoar formation (eg, aspirin, bromide, meprobamate), in nearly all cases, gastric emptying and repetitive doses of activated charcoal are sufficient treatment. Pa-

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tients with massive iron ingestions who have iron evident on radiograph after gastric emptying attempts and whole-bowel irrigation should be considered for gastrotomy if serious systemic toxicity or evidence of active gastrointestinal bleeding occurs.58,151 Surgical intervention is frequently indicated for patients who ingest strong acids or bases, not for decontamination purposes, but to treat resultant gastrointestinal necrosis and perforation.

SUMMARY Gastrointestinal decontamination is far from an exact science, and controversy and change are expected. The issues discussed in this chapter provide a framework on which to build and refine a clinical approach. As in all areas of medicine, it is expected that thoughtful analysis of further research, clinical experience, and the unique features of each case will suggest appropriate modifications of current thinking and lead to improved patient care.

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6

PRINCIPLES AND TECHNIQUES APPLIED TO ENHANCE THE ELIMINATION OF TOXIC COMPOUNDS David S. Goldfarb

may be the only opportunities available to patients with lifethreatening toxicity caused by theophylline, lithium, aspirin, or a toxic alcohol. ■ Patients in whom the normal route of elimination of the toxin is impaired. Such patients may have renal or hepatic dysfunction, either preexisting or caused by the overdose. For example, a patient with chronic renal insufficiency associated with long-term lithium use is more likely to develop toxic drug levels and to require hemodialysis as therapy. ■ Patients in whom the amount of toxin absorbed or its high concentration in serum indicates that serious morbidity or mortality is likely. Such patients may not appear acutely ill on presentation. Toxins in this group include arsenic trioxide, ethylene glycol, lithium, mercuric chloride, methanol, paraquat, salicylate, and theophylline. ■ Patients with concurrent disease or in an age group (very young or old) associated with increased risk of morbidity or mortality from the overdose. Such patients are intolerant of prolonged coma, immobility, and hemodynamic instability. An example is a patient with severe underlying respiratory disease and chronic theophylline intoxication.

Enhancement of the elimination of a drug or toxin from a poisoned patient is a logical step after techniques to inhibit absorption such as orogastric gastric lavage, multiple-dose activated charcoal, or whole-bowel irrigation are initiated. Methods that may enhance elimination are listed in Table 6–1. Some of these techniques are described in more detail in other chapters that deal with specific drugs and poisons. In this chapter hemodialysis and hemoperfusion are considered extracorporeal therapies because drug and toxin removal occurs in a blood circuit outside the body. All of these methods are used infrequently because current methods of intensive supportive care keep the overall mortality rate low in poisoned patients who reach the hospital alive.29 Because the elimination techniques are not without adverse effects and complications,16,42,71 they are indicated in a relatively small number of patients.29,72 Although undoubtedly underestimates, the number of instances in which enhancement of elimination was used in a cohort of 2.2 million patients in 1999 demonstrate the relative infrequency of their use: alkalinization of the urine was used 6247 times; hemodialysis was used 1049 times; hemoperfusion was used 33 times; and other extracorporeal procedures were used 25 times. Statistics regarding peritoneal dialysis, a slower modality that should have little or no role in such cases, are not reported (Chap. 116 and p. 1752). There are very few prospective, randomized, controlled clinical trials to determine whether or not groups of patients actually benefit from enhanced elimination of various toxins. It is unlikely that these sorts of studies will ever be performed, given the relative scarcity of appropriate cases of sufficient severity and the many variables that would have to be controlled. Thus, anecdotal evidence predominates. We must still rely on our knowledge of the principles of the methods to identify the individual patients for whom enhanced elimination is indicated. Isolated case reports in which the kinetics are studied before, during, and after enhanced elimination are also very useful in establishing the efficacy of a method.

Ideally, these techniques will be applied to poisonings for which studies have suggested an improvement in outcome in treated patients as compared to patients not treated with extracorporeal removal. As previously mentioned, these data are rarely available. The need for extracorporeal elimination is less clear for patients who are poisoned with drugs or toxins that are known to be removed by the various modalities of treatment, but which cause limited morbidity if supportive care is provided. Relatively high rates of endogenous clearance would also make extracorporeal elimination redundant. Examples of such toxins are ethanol and barbiturates. Both are subject to substantial rates of hepatic metabolism, and neither would be expected to lead to significant morbidity after an affected patient is intubated and ventilated. There may be instances of severe toxicity with these two substances in which enhanced elimination will reduce the length of ICU stays and the associated nosocomial risks; extracorporeal elimination may then be a reasonable option.5,52

INDICATIONS FOR ENHANCED ELIMINATION Enhanced elimination may be indicated in several types of patients:

CAN THE TOXIN BE REMOVED?

■ Patients who fail to respond adequately to full supportive care. Such patients may have intractable hypotension, heart failure, seizures, metabolic acidosis, or dysrhythmias. Hemodialysis or hemoperfusion are much better tolerated than in the past, and

Effective removal by any of the procedures listed in Table 6–1 is limited by a large volume of distribution. The volume of distribution (Vd) relates the concentration of the toxin in the blood or

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TABLE 6–1. Potential Methods of Enhancing Elimination of Toxic Compounds Cerebrospinal fluid drainage and replacement Chelation Diuresis Exchange transfusion Hemodialysis Hemofiltration Manipulation of pH Multiple doses of activated charcoal, cholestyramine, colestipol, Kayexalate, Prussian blue Nasogastric suction Peritoneal dialysis Plasmapheresis Sorbent hemoperfusion Toxin-specific antibody fragments Whole-bowel irrigation

serum to the total body burden. The Vd can be envisioned as the apparent volume in which a known total dose of drug is distributed after acute administration, and before metabolism and excretion occur: Vd(L) = dose (mg)/concentration (mg/L) The larger the Vd, the less the compound is available to the blood compartment for elimination. A drug with a relatively small Vd, considered amenable to extracorporeal elimination, would distribute in an apparent volume not much larger than total body water. Total body water is approximately 60% of total body weight, so that Vd equal to total body water is approximately 0.6 L/kg body weight. Ethanol is an example of a toxin with a small Vd approximately equal to total body water. A substantial fraction of a dose of ethanol could be removed by hemodialysis. In contrast, an insignificant fraction of digoxin, with a large volume of distribution (Vd = 5–12 L/kg body weight), would be removed by this therapy. Lipid-soluble drugs and toxins, and those that are highly protein bound, have large volumes of distribution, which can exceed total body water, or even total body weight. These high apparent volumes of distribution imply that the drug is not available to extracorporeal removal because only a small portion of the substance would be in the extracorporeal circuit. In addition to the alcohols, other substances with relatively low Vd include acetaminophen, phenobarbital, lithium, salicylates, and theophylline. Conversely, those with a high Vd (up to 40 L/kg body weight), which would not be removed substantially by hemodialysis, include many
adrenergic antagonists (with the possible exception of atenolol64), diazepam, organic phosphorus compounds, phenothiazines, quinidine, and the cyclic antidepressants. Whether a toxin can be removed is also determined by the pharmacokinetics of the compound. Kinetic parameters after an overdose may differ from those after therapeutic or experimental doses.62 For instance, carrier or enzyme-mediated elimination processes may be overwhelmed by higher levels of the drug or toxin in question, making extracorporeal removal potentially more useful. Alternatively, plasma protein- and tissue-binding sites may all be saturated at higher concentrations, making extracorporeal removal feasible in instances where it would have no role in less significant overdoses. An example is valproic acid, which may be poorly dialyzed at nontoxic levels associated with high rates of

ELIMINATION OF TOXIC COMPOUNDS

59

protein binding. Higher, potentially toxic concentrations saturate protein-binding sites and lead to a higher proportion of the drug free in the serum and amenable to being removed at a clinically relevant rate by hemodialysis.35 Estimates of the expected endogenous rates of elimination of a substance in the setting of an overdose should be made then, where possible, from knowledge of the pharmacokinetics obtained in relevant models of toxicity, not after therapeutic doses. When assessing the efficacy of any technique of enhanced elimination, a generally accepted principle is that the intervention is worthwhile only if the total body clearance of the toxin is increased by at least 30%.16 This substantial increase is easier to achieve when the compound has a low endogenous clearance. Examples of substances with low endogenous clearance (6.5 regardless of degree of encephalopathy.132 These criteria for orthotopic liver transplant have been widely used and validated. They are highly reliable in predicting death, but their ability to predict survival is poorer.82,100 Whether the improvement of extracorporeal devices designed to provide temporary support to the failing liver with potential for re-

CHAPTER 14

TABLE 14–8. Adapted King’s College Criteria for Liver Transplantation of Patients with APAP-Induced FHF pH of 3.3 mg/dL or prothrombin time >100 sec or INR >6.5 Adapted from O’Grady JG, Warden J, Tan KC: Liver transplatation after paracetamol overdose. BMJ 1991; 303:221.

generation will alter decision-making in patients with FHF remains to be seen.100 The auxiliary partial orthotopic liver transplant is a new modality that may allow more patients with FHF caused by toxins to survive. This modality uses part of a donor liver as an auxiliary graft that keeps the patient alive until the native liver can regenerate. It provides a smaller mass of liver, making it less useful in treatment of patients with severe encephalopathy, and it is a more complex surgery. If successful, it allows withdrawal of immunosuppression. Although it is a theoretically attractive option, its role is still being defined.11,73

OTHER THERAPIES Intravenous N-acetylcysteine benefits patients with fulminant hepatic failure caused by different etiologies and is also beneficial in the later phase of acetaminophen toxicity36,43 (Chap. 32 and Antidotes in Depth: N-Acetylcysteine). The administration of glutathione also protects the rat liver against injury by CCl4.14 Hyperbaric oxygen increases the oxygen tension throughout the liver and decreases liver injury by carbon tetrachloride in rats. Hyperbaric oxygen converts the ·CCl3 radical produced by P4502E1 metabolism of CCl4 to the ·CCl3OO radical, which, although highly reactive, is less toxic because it is rapidly detoxified by glutathione.14,116 Hyperbaric oxygen was used in one human poisoning with a good outcome.120

SUMMARY The primary role of the liver in the biotransformation of xenobiotics results in an increased risk of hepatotoxicity. The spectrum of liver injury includes combinations of cholestasis, steatosis, and hepatocellular necrosis. Injury may be a result of immunologic mechanisms, free radical initiation of lipid peroxidation, mitochondrial injury, or other less-well-defined mechanisms related to the formation of adducts. Disturbances in intracellular calcium levels likely play a role in the development of hepatocellular injury. Drug-induced liver injury can be dose-dependent and predictable, or idiosyncratic and unpredictable. Idiosyncratic injury is affected by host characteristics that include genetic makeup, concomitant or previous exposure to drugs and toxins, and the underlying condition of the liver.

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119. Thabet H, Brahmi N, Amamou M, et al: Hyperlactatemia and hyperammonemia as secondary effects of valproic acid poisoning. Am J Emerg Med 2000;18:508. 120. Truss CD, Killenberg PG: Treatment of carbon tetrachloride poisoning with hyperbaric oxygen. Gastroenterology 1982;82:767–769. 121. Tsutsumi M, Lasker JM, Shimizu M, et al: The intralobular distribution of ethanol-inducible P450IIE1 in rat and human liver. Hepatology 1989;10:437–446. 122. Vergani D, Mieli-Vergani G, Alberti A: Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane associated hepatitis. N Engl J Med 1980;303:66–71. 123. Verrotti A: Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs. Int J Clin Lab Res 1999;29:36–40. 124. Victorino RMM, Maria VA, Correia AP, et al: Floxacillin-induced cholestatic hepatitis with evidence of lymphocyte sensitization. Arch Intern Med 1987;147:987–989. 125. Wang JD, Lai MY, Chen JS: Dimethylformamide-induced liver damage among synthetic leather workers. Arch Environ Health 1991;46:161–166. 126. Watanabe M, Tsukada N, Smith CR, et al: Permeabilized hepatocyte couplets: Adensosine triphosphate-dependent bile canalicular contractions and a circumferential pericanalicular microfilament belt demonstrated. Lab Invest 1992;65:203–213.

127. Weston CF, Cooper BT, Davies JD, et al: Veno-occlusive disease of the liver secondary to ingestion of comfrey. BMJ 1987;295:183. 128. Westphal JF, Vetter D, Brogard JM: Hepatic side-effects of antibiotics. J Antimicrob Chemother 1994;33:387–401. 129. Williams DE, Reed RL, Kezierski B, et al: Bioactivation and detoxification of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver. Drug Metab Dispos 1989;17:387–392. 130. Yeong ML, Clark SP, Waring JM, et al: The effects of comfrey derived pyrrolizidine alkaloids on rat liver. Pathology 1991;23:35–38. 131. Yeong ML, Swinburn B, Kennedy M, et al: Hepatic veno-occlusive disease associated with comfrey ingestion. J Gastroenterol Hepatol 1990;5:211–214. 132. Yoshida EM, Lake JR: Selection of patients for liver transplantation in 1997 and beyond. Clin Liver Dis 1997;1:247–261. 133. Yoshida EM, McLean CA, Cheng ES, et al: Chinese herbal medicine, fulminant hepatitis, and liver transplantation. Am J Gastroenterol 1996;91: 2647–2648 134. Zand R, Nelson SD, Slattery JT, et al: Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther 1993;54:142–149. 135. Zimmerman HJ, Ishak KG: Valproate-induced hepatic injury: Analysis of 23 fatal cases. Hepatology 1982;2:591–597.

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15

IMMUNOLOGIC PRINCIPLES William J. Meggs

system shuts down the other branches through the production of inhibitory cytokines. TH1 helper cells stimulate immunoglobulin E (IgE) production and suppress cellular immunity. TH2 helper cells stimulate cellular immunity and suppress IgE production. Human disease can arise from activation of the wrong type of immunity to a given pathogen, as evidenced in chronic Candida vulvovaginitis. Women with this disease make IgE against Candida, so that infections produce severe inflammation with swelling and pruritus, even with a small burden of pathogens. Cellular immunity, the only defense humans have against Candida, is inhibited, so the Candida infection cannot be cleared.11 Immunotherapy with injections of Candida antigen cures chronic Candida vaginitis by the inhibition of IgE production and a concomitant activation of cellular immunity against Candida.84

Immunology has impacted virtually every medical specialty with improved diagnostic tools, insights into pathophysiology of a host of diseases, and new treatments. Medical toxicology has been greatly advanced by modern immunology. Both diagnosis and treatment of poisonings can depend on immunologic techniques. Toxins can damage immune function resulting in immunodeficiencies and life-threatening infections. Autoimmune states can be activated by toxic exposures through several mechanisms. Toxins can induce allergic diseases such as asthma and rhinitis. A host of chemical irritants can induce inflammation and disease by neurogenic inflammation. Immunotoxicology is now an established interdisciplinary field of considerable importance. Laboratory developments in immunology have brought new tools to the diagnosis and treatment of poisonings. Monoclonal and polyclonal antibodies are used to neutralize colchicine, digoxin, and venoms. Immune assays are used to provide qualitative and quantitative data on toxins in the body. This chapter gives a brief overview of the immune system and discusses the interaction between the immune and nervous systems and the role of neurogenic inflammation in disease; the role of toxins in immune deficiency, autoimmunity, and allergy; and the role of immunology in laboratory developments that are used to diagnose and treat poisonings.

Neurogenic Inflammation and the Immune System-Nervous System Interaction The nervous system can induce inflammation in tissues throughout the body. This type of inflammation is known as neurogenic inflammation. Inflammatory mediators are released from sensory nerve C-fibers either by local stimulation or from retrograde propagation of a nerve impulse. Local stimulation arises when chemicals bind to chemoreceptors on the C-fibers and from mechanical stimulation of tissues. Sensory nerve C-fibers are found in subepithelial tissues of the respiratory tract, gastrointestinal tract, and skin. These fibers contain chemoreceptors that are triggered by chemical irritants. Examples of chemical irritants are cigarette smoke, gases such as sulfur dioxide and chlorine, solvents such as toluene diisocyanate and formaldehyde, and some fragrances, perfumes, and pesticides. When the irritants bind to the nerve fiber chemoreceptors, chemical mediators, including substance P, calcitonin gene-related peptide, and neurokinin A, are released. These substances produce vasodilatation and edema. In addition, the binding of irritants to the chemoreceptors triggers a nerve impulse that travels to the central nervous system.70,72 Neurogenic inflammation is of clinical importance. It is responsible for reactivity to chemical irritants in the skin and respiratory system and plays a role in systemic anaphylaxis. The importance of neurogenic inflammation in many inflammatory diseases is emerging through active research into this important and often neglected area of medicine.

THE IMMUNE SYSTEM: AN OVERVIEW The immune system is a large and extended organ system with sentinels throughout the body. Bone marrow, lymphatic ducts, lymph nodes, thymus, and spleen are all intimately involved in immunity. Immune cells arise from the bone marrow and migrate throughout the body and are listed in Table 15–1. These cells communicate by the release of and response to a group of protein molecules called interleukins (Table 15–2). Immune cells have the ability to recognize specific protein markers on the surfaces of bacteria, fungi, and viruses. Host cells infected with viruses and cancer cells that have developed from host cells can also be recognized and destroyed. Antibody molecules are excreted that can locate and lead to the destruction of microorganisms (Table 15–3). The complement system consists of a groups of proteins produced by the liver, which can destroy bacteria by cell wall lysis (Table 15–4). The immune system is controlled by T lymphocytes. T helper cells potentiate the response to a specific antigen, and T-suppressor cells suppress the response. T cells secrete protein messengers called cytokines that regulate the immune system and modulate inflammatory responses. Activation of one branch of the immune

Crossover Network Immunogenic and the neurogenic inflammation are related. Human skin mast cells contain receptors for substance P,11 and the

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TABLE 15–1. Granulocytes Basophils Eosinophils

Neutrophils Lymphocytes

THE BIOCHEMICAL AND MOLECULAR BASIS OF MEDICAL TOXICOLOGY

Cells of the Immune System Bone marrow-derived cells with cytoplasmic granules and multilobed nucleii Granulocytes with surface IgE receptors, which release histamine and other mediators of anaphylaxis Granulocytes that destroy parasites by releasing major basic protein and can damage host tissues; activated in allergic reactions Granulocytes that phagocytize bacteria Bone marrow-derived white blood cells that have a spherical nucleus and scant cytoplasm

TABLE 15–2.

Sources(s) Interleukin IL-1 IL-2 IL-3 IL-4

T cells Helper cells

Regulate the immune system by producing lymphokines that control the actions of other cells Cytolytic cells Destroy host cells that are infected or cancerous; destroy transplants B cells Migrate into tissues and differentiate into plasma cells to produce antibody Plasma cells Antibody-producing cells Natural killer cells Bind to tumor cells and microbes; release chemicals that destroy the membranes of these cells Monocytes Migrate into tissues and differentiate into macrophages, which phagocytize bacteria, fungi, and mycobacterium Mast cells Fight parasites; found in connective tissues along nerves and blood vessels; have surface receptors for IgE; degranulate to release allergic mediators

IL-5 IL-6 IL-7 IL-8 IL-9 IL-10

`

binding of substance P to mast cells triggers mast cell degranulation and the release of mast cell mediators. Sensory nerve C-fibers have surface receptors for histamine. When histamine binds to the nerve fibers, substance P is released and an impulse is transmitted up the nerve fiber.9 Figure 15–1 depicts the relationship between nerve fibers and mast cells. This crossover network leads to systemic anaphylaxis.

Neurogenic Switching Most commonly, clinical symptoms appear at the site of inoculation with antigen or chemical irritant. In certain instances, the site of response can be switched to another site.60 Examples include systemic anaphylaxis to ingestions of food and drugs, in which there is a rapid development of signs and symptoms in many organ systems. Food allergens most commonly cause gastrointestinal symptoms of diarrhea, nausea, vomiting, abdominal bloating, and cramping. Ingestion of a food to which one is allergic can result in urticaria, asthma, laryngeal edema, and systemic anaphylaxis. Patients with chemical irritant rhinosinusitis and asthma report headaches, musculoskeletal symptoms, and involvement of other organ systems when exposed to airborne chemicals. The site switching is thought to occur at the level of the central nervous system, with the response to the sensory nerve signal from the site of inoculation being rerouted to another peripheral location, leading to substance P release at the other location, as depicted in Figure 15–2. Evidence for neurogenic switching comes from animal studies in which systemic anaphylaxis can be blocked by ablating nerve pathways, even though histamine release still occurs at the inoculation site.46,48 Evidence for neurogenic switching in chemically sensitive humans is provided by a recent blinded, placebocontrolled study that inoculated conjunctiva with perfume in patients breathing fresh air. Although there was no perfume exposure to the airway, respiratory symptoms were induced by perfume

Interleukins and Interferons: Sources and Actions

IL-11 IL-12

IL-13 Interferons INF-
and -

INF-

Macrophages

T-cell stimulant; hematopoiesis; fever; inflammation Activated TH1 cells, B cell and activated T cell prolifNK cells eration; NK cells Activated T cells Hematopoietic progenitor cell growth Mast cells, TH2 cells Proliferation of B cells; growth and function of eosinophils and mast cells; B cell expression of lgE and class II MHC expression; monokine production inhibition Mast cells, TH2 cells Growth and function of eosinophils Macrophages, activated Proliferation of B cells; aids TNF TH2 cells and IL-1 action on T cells Thymic cells, marrow T-and B-cell lymphopoiesis stromal cells Macrophages Neutrophil and T-cell chemoattractant T cells Affects hemato- and thymopoiesis T and B cells, CD8+ B cell proliferation; antibody cells; macroproduction inhibits phages; activated cytokine production; cellular TH2 cells immunity, and mast cell growth Stromal cells Affects hematopoiesis, thrombopoiesis Macrophages, B cells NK cell proliferation; interferon production; cell-mediated immune function TH2 cells Similar to IL-4

Macrophages, neutrophils NK and activated TH1 Cells

TABLE 15–3.

Action(s)

NK cell and macrophage activation; antiviral; class I MHC induction Class I MHC induction on somatic cells; class II MHC induction on antigen

Human Antibody Molecule Isotypes

Isotype

Forms

Molecular Weight

Function

IgA

150 kD, 300 kD, 400 kD 180 kD

Secretory, mucosal immunity

IgD

Monomer, dimer, trimer Monomer

IgE

Monomer

190 kD

IgG

Monomer

150 kD

IgM

Pentamer

950 kD

Binds B-cell surface receptor Possible role in B-cell activation Binds mast cell and basophil cell membranes; triggers degranulation Binds to bacterial surfaces, leading to phagocytosis Earliest response to infection; binds complement; agglutination reactions

CHAPTER 15

TABLE 15–4.

IMMUNOLOGIC PRINCIPLES

233

Proteins of the Complement System Classical Pathway C1 C4 C2 C3 Alternate Pathway Factor B Factor D Properdin C3 Terminal Lytic Components C5 C6 C7 C8 C9 Figure 15–2. Sensory nerve fibers communicate an inflammatory response to the central nervous system.

but not placebo.66 A study that isolated the upper and lower airways of intubated cats demonstrated that inoculating the upper airway with sulfur dioxide produced bronchospasm, even though there was no direct contact of the sulfur dioxide with the lower airway.

SYSTEMIC ANAPHYLAXIS Systemic anaphylaxis, or anaphylactic shock, is a severe lifethreatening allergic reaction that involves multiple organ systems. Onset occurs most often immediately after exposure to the triggering agent. Delayed reactions can occur several hours after expo-

sure through late-phase mechanisms. Distinction is made between the clinically indistinguishable anaphylactic and anaphylactoid reactions by mechanism. Anaphylactic reactions are initiated by the degranulation of mast cells by antigen to which the victim has IgE antibody and requires prior sensitization. Anaphylactoid reactions occur when mast cell degranulation is initiated by a substance to which there is no IgE antibody and prior sensitization is not necessary. There is no different between treatment recommendations for anaphylactic and anaphylactoid reactions. Table 15–5 lists examples of substances that can trigger anaphylactic and anaphylactoid reactions. Clinical manifestations of systemic anaphylaxis include urticaria, angioedema, and flushing of the skin. Swelling of the

TABLE 15–5. Examples of Substances Known to Cause Anaphylactic and Anaphylactoid Reactions Antibiotics Ampicillin Cephalothin Penicillin Streptomycin Tetracycline Autologous serum Horse serum Enzymes Chymotrypsin Chymopapain L-Asparginase Penicillinase

Figure 15–1. The mechanisms of neurogenic inflammation triggered by chemical irritants, immunogenic inflammation triggered by allergens, and their relationship is depicted. Chemical irritants bind sensory nerve C-fibers to release substance P and other inflammatory mediators, while antigen binds IgE molecules on mass cell surfaces to produce mast cell degranulation and the release of histamine and other mediators. Mast cells have receptors for substance P, whereas sensory nerve fibers have histamine receptors.

Diagnostic agents Radiocontrast media Diagnostic/Therapeutic agents Allergy extracts Venoms Honey bee Hornet

Rattlesnake Wasp Yellow jacket Foods Beans Carrot Cotton seed meal Egg Fish Milk Nuts Peanuts Shrimp Parenteral nutrients Vitamin E Iron dextran Nonsteroidal anti-inflammatory agents Aspirin Ibuprofen Indomethacin Naprosyn

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tongue, nasal passages, glottic structures, and vocal cords can be of life-threatening proportions. Bronchospasm and bronchorrhea compromise oxygenation. Gastrointestinal manifestations include nausea, vomiting, diarrhea, abdominal bloating, and abdominal pain. Cardiovascular involvement can be primary from the direct effect of mediators on the heart. Secondary cardiac effects result from hypoxia, treatment with cardioactive agents, and the vasodilatory effects of histamine released from mast cells and basophils. Cardiac dysrhythmias range from sinus tachycardia to ventricular tachycardia, ventricular fibrillation, and asystole. In extreme cases, cardiovascular collapse and shock occur. Myocardial infarction is reported in individuals with otherwise normal coronary arteries.20,47 The pathophysiology of systemic anaphylaxis is complex and involves multiple pathways and different initiating mechanisms. Protein antigens initiate anaphylaxis by cross-linking IgE antibodies on the surface of mast cells and basophils. A cascade of events leads to the release of preformed mediators. The degranulation process initiates the synthesis of other mediators. Table 15–6 lists mast cell mediators. Activation of the complement system can initiate anaphylaxis because the C3a and C5a fragments of the degradation of complement proteins C3 and C5, respectively, bind to mast cells and trigger degranulation. Complement-initiated anaphylaxis occurs when the transfusion of mismatched blood products leads to the formation of immune complexes that activate complement. Individuals with IgA deficiency who are infused with immunoglobulin products can have anaphylactic reactions from the formation of IgG–IgA–anti-IgA immune complexes which then activate complement. Some chemicals, including pharmaceutic products, directly degranulate mast cells through nonimmunologic mechanisms. Aspirin and other prostaglandin synthesis inhibitors can lead to anaphylaxis in susceptible individuals by blocking prostaglandin but not leukotriene synthesis. Because some prostaglandins antagonize the action of proanaphylactic leukotrienes, severe reactions can occur. Opioids, radiocontrast mediators, and vancomycin are examples of agents that are pharmacologically active against mast cells and that can lead to anaphylaxis without prior sensitization. Table 15–7 outlines treatment of anaphylaxis. Epinephrine is the first-line agent and can be given by the intramuscular, subcutaneous, endotracheal, and intravenous routes, depending on the circumstances and severity of the attack. In an animal model, epinephrine is absorbed more rapidly by the intramuscular route

TABLE 15–6.

Mast Cell Mediators Preformed mediators Histamine Tryptase Heparin Proteoglycan Chymase Cathepsin G Carboxypeptidase Mediators synthesized after degranulation Prostaglandin D2 Leukotriene C4 Platelet activating factor Cytokines (IL-1, IL-4, IL-5, IL-6, TNG) Colony stimulating factors (IL-3, GM-CSF)

than the subcutaneous route, with plasma concentrations twice as high via the intramuscular route at 5 minutes92 Airway control with endotracheal intubation is vital. In the instance of severe laryngeal edema, emergency tracheostomy may be necessary. H1 and H2 antihistamines are used. Although corticosteroids are not of immediate benefit, their use is essential to prevent recurrent or late-phase reactions and adverse consequences of the inflammatory medicators that are released in anaphylaxis.

THE TOXIC INDUCTION OF IMMUNE DEFICIENCIES The hallmark of immune deficiency is a susceptibility to infections. A number of immune deficiency syndromes are defined, and the types of infections associated with each syndrome correlate with the branch of the immune system that is deficient. Many immune deficiency syndromes are genetic in origin and present in early childhood. Examples include severe combined immune deficiency syndrome (SCIDS) in which there is an absence of both B and T lymphocytes. Both cellular and antibody deficiencies occur, and death occurs in early childhood in the absence of a bone marrow transplant or extreme environmental isolation. Bruton disease is X-linked with B-lymphocyte lineage failure, no antibody production, and infections with encapsulated bacteria. Common variable immunodeficiency syndrome is an acquired loss of the ability to produce antibodies, with a susceptibility to sinusitis and pneumonia. Table 15–8 gives examples of xenobiotics associated with immune suppression. The most devastating immune deficiency induced by toxins is aplastic anemia, in which all branches of the immune system are destroyed. A recent study in the United States, Europe, Israel, and Thailand found penicillamine, gold, and carbamazepine to be the pharmaceutical agents most strongly associated with the development of aplastic anemia34 Recent case reports have linked aplastic anemia with both the antiplatelet agent ticlopidine19,52,87,97,108 and the anticonvulsant felbamate.2 A case of aplastic anemia associated with a herbal medicine was linked to contamination with phenylbutazone.71 A French study found a vanishing role for toxins previously known to cause aplastic anemia, presumably due to preventive measures.54 In 1897, benzene was reported to cause aplastic anemia with chronic occupational inhalational exposure. The estimated incidence is 1 per 100 exposed individuals at 100 parts per million (ppm) and 1 per 10,000 exposed individuals at 10–20 ppm.94 Inhalation exposure to burning oil in Kuwait during the Persian Gulf War has also been associated with aplastic anemia,88,89 and the organochlorine pesticide lindane has also been associated with aplastic anemia.6 Agranulocytosis is most strongly associated with procainamide, antithyroid drugs, and sulfasalazine.34 Dioxins and furans may suppress cellular immunity in humans. The compound 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) suppresses T-helper cell function in exposed workers up to 20 years after exposure.102 Workers exposed to a mixture of phenoxy herbicides contaminated with dioxins and furans have an increased total and respiratory cancer mortality relative to controls.3 An increased total cancer mortality, and in particular cancer mortality from digestive and respiratory cancers, was found in workers exposed to TCDD.74 This increase in cancer mortality may be a result of impaired cellular immunity against tumors. The toxic suppression of antibody production leads to bacterial infections. IgG deficiency is associated with sinusitis, bronchitis,

CHAPTER 15

TABLE 15–7.

235

Guidelines for Treatment of Anaphylaxis

Agent

Dose

Complications

Airway reactions: Goal: Maintain airway patency Initial Therapy Epinephrine 0.01 mL/kg (up to 0.5 mL) of 1:1000 dilution SQ every 10–20 min Oxygen Inhaled 40–100% 2-adrenergic Through nebulizer 0.3–0.5 mL in agonists 2.5 mL of 0.9% NaCI Secondary Therapy Corticosteroids H1 antagonists H2 antagonists

125–250 mg of methylprednisolone or equivalent Q 6 hr for 2–4 doses 1 mg/kg of diphenhydramine or equivalent 300 mg of cimetidine or equivalent

Cardiovascular reactions: Goal: Maintain hemodynamic stability Initial Therapy Intravenous fluids 10–30 mL/kg, titrated to effect Epinephrine

Secondary Therapy Norepinephrine H1 and H2 antagonists Glucagon

IMMUNOLOGIC PRINCIPLES

Dysrhythmias, hypertension None Dysrhythmias, hypertension

Hyperglycemia, fluid retention Anticholinergic effects None

Congestive heart failure

See Airway Reactions 1 mL of a 1:10,000 solution IV added to 9 mL of 0.9% NaCI to create a 1:100,000 solution infused slowly

Dysrhythmias, hypertension

2–12 µg/min IV in adults

Same as epinephrine

See Airway Reactions

See above

5–15 µg/min

Nausea, vomiting, hyperglycemia

and pneumonia. IgA deficiency is associated with upper respiratory infections and gastroenteritis. A number of xenobiotics suppress antibody production, and in many cases, the association was verified by rechallenge. One or more IgG subclass deficiencies are observed in 66.7% of asthmatics treated with chronic corticosteroids, but in only 6.7% of asthmatics not treated with chronic corticosteroids.42 Carbamazepine produces hypogammaglobulinemia with absent B lymphocytes accompanied by agranulocytosis.95 In workers occupationally exposed to lead, there is a

TABLE 15–8. Examples of Xenobiotics Implicated in the Induction of Immunosupression Agranulocytosis Angiotension-converting enzyme inhibitors; antithyroid agents; phenothiazines Aplastic anemia Antineoplastic agents; arsenic; benzene; bismuth; carbamazepine; chlordane; chloramphenicol; DDT; felbamate; gold compounds; mercury; penicillamine; phenytoin; silver; sulfonamides; ticlopidine; trimethadione; zidovudine Cellular immune impairment Chlordane; DDT; lindane; malathion; HCDD; PBBs; TCDD; 2, 3, 7, 8TCDF; phencyclidine Hypogammaglobulinemia Carbamazepine; cigarette smoke; corticosteroids; phenytoin; sulfasalazine; solvents

decrease in immunoglobulin levels with increasing lead levels.8 Sulfasalazine depresses IgG, IgM, and IgA in patients with inflammatory arthritis, with an incidence of 2%, 5%, and 3%, respectively.21 Suppression of serum immunoglobulins by cigarette smoking and exposure to industrial solvents is synergistic.68 A number of studies link phenytoin to selective IgA deficiency, and the link has been verified in some reports by rechallenge.31,90,99 Recurrent respiratory infections and decreases in serum levels of IgA, IgG2, and IgG4 are documented in patients on phenytoin, with clinical improvement and normalization of antibody levels with discontinuation of phenytoin.5 Selective IgA deficiency is associated with captopril27,107 and penicillamine.29,79 Three patients with juvenile rheumatoid arthritis treated with aspirin developed an IgA deficiency that resolved with discontinuation of aspirin therapy.43

LABORATORY EVALUATION OF THE HUMAN IMMUNE SYSTEM A tiered approach should be used in evaluating the human immune system for immune deficiency following a toxic exposure, with the tests ordered determined by the toxic exposure and the clinical consequences. A complete blood count with differential screens for “cytopenias” Should be obtained. Neutropenia can result from exposure to a number of drugs and toxins, and results in bacterial and fungal sepsis.41 Lymphopenia is most notably associated with iatrogenic corticosteroid administration, and results in susceptibility to viral, fungal, and mycobacterial infections.13 Recurrent

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TABLE 15–9.

THE BIOCHEMICAL AND MOLECULAR BASIS OF MEDICAL TOXICOLOGY

Xenobiotic Induction of Autoimmunity

Autoimmune hemolytic anemia Methyldopa; penicillin; pencillamine Autoimmune thyroid disease Polybrominated biphenyl; polychlorinated biphenyl; lithium; penicillamine; amiodarone Autoimmune hepatitis Methyldopa; oxyphenisatin; halothane Immune complex glomerulonephritis Cadmium; gold; mercury Myasthenia gravis Pencillamine; tiopronine; trimethadione Pemphigus
-Mercaptopropionylglycine; captopril; penicllamine, Polymyositis Penicillamine Scleroderma Rapeseed oil contaminated with anilines; silica dust; vinyl chloride Systemic lupus erythematosus Hydralzaine; procainamide; phenytoin; hydrazine; tartrazine; alfalfa sprouts

respiratory infections including sinusitis is associated with hypogammaglobulinemias, which is assessed by ordering immunoglobulin levels. A total IgG level is insufficient to exclude IgG subclass deficiencies, which are associated with infections. Integrity of cellular immunity can be assessed with delayed hypersensitivity skin tests to mumps, measles, and Candida. Intradermal injections of antigen should lead to erythema and induration at 24–48 hours. In vitro evaluation of cellular immunity may be determined by lymphocyte proliferation assays to specific antigens and mitogens. Deficiencies of cellular immunity are associated with viral, fungal, and mycobacterial infections, and are thought to impart an increased risk of cancer. Some toxins selectively decrease T-helper cell counts, and total T-helper and T-suppressor cell counts, as well as the ratio of helper to suppressor cells which can be determined by flow cytometry. Dioxin exposure lowers the helper-to-suppressor ratio102 and is associated with an increased risk of cancer.74

THE TOXIC INDUCTION OF AUTOIMMUNITY Autoimmune diseases are diseases in which an immune response is mounted against noninfected host tissues, leading to inflammation and tissue destruction. The toxic induction of autoimmunity is associated with some pharmaceutic and environmental chemicals. Table 15–9 provides examples of xenobiotics that are associated with the induction of autoimmune diseases. There are several mechanisms by which a xenobiotic can induce autoimmune disease.

1. A chemical can bind to host tissue so that modified host tissue antigens are recognized as foreign and the tissue is destroyed. Autoimmune hemolytic anemia associated with penicillin results if an immune response is mounted against penicillin bound to red blood cell membranes.24 2. In a process termed molecular mimicry, an immune response can be mounted against an agent that is chemically similar to host tissue, and the host tissue can be secondarily destroyed. Examples in which infectious agents can induce autoimmunity by molecular mimicry include type I diabetes mellitus26,33,101 and rheumatic heart disease.15 3. A chemical can alter the regulatory system that prevents the immune system from attacking self-antigens. Examples of this mechanism include autoimmune hemolytic anemia induced by the antihypertensive methyldopa,40 which inhibits T-suppressor cell function. Procainamide stimulates T-helper cell function65 and induces autoimmunity. Epidemics of autoimmune disease have occurred when populations were exposed to an environmental chemical that induced autoimmunity. The Spanish Toxic Oil Syndrome began in May 1981, when street vendors in the region of Madrid, Spain, sold bottles of cooking oil which were later found to be rapeseed oil that was contaminated with anilines. Of approximately 100,000 exposed individuals, some 20,000 developed a disease with arthralgias and myalgias, gastrointestinal symptoms, fever, rash, pruritus, pneumonitis with dyspnea, often with laboratory abnormalities of eosinophilia, and thrombocytopenia.73 The disease was self-limited in most individuals, but approximately 15% of those with illness developed a progressive collagen vascular disease with features of progressive systemic sclerosis, Sjörgen syndrome, Raynaud’s phenomena, and pulmonary hypertension.1,22 A revealing feature of this epidemic was that those who developed progressive autoimmune disease from the exposure were more likely to have HLA haplotypes associated with collagen vascular disease.32,106 These data suggest that a combination of environmental exposure and genetic susceptibility can lead to the onset of some cases of autoimmune disease. In 1960, an epidemic of erythema multiforme was associated with a margarine preparation, with approximately 20,000 of some 600,000 exposed individuals developing the disease.50 Systemic lupus erythematosus is commonly associated with xenobiotic exposure. Pharmaceutical agents that can induce lupus include hydralazine and procainamide, and, less commonly, phenytoin and isoniazid.109 Inhalation of the laboratory reagent hydrazine has also lead to lupus.81 Ingestion of alfalfa sprouts and the yellow coloring agent tartrazine77 can also induce lupus. Many cases thought to represent idiopathic lupus may be related to environmental chemicals that induce the disease,81 and careful environmental histories of exposures are essential for any patient presenting with lupus.

ALLERGIC DISEASES AND TOXINS Disorders that may be triggered by exposure to allergens include asthma, rhinitis, sinusitis, gastroenteritis, migraine,67,104 urticaria, and angioedema (see Table 15–10). Disease results from the combination of allergy and end-organ sensitivity. For example, an attack of allergic asthma occurs with a combination of exposure to an allergen in a host with asthmatic airways. Toxic exposures may

CHAPTER 15

TABLE 15–10. Hypersensitivity Associated With Drugs and Chemicals Cardiovascular Myocarditis: amphetamine; cyclic antidepressants; hydrochlorthiazide; vaccines Vasculitis: barbiturates; cephalosporins; dapsone; griseofulvin; insulin; penicillin; phenylbutazone; phenytoin; sulfonamides; vaccines; antivenoms Hematologic Hemolytic anemia: cephalosporins; methyldopa; procainamide; sulfonamides Hepatic Halothane; p-aminosalicylic acid; methyldopa; sulfonamides Renal Interstitial nephritis: methicillin; penicillins; phenytoin Respiratory Asthma: aspirin; cephalosporins; penicillin; sulfonamides; diisocyanates; phthalic anhydrides; trimellitic anhydrides; formaldehyde; cobalt salts; nickel salts; platinum salts Skin Contact dermatitis: benzocaine; beryllium salts; chlorpromazine; chromium salts; isoniazid; neomycin; nickel salts; phenols; pyrethrins; quinidine Exanthems: numerous pharmaceutical agents Erythema multiforme: penicillin; salicylates; phenytoin; phenylbutazone; sulfonamides Fixed drug eruptions: barbiturates; phenolphthalein; quinine; sulfonamides; tetracycline Cutaneous vasculitis: penicillins; phenytoin; pyrazalones; sulfonamides Purpura: phenytoin; quinine; quinidine; sulfonamides Erythema nodosum: oral contraceptives Toxic epidermal necrolysis: allopurinol; mithramycin; phenytoin; sulfonamides

induce both antibody production against previously benign substances and induce end-organ sensitivity to allergic stimuli. The reactive airways dysfunction syndrome (RADS) is described as an asthmalike illness occurring after a single high-dose irritant exposure that persists long after the initial exposure.7 Substances reported to induce asthma include acetic acid;80 ammonia;23 chlorine;25,28,37 ethylene oxide;16 sulfur dioxide;10 glacial acetic acid;39 smoke; dust;7 and toluene diisocyanate.49 Patients with RADS have asthma attacks as well as constitutional symptoms associated with previously tolerated levels of chemical irritants.61 Chronic inflammation with lymphocytic infiltrates is seen on pulmonary biopsy.25 Reactive upper-airways dysfunction syndrome (RUDS) refers to the induction of chronic rhinitis following an irritant exposure, and these individuals have a persistent intolerance to chemical irritants.58 Nasal biopsy findings in patients with RADS and RUDS include proliferation of peripheral nerves, basement membrane thickening, chronic inflammation with lymphocytic infiltrates, and gaps in tight junctions.61 These findings suggest a mechanism for the persistent reactivity to chemicals and inflammation seen in this patient population.62 Toxins can induce allergic diseases by acting as environmental adjuvants. An adjuvant is a substance that enhances the develop-

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ment of immunity to a second substance. The branch of the immune system activated is specific for each adjuvant. Alum is an adjuvant that induces IgE antibody to a coinjected protein. Killed mycobacteria in oil (Freund’s complete adjuvant) induces cellular immunity to a coinjected protein. Environmental adjuvants are chemicals found in the environment, which induce immune responses to other substances in the environment. Environmental adjuvants are thought to be responsible for the increasing prevalence of respiratory allergy in industrialized countries.55–57 Diesel exhaust particles,69 sulfur dioxide,55–57,83 nitrogen dioxide,55–57 and ozone4,55–57 are verified inducers of IgE antibody to simultaneously inhaled proteins in experimental models. Polyaromatic hydrocarbons in diesel exhaust particles enhance the production of IgE antibodies by B cells in vitro98and enhance the in vivo IgE production in the human upper airway.18 After in vivo nasal challenge with diesel exhaust particles, cytokine production is increased in the human upper airway.18 It is suggested that diesel exhaust particles may play a role in the worldwide increase in allergic respiratory disease.78 Both in vivo and in vitro tests are available for establishing hypersensitivity. Scratch tests are performed by placing an antigencontaining solution on the skin and puncturing the dermis with a needle. A wheel-and-flare reaction correlates with the presence of specific IgE against the antigen. Intradermal injection of antigen is used to establish both immediate and delayed hypersensitivity. Patch tests, in which a material is applied to the skin and covered with an occluding dressing, is used to test for contact dermatitis. Radioimmunoabsorbent tests (RAST) and related tests such as enzyme-linked immunosorbent assay (ELISA) are in vitro tests to detect specific IgE antibody. Intradermal skin testing is much more sensitive than in vitro tests for specific IgE.

Chemical Sensitivity Many individuals have a heightened response to chemical irritants, the most common of which are listed in Table 15–11. Chemical sensitivity differs from allergy in the size of the molecules, the binding sites, and the mediators released. Chemical sensitivity when low-molecular-weight (10,000 daltons) react with IgE antibodies on mast cell surfaces to release histamine and other allergic mediators. Respiratory symptoms are very prominent in chemically sensitive individuals.58 The majority of individuals with asthma or rhinosinusitis have some degree of chemical sensitivity.59,89 Chemical sensitivity is a general term that refers to individuals with sensitivity to chemical irritants and includes individuals with disorders that are exacerbated by exposures to chemical irritants, such as rhinosinusitis and asthma. The multiple chemical sensitivity syndrome is a term from the occupational medicine literature that refers to individuals with severe and disabling intolerance to multiple chemicals of diverse classes, with multiple organ system involvement. Sick building syndrome is a disorder associated with poorly ventilated buildings, and symptoms are predominantly respiratory and neurologic. Workers in sick buildings complain of mucosal irritation, with cough, rhinosinusitis, and dry or burning eyes. Neurologic symptoms associated with sick building syndrome are headache, difficulty with concentration, and memory problems. Environmental illness and 20th century disease are expressions used in the popular literature to refer to sensational cases of individuals who have retreated from the modern world because of an intolerance of indoor and outdoor air contaminants. Idiopathic environmental intolerances refers to a condition with no documentable abnormalities except a subjective intolerance of chemicals. It is important to note that individuals with asthma, rhinosinusitis, and dermatitis associated with exposures to a broad class of chemical irritants do not have idiopathic environmental intolerances. There is considerable overlap between these disorders. Persons with chemical-irritant asthma and rhinosinusitis often have headaches and fatigue associated with chemical exposures, and hence meet case definitions for the multiple chemical sensitivity syndrome.61 In sick building episodes, the most severely affected often become chronically ill with the multiple chemical sensitivity syndrome.110 Persons with occupationally related asthma and rhinosinusitis are sometimes labeled as having noncompensable psychologic problems and idiopathic environmental intolerances by physicians testifying against workers seeking worker’s compensation insurance benefits. Chemical sensitivity is very common in general populations. A telephone survey by the California Department of Health found that 15.9% of the 4,046 adults residing in California reported being “allergic to or unusually sensitive to everyday chemicals,” and 6.3% of those surveyed had been given a diagnosis of the multiple chemical sensitivity syndrome by a physician.44 A general population telephone survey of 1446 households contacted in North Carolina found that chemical sensitivity was of comparable prevalence to allergy with 35% reporting allergies, 33% of adults reporting chemical sensitivity and 4% of this latter group affected daily.63 Early hypotheses considered chemical sensitivity to be a psychologic or psychiatric disorder, but these hypotheses have been thoroughly investigated and found to be incorrect. Controlled scientific studies have shown that although there is an increased incidence of anxiety and depression among those patients with chemical sensitivities relative to control groups, the majority of patients with chemical sensitivities do not have psychiatric illness.91

IMMUNOLOGIC THERAPY OF POISONINGS There are two types of antibodies that can be administered to treat poisonings. Antibodies can bind directly to a toxin and neutralize its action. Alternatively catalytic antibodies enhance the metabolism of toxins to nontoxic chemicals. Table 15–12 lists the antibody therapies currently available in the United States. Scherrman and collaborators85 have defined immunotoxicotherapy as the procedure to sequester, extract, or redistribute, and to eliminate a toxin from the body by the use of antibody molecule entities with specific active binding sites (SABS). A schematic of an antibody molecule is given in Fig. 15–3. The variable region V is the site on the antibody molecule that binds specific antigens. A fragment of an antibody molecule that contains a variable region should be as effective in neutralizing a toxin as the entire molecule. Nonmenclature for possible fragments of antibiotic molecules are given in Fig. 15–3. Polyvalent sera contain antibodies to multiple binding sites. Polyvalent sera are produced by immunizing an animal and harvesting antibody without regard to specificity. The serum is collected and the globulin fraction is extracted for injection. This serum contains antibody against a host of substances, and also contains other serum proteins. Monovalent sera, which contains antibody to a specific substance, is purified from polyvalent serum by affinity chromatography. Monoclonal antibody is produced by a hybridoma, which is the fusion product of a plasma cell producing specific antibody and a tumor cell. Hybridomas produce large quantities of specific antibody in culture, and have provided a source of previously unimaginable quantities of specific antibody. Recombinant DNA technology can be used to insert the gene for a specific antibody into a bacterial cell, which then manufactures the antibody.

TABLE 15–12. Immunotoxicotherapy for Poisoning Currently Available in the United States Toxin

Serum

Manufacturer/Supplier

Microcrura venom (coral snake) Bark scorpion venom Lactrodectus mactans (Black widow spider) venom Botulinum toxin

Horse

Wyeth

Goat Horse

University of Arizona Merck

Horse

Centers for Disease Control Wyeth Protherics

Crotalidae venom* (pit viper) Digoxin

Loxoscles reclusa (brown recluse spider; experimental)

Tetanus toxin

Horse Cro Tab (Fab fragment) Fab fragment of sheep antibody Rabbit immunoglobulin isolated with affinity chromatography Human

GlaxoSmithKline

Vanderbilt University

Bayer Biological

*Antivenom for nonnative snakes can be obtained from zoologic parks. Consult poison centers for sources.

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Figure 15–3. A. A monomeric antibody molecule consists of two light chains and two heavy chains joined by disulfide bonds. Antigen binding sites are marked with an asterisk. B. Papain digestion divides the antibody molecule into three fragments, with two Fab (fragment, antigen-binding) molecules and one Fc (fragment, crystalline) molecule. C. Pepsin digestion cleaves the molecule so that there is a (Fab)2 fragment with two antigen binding sites and small peptide fragments.

Fig. 15–4 depicts electrophoresis of four different antibody products. An affinity purified or monoclonal antibody against a single epitope would appear as a monoclonal spike in the gamma region of the electrophoretic spectrum. It can be seen from the figure that increasing levels of purification lead to a predominance of γ-globulins. Cleaving the antibody molecules with enzymes produces antibody fragments. Fragments containing variable regions specific for a toxin are obtained. The advantage of treating poisoning with antibody fragments is that the reduced molecular weight of fragments results in a lower protein load. Fragments lack the Fc portions of antibody molecules that are associated with serum sickness, activation of complement, and allergic reactions. In a rat model, doses of Fab fragments up to several g/kg were well tolerated.39 Humanized antibodies are prepared by combining antibody fragments containing variable regions from a nonhuman species with a human Fc fragment. Humanized antibodies have greater utility in the treatment of infectious diseases than in the treatment of poisonings because the human Fc portion aids in fighting infections by activating complement. Adverse reactions to autologous sera include allergic reactions and serum sickness. Anaphylactic shock, urticaria, and bronchospasm can occur during the administration of sera. A positive skin test to the sera increases the probability of an allergic reaction. Treatment is with epinephrine, antihistamines, oxygen, fluid support, and corticosteroids, as given in Table 15–7. If a patient with known allergy to a serum has to be treated, the patient can be desensitized by beginning therapy with a dose too small to produce a reaction, and then progressively increasing the dose. Serum sickness occurs 7–14 days after initial exposure to foreign protein such as those contained in sera. Urticaria, vasculitis, arthralgias, myalgias, fever, and, in some cases, glomerulonephri-

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tis occur in serum sickness. With prior exposure, onset may be as early as 2 days. Serum sickness can be effectively treated with corticosteroids. Plasma apheresis is effective but seldom needed. Both anaphylaxis and serum sickness are avoided by using antibody fragments rather than whole-antibody molecules. Factors that determine the clinical utility of an antibody or fragment specific for a toxin are the size of the product; the volumes of distribution of the toxin and antibody product; the kinetics of the binding of the toxin to the variable region; the kinetics of the binding of the toxin to active sites such as receptors; the stability of the product in vivo; and the elimination kinetics of the toxinantibody complex.85 The volume of distribution of IgM and IgG in humans is 5 L, whereas the volume of distribution of Fab fragments is 30 L. Volume of distribution of toxins varies greatly, and ideally the volume of distribution of the antibody product should equal that of the toxin. The rate at which the antibody product is distributed in tissue can also influence efficacy. IgG and (Fab)2 equilibrates with interstitial fluid within 12–24 hours, whereas Fab equilibrates within 2–4 hours.100 To reverse toxicity, the specific antibody must have a high affinity for the toxin. Treatment of digoxin toxicity with monoclonal antibodies results in a marked redistribution of toxin, with total digoxin in plasma increasing by approximately 6-fold while free plasma digoxin falls dramatically. The high molecular weight and small volume of distribution of antibody molecules limits their use to those substances that do not require large amounts of neutralizing antibody. Although factors in addition to stoichiometry play a role in determining the effective dose of an antibody or fragment, toxins with small lethal doses will generally require less neutralizing antibody. One antibody molecule has two binding sites for antigen, so from the standpoint of stoichiometry 1 antibody molecule and 1 (Fab)2 fragment neutralizes 2 molecules of drug. A Fab fragment neutralizes 1 molecule of drug.

IMMUNOTOXICOTHERAPY OF DRUG OVERDOSES A product currently available in the United States for treating drug overdoses is Digibind (GlaxoSmithKlein), which is a Fab fragment of specific antibody to digoxin from the sera of immunized sheep. The digoxin specific antibody is purified by affinity chromatography, and the Fab fragment is obtained by digestion of the antibody with papain. The molecular weight is 46,200. Digibind is a safe and effective treatment for digoxin poisoning (see Chap. 48 and Antidote in Depth: Digoxin Specific Antibody Fragments). DigiTab (Protherics) is another product that neutralizes digoxin. Colchicine poisoning has also been effectively treated with Fab antibody fragments.86 Antibodies have been developed against and demonstrated to be effective in animal models for poisonings with desipramine. Ricin toxicity has been reversed by neutralizing monoclonal antibodies in a mouse model,45 while phencyclidine has been studied in dogs.75 For substances in which ingestions of a large mass of drug occur, such as theophylline, antibody therapy is possible only if a small variable region fragment can be developed. Consider a 100kg patient who ingests enough theophylline to develop a toxic blood level of 100 µg/mL. The amount of drug ingested would be

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Figure 15–4. Protein electrophoresis of equine-derived (A) skin test material (normal serum; Merck Sharpe & Dohme); (B) Latrodectus antivenom (crude hyperimmune serum; Merck Sharpe & Dohme); (C) Crotalidae antivenom (ammonium sulfate precipitation, filtration; Wyeth); (D) Latrodectus antivenom (pepsin digestion, ammonium sulfate precipitation, filtration; Commonwealth Serum Laboratories). With increasing purification, a relative increase in immunoglobulins and decrease in other fractions can be seen.

Total drug (mg) = serum drug concentration × Vd × weight in kg = 100 g / mL × 0.5 L / kg × 100 kg =5g The molecular weight of Fab needed to stoichiometrically bind 5 g of theophylline is Ratio of Fab to drug needed = (molecular weight of Fab) / (molecular weight of drug) = 261:1 The mass of Fab needed = 261 × 5g = 2.81 kg. Clearly it would be impossible to infuse this amount of Fab fragment into a person. Also, the cost would be prohibitive. This example illustrates that immunotoxicotherapy will probably be limited to those situations in which milligram amounts of the substance is toxic, unless small fragments containing variable regions can be developed. Technical problems can impede the development of an antibody to specific drugs. The molecular weight of most drugs is too small for them to be immunogenic, so the drug must be conjugated to a protein. Antibodies have to be raised against the drug-protein conjugate. The affinity for antibody molecules raised against a

drug-protein adduct to the drug alone varies with the specific epitope on the adduct that the antibody recognizes. Monoclonal Fab fragments specific for phencyclidine reduces toxicity in rats.103 Progress has been made in developing catalytic antibodies that hydrolyze the organic phosphorus compound VX.35,105 This work gives hope that in the future, catalytic antibodies may be used to treat exposure to chemical warfare agents and other toxins. A catalytic antibody that metabolizes cocaine to nontoxic metabolites protected rats from cocaine-induced seizures and sudden death in a dose-dependent fashion, whereas a noncatalytic anticocaine antibody did not reduce toxicity.64

IMMUNOTOXICOTHERAPY OF ENVENOMATIONS The venom of the various pit viper species in the United States is sufficiently similar that one product, Antivenin (Crotalidae) Polyvalent (equine origin; ACP, Wyeth Laboratories, Philadelphia, PA) is useful for all pit viper envenomations. This antivenin is derived from horse sera, contains whole-antibody molecules, and has a greater than 75% rate of hypersensitivity reactions.12 Antivenom Polyvalent Crotalidae (Ovine) Fab (CroFab, Protherics, Inc.) is an affinity-purified sheep Fab fragment that was approved in October 2000 for use in the United States. In a murine model using lethality as an outcome, the Fab product was found to be 3.1–9.6 times

CHAPTER 15

more potent than the whole-antibody product when tested against the venom of 9 pit vipers indigenous to the United States.12 Experience with other Fab products suggests that incidence of hypersensitivity reactions will be greatly reduced with the Fab product. Internationally, a host of antivenoms are available for many local poisonous species. Envenomations by nonnative species occurs as a result of importation for research, display in zoos, and pets. Antivenom is stocked by zoos and other institutions and may be located by consulting a regional poison center.

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spider is not always identified, the simultaneous availability of an antivenom and a diagnostic test would greatly impact treatment. EMIT and FPIA are similar to RIA, but fluorescein-labeled analyte is used instead of radiolabeled analyte. Advantages of the fluorescence assays over RIA are cost and avoidance of radioactive reagents. EMIT and FPIA are used in toxicologic screens to detect drugs of abuse and drugs associated with overdoses.

SUMMARY

IMMUNOTOXICOTHERAPY FOR BACTERIAL TOXINS Antibody products are currently used to treat poisoning with Botulinum toxin (Chap. 75) and as a prophylaxis against tetanus toxin. Immunotoxicotherapy using monoclonal antibodies against the toxins and mediators of septic shock has not been successful. Immunotoxicotherapy directed against Clostridium difficile toxoids is successful against C. difficile enteritis for both in vitro and in vivo models. A case of severe pertussis treated with specific γ-globulin with high titers of antipertussis toxin antibody had a good clinical outcome.30

IMMUNE TECHNIQUES FOR DETECTING TOXINS A number of techniques have been developed that use specific antibody against a substance to quantitate the amount of substance present in a specimen. Radioimmunoassay (RIA) heralded a new era in laboratory medicine. Techniques that followed include the ELISA, the enzyme-multiplied immunoassay technique (EMIT), and the fluorescence polarization immunoassay (FPIA). In the RIA method, a known amount of antibody against the substance to be measured (analyte) is incubated with the specimen, and then radiolabeled analyte of known quantity is added to the specimen. Determination of the amount of radioactivity bound to antibody allows a calculation of the amount of analyte in the original specimen. Disadvantages of RIA are expense, hazards of radioisotope use and disposal, and the long time required to complete assays. Its uses are limited to hormone assays, for which it was originally developed, and measurement of therapeutic drug levels. In the ELISA assay, specific antibody against the analyte is conjugated to an enzyme, which changes the optical characteristics of a reagent. The specimen with unknown amount of analyte is mixed with the antibody-enzyme complex, the solution is cleansed by removal of excess complex, the reagent that undergoes an optical change in the presence of the enzyme is added, and quantitation of the color change allows a calculation of the amount of analyte in the original specimen. ELISA assays are used in Sweden to measure plasma levels of viper venom before and after administration of Fab antivenom93 (Chap. 7). Such technology is not as essential in the United States as it is in other countries, because the two groups of poisonous snakes found in the United States are easily distinguished. Immunodiagnosis following envenomation can be used to help determine the need for treatment after bites when there is delayed toxicity, such as envenomation by the coral snake and the Mohave rattlesnake. Because brown recluse spider bites have delayed toxicity and the

An understanding of immunology is essential for new concepts in pathophysiology, diagnostic techniques, and treatment. Broad new advances in these areas will dramatically improve our comprehension of immunotoxicology.

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63. Meggs WJ, Dunn KA, Bloch RM, et al: Prevalence and nature of allergy and chemical sensitivity in a general population. Arch Environ Health 1996;51:275–282. 64. Mets B, Winger G, Cabrera C, et al: A catalytic antibody against cocaine prevents cocaine’s reinforcing and toxic effects in rats. Proc Natl Acad Sci U S A 1998;95:10176–10181. 65. Miller KB, Salem K: Immune regulatory disorders produced by procainamide. Transplant Proc 1982;73:487–492. 66. Millqvist E, Bengtsson U, Lowhagen O: Provocations with perfume in the eyes induce airway symptoms in patients with sensory hyperreactivity. Allergy 1954;54:495–499. 67. Monro J: Food-induced migraine. In: Brostoff J, Challacombe SJ, eds: Food Allergy and Intolerance. Bailliere Tindall, London. Chapter 37, 1987, p. 633. 68. Moszczynski P, Slowinski S, Moszczynski P: Synergistic effect of organic solvents and tobacco smoke on the indicators of humoral immunity in humans. Gigiena Truda i Professionalnye Zabolevaniia 1991;3:34–36. 69. Muranaka M, Suzuki S, Koizumi S, et al: Adjuvant activity of diesel-exhaust particulates for the production of IgE antibody in mice. J Allergy Clin Immun 1986;77:616–623. 70. Nadel JA: Neutral endopeptidase modulates neurogenic inflammation. Eur Respir J 1991;4:745. 71. Nelson L, Shih R, Hoffman R: Aplastic anemia induced by an adulterated herbal medication. J Toxicol Clin Toxicol 1995;33:467–470. 72. Nielsen GD: Mechanisms of activation of the sensory irritant receptor by airborne chemicals. Crit Rev Toxicol 1991;21:183–208. 73. Noriega AR, Gomez-Reino J, Lopez-Encouentra A, et al: Toxic epidemic syndrome, Spain, 1981. Lancet 1982;2:697–702. 74. Ott MG, Zober A: Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occup Environ Med 1996;53:606–612. 75. Owens SM, Mayersohn M: Phencyclidine-specific Fab fragments alter phencyclidine disposition in dogs. Drug Metab Dispos 1986;14: 52–58. 76. Pentel PR, Ross CA, Landon J, et al: Reversal of desipramine toxicity in rats with polyclonal drug-specific antibody Fab fragments. J Lab Clin Med 1994;123:387–393. 77. Pereyo N: Hydrazine derivatives and induction of systemic lupus erythematosus. J Am Acad Dermatol 1986;14:514–515. 78. Peterson B, Saxon A: Global increases in allergic respiratory disease: The possible role of diesel exhaust particles. Ann Allergy Asthma Immunol 1996;77:26308. 79. Proesmans W, Jaeken J, Eeckels R: D-Penicillamine-induced IgA deficiency in Wilson’s disease. Lancet 1976;2:804–805. 80. Rajan KG, Davies BH: Reversible airways obstruction and interstitial pneumonitis due to acetic acid. Br J Ind Med 1989;46:67–68. 81. Reidenberg MM, Durant PJ, Harris RA, et al: Lupus erythematosuslike disease due to hydrazine. Am J Med 1983;75:365–370. 82. Rees R, Campbell D, Reiger E, et al: The diagnosis and treatment of brown recluse spider bites. Ann Emerg Med 1987;16:945–949. 83. Riedel F, Kramer M, Scheibenbogen C, Rieger CH, Effects of SO2 exposure on allergic sensitization in the guinea pig. J Allergy Clin Immunol 1988;82:527–534. 84. Riggs D, Miller MM, Metzger WJ: Recurrent allergic vulvovaginitis. Treatment with Candida albicans allergen immunotherapy. Am J Obstet Gynecol 1990;162:332–336. 85. Scherrman JM, Terrien N, Urtizberea M, et al: Immunotoxicotherapy: Present status and future trends. J Toxicol Clin Toxicol 1989; 27:1–35. 86. Scherrmann JM, Sabouraud A, Urtizberea M, et al: Clinical use of colchicine-specific Fab fragments in colchicine poisoning [abstract]. Vet Hum Tox 1992;34:334, 1992. 87. Shapiro CD, Walk D: Aplastic anemia associated with ticlopidine. Neurology 1996;47:300. 88. Shem SC, Kumar R, Roberts IA: Aplastic anaemia after exposure to burning oil. Lancet 1995;346:183.

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89. Shim C, Williams MH Jr: Effect of odors in asthma. Am J Med 1986;80:18–22. 90. Shindo K, Kono T, Kitajima J, et al: Crusted scabies in acquired selective IgA deficiency. Acta Derm Venereol 1991;71:250–251. 91. Simon GE: Psychiatric symptoms in multiple chemical sensitivity. Toxicol Indus Health 1994;10:487–96. 92. Simons FER, Roberts JR, Gu X, Simons KJ: Epinephrine absorption after different routes of administration in an animal model. J Allergy Clin Immunol 1998;101:33–37. 93. Sjostrom L, Karlson-Stiber C, Persson H, et al: Development and clinical application of immunoassays for European adder (Vipera berus berus). Toxicon 1996;34:91–98. 94. Smith MT: Overview of benzene-induced aplastic anaemia. Eur J Haematol Suppl 1996;60:107–110. 95. Spickett GP, Gompeis MM, Saunders PW: Hypogammaglobulinaemia with absent B lymphocytes and agranulocytosis after carbamazepine treatment. J Neurol Neurosurg Psychiatry 1996;60:459. 96. Stern MA, Eckman J, Otterman MK: Aplastic anemia after exposure to burning oil [letter]. N Engl J Med 1994;331:358. 97. Su CC, Tseng CD, Hwang JJ, et al: Severe aplastic anemia induced by ticlopidine. Report of a case. J Formos Med Assoc 1995;94: 689–691. 98. Takenaka H, Zhang K, Diaz-Sanchez D, et al: Enhanced IgE production results from exposure to the aromatic hydrocarbons from diesel exhaust: Direct effects on B-cell IgE production. J Allergy Clin Immunol 1995;95:103–115. 99. Talesnik E, Rivero SJ, Gonzalez B: Serum IgA deficiency induced by prolonged phenytoin treatment. Rev Invest Clin 1989;41: 331–335. 100. Thanh-Barthet CV, Urtizberea M, Sabouraud AE, et al: Development of a sensitive radioimmunoassay for Fab fragments: Application to Fab pharmacokinetics in humans. Pharm Res 1993;10: 692–696. 101. Tisch R, McDevitt H: Insulin dependent diabetes mellitus. Cell 1996;85:291–297. 102. Tonn T, Esser C, Schneider EM, et al: Persistence of decreased T-helper cell function in industrial workers 20 years after exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin. Environ Health Perspect 1996;104:422–426. 103. Valentine JL, Mayersohn M, Wessinger WD, et al: Antiphencyclidine monoclonal Fab fragments reverse phencyclidine-induced behavioral effects and ataxia in rats. J Pharmacol Exper Therap 1996; 278:709–716. 104. Vaughn R, Lyndon E: Neurologic reactions to foods and food additives. In: Metcalfe DD, Sampson HA, Simon RA, eds: Food Allergy. Oxford, Blackwell Scientific, 1991, pp. 355–369. 105. Vayron P, Renard PY, Taran F, et al: Toward antibody-catalyzed hydrolysis of organophosphorus poisons. Proc Natl Acad Sci U S A 2000;97:7058–7063. 106. Vicario JL, Serrano-Rios M, San Andres F, et al: HLA-DR3, DR4 increase in chronic stage of Spanish oil disease [letter]. Lancet 1982; 1:276. 107. Vil’chinskaia M, Nasonov EL, Zharova EA, et al: Immunological effects of captopril and ramipril in patients with hypertension. Klin Med (Mosk) 1990;68:61–64. 108. Weiner P, Zidan F, Paz R: Severe aplastic anemia due to ticlopidine. Isr J Med Sci 1995;31:444–445. 109. Weinstein A: Drug-induced lupus erythematosus. In: Schwartz RS, ed: Progress in Clinical Immunology, Vol 4. New York, Grune Stratton, 1980, pp.1–21. 110. Welch LS, Sokas R: Development of multiple chemical sensitivity after an outbreak of sick-building syndrome. Toxicol Indust Health 1992;8:47–50. 111. Witkens SS, Jeremias J, Ledger WJ: A localized allergic response to Candida in woman with recurrent vaginitis. J Allergy Clin Immunol 1988; 81:412–416.

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16

MUTAGENS, CARCINOGENS, AND TERATOGENS Gideon Koren / Kathleen A. Delaney / Debra Kennedy

Toxins injure living organisms by interfering with critical metabolic processes, causing structural injury to cells, or altering the cellular genetic material. Many specific types of injury to the genome that may result in genetic mutations are described. Mechanisms of tumor formation or carcinogenesis are less clearly understood and documented. The general principles relevant to an understanding of the mechanisms of mutagenesis and carcinogenesis are outlined below. The teratogenesis section of the chapter focuses on the different ways in which the extent of fetal xenobiotic exposure can be more accurately determined. The various biologic markers of fetal exposure that are currently available and the ways in which they may be used to counsel couples at risk, as well as to gain a more quantitative estimate of the true extent of fetal xenobiotic exposure, are also discussed.32

acid. This hypothetical segment of mRNA would code for a protein with the following amino acid sequence: 5′ − AAA UUG GGC CUA CGG CUA – 3′ lysine - leucine - glycine - leucine - threonine - leucine

MUTAGENS Mutagens are agents that produce alterations in DNA. They may interact with the DNA molecule in a number of ways to produce chemical injury. Not every alteration or mutation in DNA has an effect on gene expression. For example, a DNA alteration such that the third base of mRNA in the above sequence is changed from A to G would have no effect on the protein synthesized, as both AAA and AAG code for the amino acid lysine. However, a change of the second base to guanine (A to G) would result in arginine being incorporated into the protein, as AGA codes for arginine. The significance of this change depends on the importance of that particular amino acid alteration to protein structure and function. Some amino acid changes have no clinical effect at all and are known as polymorphisms. Other changes have profound clinical effects and result in absent or abnormal protein (gene product). For example, the common genetic disorder sickle cell disease results from a single amino acid change in the hemoglobin molecule, which produces an abnormal hemoglobin called hemoglobin S. In the above mRNA (AAAUUG), a mutation that would cause the fifth base (uracil) to change to adenine (U to A) would result in the codon UAG, which is a stop codon that signals the termination of protein synthesis, which could have a deleterious effect on the final protein product, depending on the part of the sequence where it occurred. Deletion or addition of a DNA base pair causes a frameshift mutation, which puts the triplet code out of sequence. Again, depending on where in the sequence it occurs, a frameshift may have a significant impact on the final protein product. The following simple linguistic example illustrates the effect of a frameshift mutation:

THE CHEMISTRY OF THE GENOME DNA (deoxyribonucleic acid) is the primary genetic material of eukaryotic cells. It is composed of chains of nucleotide bases that pair with a second, complementary chain to form a doublestranded structure known as a double helix. The human genome is incorporated into 23 pairs of chromosomes (22 autosomes and 1 pair of sex chromosomes). All somatic cells contain a diploid number of chromosomes,45 whereas germ cells contain a haploid number.23 DNA is transcribed into RNA (ribonucleic acid), which is then translated into amino acids, the building blocks of protein. In DNA, the purine bases adenine and guanine always pair with the pyrimidine bases thymine and cytosine, respectively. In RNA, the pyrimidine base uracil substitutes for thymine. Figure 16–1 illustrates the structures of the nucleotide base precursors. A typical hypothetical DNA sequence might be: 5′ − AAATTGGGCCTACGGCTA − 3′ 3′ − TTTAACCCGGATGCCGAT − 5′ The 3′–5′ section of this sequence would be transcribed into single-stranded messenger RNA (mRNA) with the following sequence:

CAN THE CAT EAT THE RAT becomes:

5′ AAAUUGGGCCUACGGCUA − 3′

CAN HEC ATE ATT HER AT This makes no sense at all. A comparable effect would be seen in the protein product of mRNA transcribed from a frameshift mutation.

When the mRNA strand is translated into protein, each set of three bases will code for a specific amino acid. The code is redundant, so that several different triplets may code for the same amino

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245

Other mutagens act on the chromosomes during cell division, causing large breaks and, consequently, deletions and rearrangements at the time of crossover during mitosis.40 Mutations can occur both in somatic (body) cells and in germ (gonadal) cells. The implications of germ cell mutations are that these errors may be passed on to the individual’s offspring and hence to subsequent generations. A number of biochemical mechanisms may lead to the abovementioned alterations in cellular DNA. Base-pair changes can result from a direct chemical action on a base. For example, nitrous acid (HNO2) deaminates adenine to form hypoxanthine, which pairs with cytosine. This leads to an A:T to G:C mutation (Fig. 16–2). Alkylation of the N7 or O6 positions of guanine may cause a G:C to A:T change40 (Fig. 16–2). Incorporation of abnormal analogues into DNA occurs only when the cell is dividing and DNA is being replicated. These abnormal analogues may result in single base-pair mutations. For example, the keto form of 5-bromouracil closely resembles thymine and may be inserted as a nucleotide in place of thymidine triphosphate during DNA replication. It may then spontaneously convert to its enol form, which pairs more readily with guanine. Further replication would therefore result in an A:T to G:C base-pair mutation.40 Frameshift mutations may be caused by interference in

Figure 16–1. (A) The structures of the purine and pyrimidine bases. (B) The general structure of a nucleotide. (Reprinted with permission from Lehninger AL: Principles of Biochemistry. New York, Worth 1982.)

Figure 16–2. Deamination of cytosine and adenine by nitrous acid, a metabolite of nitrosamines. Methylation of guanine leads to faulty base pairing. (Reprinted with permission from Lehninger AL: Principles of Biochemistry. New York, Worth 1982.)

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the DNA chain by a foreign molecule prior to replication, such as noted with acridine. When the chain is replicated, an additional base is inserted opposite acridine. Alkylating agents may cause alteration of bases so that they cannot pair, leading to deletion of a base pair and a frameshift mutation. Alkylation and cross-linking of DNA strands during replication may also result in disruption of the chromosome during mitosis. These effects are more prominent in growing tissues, and this ability of alkylating agents is responsible for their therapeutic action of killing cancer cells as well as their carcinogenic property. A simple in vitro measure of mutagenicity is the Ames test, which uses Salmonella bacteria that are unable to synthesize histidine. Mutagenic chemicals increase the likelihood of back mutations, which allow these bacteria to grow on histidine-free media. The number of colonies of altered bacteria growing on histidinefree media gives a quantitative measure of the capacity of the tested chemical to alter DNA.1,2 Mutagens that require metabolic activation are identified by the addition of liver homogenate to the Ames test. The Ames test is a good screening technique to determine whether a chemical has the potential to interact with DNA. However, it is clear that a simple in vitro test such as the Ames test cannot take into account all the complexities of the intact organism.

CARCINOGENS Most classic carcinogens are also mutagens in that they alter DNA. When the Ames test is used as a predictor of carcinogenicity, approximately 90% of known carcinogens react positively. Although the biochemical mechanisms of alteration of DNA by foreign chemicals are fairly well characterized, the ultimate events leading to the unregulated growth of cells is not well understood. Carcinogens such as estrogen and asbestos, which do not appear to affect DNA, are called epigenetic carcinogens. Their mechanisms of carcinogenicity are poorly understood and are not further addressed here. This section focuses on the toxicology of a number of well-studied mutagenic compounds known to be carcinogens. The list of agents in Table 16–1 makes clear that carcinogens are found in a wide variety of chemical classes and that they may be naturally occurring or synthetic agents.2 For example, aflatoxin B1 is a potent liver carcinogen that is formed by molds that contaminate improperly stored foodstuffs. Polycyclic aromatic amines, such as benzo(a)pyrene are generated by partial combustion processes such as the charcoal cooking of food and burning wood.51

TABLE 16–1. Examples of Agents Implicated in Human Carcinogenesis and the Specific Cancer Induced Acetophenitidin (phenacetin), renal Aromatic amines — bladder Aflatoxins — liver Benzene — leukemia Benzidine — bladder Cadmium — lung Carbon tetrachloride — liver Chromium — lung

Diethylstilbestrol (DES) — vaginal Ionizing radiation — renal cell Phenytoin — neuroblastoma Tars, soots, mineral oils — lung Tobacco smoke — lung Ultraviolet radiation — skin Vinyl chloride — liver

There are no known simple structure-activity relationships that can be applied to determine whether a given compound can be designated as a carcinogen (or noncarcinogen) solely on the basis of its chemical structure. Most mutagenic carcinogens interact with DNA in a way that may lead to persistent alteration of the cell’s genome and its ability to normally regulate cell division. Whether or not the cellular DNA is permanently altered depends on a number of factors, including distribution, access to tissues, and biotransformation. Many mutations in DNA strands are recognized by the cell and are repaired before the damaged DNA is replicated and incorporated into new DNA or transcribed into RNA. The availability and efficiency of DNA repair systems in a particular tissue is an important factor influencing carcinogenicity. Replication of the cell with the unrepaired DNA still present is a requirement for permanent alteration of the genome.47,69 Many DNA mutations are probably lethal to the cell carrying them. Individuals with conditions such as xeroderma pigmentosum in which there is a genetic deficiency of DNA-repair enzymes, exhibit an increased risk for the development of some, but not all, forms of cancer. Carcinogenesis is a multistage biochemical and biologic process. In its simplest form, the process can be divided into two major events: initiation and promotion. Initiation or neoplastic transformation involves the covalent binding of the ultimate carcinogen to DNA, resulting in alteration of the genetic code. Initiation can occur after a single exposure to the putative agent. However, many chemicals known to cause cancer are not carcinogenic in the form in which they enter the body and require biotransformation to convert them from an inactive state into their ultimate carcinogenic form.47 For example, polycyclic aromatic hydrocarbons such as benzo(a)pyrene are chemically inert in their parent form and are unable to form covalent bonds with DNA. Enzyme systems biotransform these nonreactive pro- or precarcinogens into chemically reactive (electron-deficient) products that can covalently bind with nucleophilic sites on cellular macromolecules. Metabolic activation generally requires more than one enzymatic step. Initial activation is often carried out by different enzymes of cytochrome P450, but activation by enzymes in the prostaglandin synthesis pathway, as well as by reductases and peroxidases, is also well established.51 Promotion refers to a poorly defined series of events that enable initiated cells to proliferate into tumors. Several chemicals that are not in themselves carcinogens are able to promote the development of tumors that have been initiated by other agents. Examples in experimental animals include phenol, DDT, cigarette smoke extracts, and polychlorinated biphenyls (PCBs). In contrast to initiating agents, promoting agents do not appear themselves to be mutagens. In experimental settings, promoting agents must be given after treatment with the initiator and need to be given repeatedly over a prolonged period of time. The actions of promoters, unlike those of initiators, appear to be reversible, at least in the early stages of the process. In recent years, there has been great interest in “cancer genes.” As a general model, it is proposed that the conversion of protooncogenes into oncogenes is a key event in the initiation of tumors. Proto-oncogenes are normal cellular genes, most of which appear to code for cellular growth factors or growth factor receptors. When a proto-oncogene is damaged by a carcinogen (for example, undergoes mutation or chromosomal breakage and trans-

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location) the resulting oncogene drives the abnormal cell division and differentiation that is typical of neoplasia.68 The site of tumor development is determined by the tissue- and species-specific DNA repair systems, tissue activation and deactivation, the structure of the carcinogen, as well as the dosage. For example, the symmetric dialkylnitrosamines (Fig. 16–3) cause tumors in rats according to the chemical structure of the R group. The dimethyl and diethyl compounds cause liver cancer, whereas the dibutyl compound causes bladder cancer, and lung cancer is associated with the diamyl compound. Large single doses of dimethylnitrosamine in rats lead to renal rather than to hepatic carcinomas. Hamsters are deficient in a specific liver enzyme that repairs alkylated guanine bases in DNA, and are thus highly susceptible to the hepatic carcinogenic effects of dimethylnitrosamine. In contrast, diethylnitrosamine primarily causes lung tumors in hamsters. Asymmetric nitrosamines cause cancer of the esophagus in rats.75 These effects are specific to the structure of the carcinogen, the tissue affected, and the species, and in a very general way, illustrate the enormous complexity of the interaction between living tissues and potential carcinogens.

TERATOGENS Environmental insults that result in structural defects after fertilization are known as teratogens. The term is derived from the Greek words teratos (monster) and gen (producing). Those environmental influences that produce abnormalities of function rather than visible structural anomalies are termed hadegens (derived from Hades, the Greek god of the underworld, who wore a helmet to render himself invisible). A third term, trophogen, is used to describe environmental agents that alter growth. Constituents of tobacco smoke are an example. A given environmental agent may cause all three types of effects, or may cause different effects according to the gestational timing of the exposure.25 For example, rubella infection is teratogenic, hadegenic, and trophogenic in the first trimester, whereas after 20 weeks’ gestation it is only hadegenic. For both medicolegal and scientific reasons, there has been increasing interest in the field of teratology, particularly with regard to the relatively new field of neurobehavioral teratology (hadegenic agents). There has also been increased emphasis on providing “proof” of human teratogenicity. Unfortunately, it may be difficult to prove that a particular insult or agent is teratogenic, hadegenic, or trophogenic. A number of approaches may be used to try and delineate potentially harmful fetal exposures.6

MUTAGENS, CARCINOGENS, AND TERATOGENS

gens do not fulfill all of the criteria shown in Table 16–2. For example, thalidomide, a major human teratogen, was not shown to be teratogenic in animal models. Therefore, these criteria can be used only as guidelines and need to be considered in conjunction with other relevant data. Another approach to attempt to qualify and/or quantify fetal exposure is to measure biologic markers of the putative teratogen in the fetus or neonate (or even in the mother), thereby gaining a semiquantitative estimate of the extent of teratogen exposure in utero. This approach may also yield a “fetal dose response” by estimating the dose and timing of a particular exposure.25 However, this approach is not universally applicable for several reasons: 1. Exposure may be too early in gestation to be measured at a later stage of pregnancy. 2. Appropriate biologic markers may not exist for the particular xenobiotic. 3. Suitable body fluid samples may not be readily obtainable. There are also a number of ethical issues that go beyond the scope of this text involved in the measurement, particularly in neonates, of biologic markers of in utero exposure to xenobiotics, especially to illicit drugs such as cocaine and opioids. It is clear that neither documentation of the extent of fetal exposure nor measurement of biologic markers alone can prove teratogenicity in a particular situation. A rational approach is to combine both the qualitative criteria and the biologic markers where available, in an attempt to provide the mother with the best possible information and risk estimate.

TABLE 16–2. Criteria for the Establishment of Human Teratogenicity 1.

2.

3. 4.

Qualitative Criteria for Proof of Teratogenicity The first approach is to establish certain qualitative criteria for the proof of human teratogenicity.67 Many recognized human terato5.

6.

Figure 16–3. These symmetric dialkylnitrosamines cause tumors in rats, the type of which depends on the chemical structure of the R group.

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There should be proof of exposure to the agent having occurred at a critical stage(s) in prenatal development (evidence from prescriptions, physicians’ records, dates of ingestion). There should be findings from appropriately controlled epidemiolgoic studies that show that exposure to the agent produces an increase in the occurrence of specific phenotypic effects, and a recognizable pattern of both major and minor malformations. A particular defect (eg, Ebstein’s anomaly in association with lithium exposure) or constellation of defects (eg, fetal hydantoin syndrome) is particularly helpful. There should be animal models of the exposure that mimic the effects in humans, ideally at clinically comparable doses. There should be a dose-response relationship that has been demonstrated in either animal models or human exposures, such that the greater the exposure, the more severe the fetal phenotypic effects. It should be noted that dose-response has not been shown for any of the well-known human teratogens, including retinoic acid, thalidomide, and diethylstilbestrol. There should be biologic plausibility for the mechanism of action of the putative teratogenic agent (eg, retinoic acid appears to interfere with normal neural crest cell function and migration). There may be a subset of exposed individuals who are intrinsically predisposed to the teratogenic effects of a particular agent due either to an inborn error of metabolism or to some other genetic polymorphism. This would provide a biologic explanation for the clinically well-recognized variability of teratogenic effects.

Holmes L: Fetal environmental toxins. Pediatr Rev 1992;13:364 and Shephard TH: “Proof” of human teratogenicity. Teratology 1994;50:97.

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PROBLEMS IN ASSESSING POSSIBLE FETAL EXPOSURE Recall and Reporting Bias A major limitation in risk assessment is the mother’s recall of her xenobiotic exposure. There may be a number of reasons for this, including genuine inability to recall details, guilt, denial, or because the substances involved are illicit and admission of their use may result (in the mother’s perception at least) in prosecution or the involvement of children’s welfare agencies. For example, women who have given birth to children with congenital defects tend to retrospectively minimize their history of alcohol ingestion as compared with their reported consumption when questioned antenatally.15 There is also a less-than-optimal recall not only of drug dosages and gestational timing of the exposure, but also of the actual agents, especially when there are multiple exposures. In addition, the manner in which the mother is questioned may alter her responses.48 With regard to substance abuse, it has been shown that maternal history does not reliably predict fetal exposure, although actual drug abusers are more likely to admit use than infrequent drug users.18,52

Biologic Variability Most human teratogens (including alcohol and thalidomide) affect only some of the fetuses exposed and there is considerable variability in phenotypic effects. Causes of this variability may include differences in placental transfer and metabolism as well as genetic polymorphisms in enzymatic function and expression. After a mother has had a child affected by in utero exposure to phenytoin, for example, she is more likely to have a second affected child than another mother whose first infant was not similarly affected. It has been proposed that the reason for this is that the child has inherited from at least one parent a gene that results in a diminished ability to deactivate a toxic metabolite, and therefore increases the likelihood of the drug’s teratogenic effects.69 In the future, it may be possible to predict which fetuses are at highest risk of teratogenicity, based on their drug-metabolizing genotype.6 By performing analysis on neonatal samples such as hair, urine, blood, meconium, and amniotic fluid, a better understanding of the sources of mother-infant variability may be gained.57 This can be useful in the study of environmental agents and drugs of abuse, as well as in the study of prescribed drugs and medicinal teratogens, such as warfarin and valproic acid, as well as fetotoxins such as captopril.30

BIOLOGIC MARKERS OF FETAL EXPOSURE

Similarly, measurement of blood and urine levels of nicotine and cotinine reflect only very recent exposure. Tissue hypoxia causes increased production of erythropoietin, and elevated cord-blood erythropoietin levels occur in chronic fetal hypoxia in association with conditions such as maternal preeclampsia, diabetes, and Rh isoimmunization. Because maternal smoking affects fetal hemodynamics and increases the level of fetal carboxyhemoglobin, it is likely that a proportion of fetuses of smoking mothers are chronically hypoxic in utero. Erythropoietin and hemoglobin levels are indirect biologic markers of fetal exposure to maternal cigarette smoking.72 About 20% of neonates whose mothers smoked during pregnancy had mean cord-blood erythropoietin concentrations higher than in infants whose mothers were nonsmokers, suggesting chronic hypoxia. There was also a positive correlation between cord-blood hemoglobin and erythropoietin concentrations.72 Lead is recognized as a neurodevelopmental toxin,49 but it is only recently that concerns were raised about its teratogenic effects. An association between cord-blood lead levels greater than 10 µg/dL and lower cognitive achievements at 6, 12, 18, and 24 months of age has been demonstrated.4 Of note, postnatal blood lead levels were not associated with low cognitive scores.4 Obstetric complications associated with elevated lead exposure include spontaneous abortion, premature rupture of the membranes, and preterm delivery.50 Lead crosses the placenta freely, probably by both passive and active transport mechanisms. Transplacental transfer of lead occurs as early as 12–14 weeks of gestation with increasing amounts of lead being detected in fetal tissues with advancing gestation.58 Lead also accumulates in fetal liver and bones. It is important to detect babies potentially exposed in utero to excess lead as early as possible. Several studies demonstrate good correlation between maternal and cord-blood lead levels.3,22,48 However, lead exposure throughout pregnancy cannot be assumed from a single blood measurement, because of changes in maternal blood levels and placental permeability to lead. Thus, neonatal hair analysis (as discussed later) may be a more accurate way of assessing cumulative in utero lead exposure.38

Urine Urine reflects only a very small window of time in terms of fetal exposure. For example, the cocaine metabolite, benzoylecgonine, is measurable in urine only 96–120 hours after the last exposure to cocaine; thus, urine analysis alone may underestimate the true extent of prenatal cocaine exposure. One group of researchers found that when sufficiently sensitive analytic methods were used, maternal urine, neonatal urine, and meconium analyses yielded similar results for detection of prenatal cocaine exposure.8 Rapid mass screening techniques with high sensitivity and specificity (96% and 100%, respectively) have been developed to test urine and to identify neonates exposed in utero to cocaine.74

Blood

Meconium

Cord blood is a readily available biologic fluid, collection of which does not entail invasive procedures. Frequently, however, cord-blood levels of a xenobiotic may have a very limited clinical applicability and the potential for analytic value may be restricted. For example, measurement of carboxyhemoglobin from cordblood samples in the neonate reflects exposure to carbon monoxide only over the few hours immediately prior to delivery, a time when most women are in a hospital and therefore do not smoke.

Meconium is an ideal specimen for analysis of drugs and metabolites in the newborn period for these reasons: 1. The collection of meconium is simple and noninvasive. 2. Meconium is available for up to 3 days after delivery. 3. Initial testing can be performed with common laboratory techniques for mass screening, with confirmatory testing using gas chromatography-mass spectrometry (GC-MS).

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4. Testing is sensitive and specific. 5. It is a window to the last 30 weeks of gestation. Opioids and cannabinoids as well as cocaine and nicotine and their metabolites can all be measured in meconium, and several different analytic methods are validated.9,46,53,54 Meconium is formed from a composite of desquamated intestinal and cutaneous epithelial cells, bile, pancreatic and intestinal secretions, and swallowed amniotic fluid. Fetal swallowing first occurs at around 12 weeks’ gestation so that the accumulation of drugs in meconium via fetal urine production and swallowing of amniotic fluid should theoretically be demonstrable after this time. Postmortem analysis of meconium from a fetus that was spontaneously aborted at 17 weeks gestation revealed the presence of cocaine, at a concentration that could be related to the amount and timing of maternal cocaine use during the pregnancy.55 A study of 59 infants showed that the analysis of newborn infants’ hair by radioimmunoassay or of meconium by GC-MS was more sensitive than analysis by immunoassay of urine and can detect fetal exposure to cocaine during the last 2 trimesters of pregnancy.7 Another study of 1201 mother-infant pairs showed that meconium testing detected an additional 33% of exposed infants compared with urine testing.65 Furthermore, cocaethylene, a metabolite of both cocaine and ethanol, accumulates in greater concentrations in meconium than in urine, and thus is a useful analyte for identifying both cocaine and ethanol exposure.14,41,59 A large-scale prospective drug screening study of over 3000 neonates using analysis of meconium for morphine (opioids), cocaine, and cannabinoids showed a 4-fold increase in the incidence of drug exposure in newborns as compared to the maternal self-report. This was particularly significant in the less-heavily-exposed group of neonates with no obvious manifestations at birth and whose mothers denied drug use during pregnancy, as compared with the more-heavily-exposed group who either had obvious clinical signs and/or mothers who were drug abusers (consistent and substantial users) and who were more likely to admit to drug use.52 The nicotine metabolites cotinine and trans-3′-hydroxycotinine can be measured in the meconium of infants of active smokers, and their concentrations are directly related to the degree of smoking by the mother. Similarly, metabolite levels are detected in the meconium of infants of passive smokers, with concentrations found to be comparable to those of infants whose mothers are light smokers.54 There are, however, a number of limitations to using meconium as opposed to hair samples to determine intrauterine drug exposure in a clinical setting. As yet no dose-response curves have been established with meconium (as opposed to hair). Meconium is present in only the first few days of life, so that if the exposure is not initially suspected or if the first specimen(s) of meconium are discarded, then analysis cannot be performed. It is also not clear how much of the drugs and their metabolites that are present in meconium result from the swallowing of amniotic fluid and how much results from the enterohepatic circulation. Results of meconium analysis may be inaccurate if there is in utero passage of meconium and the infant is meconium-stained at birth (often a sign of fetal distress, which may or may not be related to the particular in utero exposure). In these situations, the first postnatal meconium specimen may contain less drug than the initial meconium, which was unaffected by exogenous feeding, but was passed in utero and therefore unable to be analyzed.55

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After birth, the amount of drug measurable in meconium may be diluted as the baby feeds and new stool is formed. For example, although measurable in the first 3 meconium stools, the amount of cocaine metabolite diminishes significantly after the second stool.62 Another confounding issue is contamination of meconium specimens by neonatal urine. Thus, high concentrations of drug metabolites in meconium may actually represent urinary contamination.42

Hair The hair that neonates are born with grows during the last 3–4 months of pregnancy. Thus, the presence of drugs or environmental toxins in neonatal hair reflects the xenobiotic milieu over the last trimester of gestation.16,21 Animal and human studies demonstrate that both maternal and fetal accumulation of cocaine and its major metabolite, benzoylecgonine, follow a linear pattern within clinically used doses, and thus hair measurements may be used to estimate maternal use.17 Benzoylecgonine can also be measured in neonatal hair.29 Pyrolysis of crack cocaine results in hair accumulation of cocaine, but not its benzoylecgonine metabolite as the accumulation is a result of environmental exposure. Additionally, external contamination with crack smoke is washable, whereas systemic exposure is not. Also, in the context of the neonate, “external contamination” is irrelevant, as fetal hair is in contact with amniotic fluid, which is swallowed and excreted via the urinary tract of the unborn baby.34 Thus, measurement of fetal hair benzoylecgonine can distinguish between passive and active maternal crack cocaine exposure. Maternal cigarette smoking is associated with negative obstetric outcome, including decreased birth weight, prematurity, spontaneous abortions, perinatal mortality, and the sudden infant death syndrome.12 Infants of passive smokers are also at risk of measurable exposure to cigarette smoke. Cigarette smoke emits numerous toxins, including nicotine, carbon monoxide, hydrogen cyanide, and benzo(a)pyrene. Because of its oxygen dissociation properties, fetal hemoglobin has a higher affinity for carbon monoxide than does normal adult hemoglobin; thus, levels of carboxyhemoglobin are higher in fetal than in maternal blood. This results in lower amounts of oxygen reaching developing fetal tissues, as well as reduced function of cytochrome enzymes and impaired cellular respiration.43 There is also increasing evidence that intrauterine exposure to cigarette smoke and its toxic metabolites may result in neurobehavioral teratogenicity.19,20,64 Accumulation of nicotine and cotinine in neonatal hair reflects chronic systemic exposure to these toxins and therefore may correlate with neonatal risks. Because it is lipid soluble, nicotine has a large volume of distribution (2–3 L/kg) and readily permeates cell membranes. It is absorbed through the lungs and skin, as well as the mucous membranes of the gastrointestinal tract and nasal passages. Once absorbed, nicotine disappears rapidly from the bloodstream because of widespread tissue uptake and hepatic metabolism. Nicotine is filtered and actively secreted by the renal tubules. Nicotine’s elimination half-life in adult humans is between 1 and 3 hours; thus, monitoring in the blood is unlikely to reflect the true extent of chronic smoking. Cotinine is the major metabolite of nicotine, formed by a double oxidation reaction catalyzed by cytochrome P450 and then by cytosolic aldehyde oxidase.56 Cotinine has a considerably longer elimination half-life than nicotine (10–14

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hours) and is predominantly excreted in the urine.37 Accumulation of nicotine and its major metabolite, cotinine, may be measured in neonatal hair to estimate fetal exposure to maternal cigarette smoking.13,27 A study measuring hair concentrations of both cotinine and nicotine in 94 mother-infant pairs, including mothers who were smokers, nonsmokers, and passive smokers, found significantly high concentrations of nicotine and cotinine in the hair of smokers and their infants when compared with nonsmoking mothers and their infants. Concentrations in passive smokers and their infants were also significantly higher than in nonsmokers and their infants. There was also a significant correlation between maternal and neonatal hair concentrations of both nicotine and cotinine.13 Unfortunately, maternal reporting of cigarette use in pregnancy is often inaccurate because of guilt, perception of fetal risk, and fear. It is probably for these reasons that reported use correlates poorly with hair accumulation of nicotine and cotinine in mother and infant. This highlights the importance of an independent biologic marker, such as hair nicotine and cotinine measurement, to more accurately evaluate fetal exposure to cigarette smoke. Because there frequently is only a small amount of neonatal hair available for analysis, a method to detect both cocaine and nicotine in the same hair sample was developed.28 This has clear benefits in quantifying specific exposures and in correlating potential neonatal effects, particularly as the majority of mothers who use cocaine also smoke cigarettes. The tragic experience from Minamata Bay, Japan, (see Chapter 2 and 81) revealed the devastating neurotoxicity of methylmercury, with fetuses and infants showing particular susceptibility. Research supports that the developing nervous system is particularly vulnerable during the second and third trimesters of pregnancy and during early postnatal life. Methylmercury actually crosses the placental barrier and achieves higher concentrations in the fetus than in the mother.60 Methylmercury is distributed evenly throughout the body and is also incorporated into growing hair. Based on toxicokinetic and practical considerations, hair is the optimal biomarker of methylmercury exposure in both mothers and infants. Mercury levels in cord blood and in maternal scalp hair correlate well. However, dose-response relationships, particularly with regard to developmental neurotoxicity, are not completely known.23–25 Methylmercury may also be transferred to neonates via breast milk, thus representing a further potential neurotoxic risk. Urinary mercury excretion is a good marker of inorganic mercury exposure but does not reflect methylmercury exposure.

In one study, amniotic fluid and urine samples were obtained from 23 subjects with documented cocaine abuse. Cocaine and benzoylecgonine were detected in 74% of amniotic fluid samples taken from the known cocaine abusers, while in the same subjects, conventional maternal and neonatal urine toxicology screens were positive in only 61% and 35%, respectively.26 Other data suggest that measurement of cocaine and its metabolites in amniotic fluid offers no benefits over urinary drug evaluation.10 Cotinine may be measured in amniotic fluid collected during routine second trimester amniocentesis. Although the mechanism is not understood, it appears that nicotine and its metabolites accumulate both in the fetus and in the amniotic fluid, as levels in neonatal cord blood and in amniotic fluid are found to be higher than in maternal blood.63

Ultrasonography Another prenatal biologic marker of fetal exposure is ultrasound examination with particular emphasis on fetal biometry and specific structural defects, such as neural tube defects (for example in association with valproic acid or carbamazepine exposure). With improved ultrasound technology over the past decade, there has been an increased awareness and reporting of fetal anomalies associated with known or potential teratogen exposures detected on midtrimester ultrasound examination.35,73 There are reports of specific fetal anomalies being detected on midtrimester ultrasound, for example, radial ray defects, following valproic acid exposure,39,66,76 as well as a major cardiac defect and hydrocephalus associated with first trimester retinoic acid exposure.71

COUNSELING ISSUES The main aim of counseling women following potential teratogenic exposure is to present an accurate, up-to-date estimate of their specific risk in an easily understood, nondirective manner. Different women will perceive and interpret the same data very differently, partly because of their educational, ethnic, and social backgrounds, and partly because of their levels of fear, anxiety, and guilt. Hence, the counseling they receive should be specifically tailored to their needs, so that they are able to understand the particular issues concerning the teratogenic exposure during their pregnancy and in particular what should be done regarding the future of the pregnancy.

Perception of Risk and Decision Making Amniotic Fluid It is well-documented in both animals and humans that drugs may be detected in amniotic fluid after maternal drug administration.5,70 The appearance of drug in the amniotic fluid is usually delayed after a single dose of drug to the mother. However, with chronic drug use, the concentration in amniotic fluid gradually increases. Peak concentrations may greatly exceed simultaneously obtained concentrations in maternal and fetal plasma.70 Many drug metabolites, as well as the parent compound, also appear in amniotic fluid; for example, cocaine and its metabolites benzoylecgonine, ecgonine methyl ester, and cocaethylene.61 The fetus may be repeatedly exposed to the effects of these drugs via contact with amniotic fluid that contains these substances.44

The major decision to be made by women exposed to a xenobiotic is whether or not to continue with their pregnancy. Clearly there may be several possible reasons why a woman (and her partner) would want to terminate a pregnancy, but incorrect perception of teratogenic risk is an important factor.31 Since the tragedy of thalidomide in the 1960s, there has been increased public and media awareness of the possibility of teratogenic effects of drugs and environmental agents, even though there are relatively few proven human teratogens. Both the mass media and reputable scientific publications tend to publish and emphasize the positive findings (ie, fetal abnormalities) and potentially harmful effects of xenobiotics rather than their safety and lack of documented teratogenicity.11,33

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drugs of abuse, but also for medicinal teratogens (eg, phenytoin) and fetotoxins (eg, captopril).

REFERENCES

Figure 16–4. A visual analog scale depicting an individual’s feeling about the need for termination of pregnancy and the individual’s perception of the teratogenic risk for drug or chemical exposure.

One study, using the visual analogue scale depicted in Fig. 16–4, assessed the perception of teratogenic risk of 80 women attending an antenatal consultation clinic for drug and chemical exposure and found that women exposed to agents not known to be teratogenic assigned themselves a risk of 24% ± 2.8% (comparable to the risk of one of the major known teratogens—thalidomide). After they received appropriate counseling, their perception of risk was reduced to 14.5% ± 3%, and their tendency to terminate the pregnancy also decreased significantly after the consultation. In contrast, women exposed to known teratogens perceived their risk as being 36.2% ± 11.7% before the interview and did not change their perception afterwards. They also did not change their tendency toward terminating the pregnancy.36 Thus appropriate intervention (counseling) in early pregnancy can prevent unnecessary termination of pregnancy by correcting misinformation and misconceptions and thereby decreasing the unrealistically high perception of risk by women exposed to nonteratogens.

SUMMARY Increasingly and predominantly because of medicolegal influences, it is necessary to determine as precisely as possible the nature of fetal xenobiotic exposure. The use of biologic markers is a way to semiquantitatively determine exposure to a number of these agents. In the future, it is likely that there will be more substances, both environmental and medicinal, that will be amenable to this form of analysis, and that new techniques will result in increased accuracy and improved quantification of the exposure. Most human teratogens affect some fetuses while sparing others. It is possible that interpreting variability in the rate and extent of placental transfer of drugs is one source of variability in toxicologic response. Thus, neonatal hair and meconium analysis may enable a better understanding of the sources of variability that clearly exist between some mother-infant pairs. This approach may well have relevance not just for environmental agents and

1. Ames BN: Identifying environmental chemicals causing mutations and cancer. Science 1979;204:587–593. 2. Ames BN, Magaw R, Gold LS: Ranking possible carcinogenic hazards. Science 1987;236:271–280. 3. Angell NF, Lavery JP: The relationship of blood lead levels to obstetric outcome. Am J Obstet Gynecol 1982;142:40–46. 4. Bellinger D, Leviton A, Waternauz C, et al: Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med 1987;316:1037–1043. 5. Brien JF, Clarke DW, Smith GN, et al: Disposition of acute, multipledose ethanol in the near-term pregnant ewe. Am J Obstet Gynecol 1987;157:204. 6. Buehler BA, Delimont D, van Maes M, Finnell RH: Prenatal prediction of risk for the fetal hydantoin syndrome. N Engl J Med 1990; 322:1567–1572. 7. Callahan CM, Grant TM, Phipps P, et al: Measurement of gestational cocaine exposure: Sensitivity of infants’ hair, meconium, and urine. J Pediatr 1992;120:763–768. 8. Casanova OQ, Lombardero N, Behnke M, et al: Detection of cocaine exposure in the neonate. Analyses of urine, meconium, and amniotic fluid from mothers and infants exposed to cocaine. Arch Pathol Lab Med 1994;118:988–993. 9. Clark GD, Rosenweig IB, Raisys VA, et al: The analysis of cocaine and benzoylecgonine in meconium. J Anal Toxicol 1992;16:261–263. 10. DiGregorio GJ, Barbieri EJ, Ferko AP, Ruch EK: Prevalence of cocaethylene in the hair of pregnant women [letter]. J Anal Toxciol 1993;7:445–446. 11. Easterbrook PJ, Berlin JA, Copalan R, Matthews DR: Publication bias in clinical research. Lancet 1991;337:867–872. 12. Eh S: Cigarette smoking during pregnancy. Am J Obstet Gynecol 2000;183:1045–1046. 13. Eliopoulos C, Klein J, Phan MK, et al: Hair concentrations of nicotine and cotinine in women and their newborn infants. JAMA 1994;271: 621–623. 14. Farre M, de la Torre R, Llorente M, et al: Alcohol and cocaine interactions in humans. J Pharmacol Exp Ther 1993;266:1364–1373. 15. Feldman Y, Koren G, Mattice D, et al: Determinants of recall and recall bias in studying drug and chemical exposure in pregnancy. Teratology 1989;40:37–45. 16. Forman R, Klein J, Meta D, et al: Prevalence of fetal exposure to cocaine in Toronto, 1990–1991. Clin Invest Med 1994;17:206–211. 17. Forman R, Schneiderman J, Klein J, et al: Accumulation of cocaine in maternal and fetal hair: The dose-response curve. Life Sci 1992;50:1333–1341. 18. Frank DA, Zuckerman BS, Amaro H, et al: Cocaine use during pregnancy: Prevalence and correlates. Pediatrics 1988;82:888–895. 19. Fried PA, O’Connel CM, Watkinson B: Sixty- and 72-month followup of children prenatally exposed to marijuana, cigarettes and alcohol: Cognitive and language assessment. Dev Behav Pediatr 1992;13: 383–391. 20. Fried PA, Watkinson B, Gray BA: A differential effect-on-cognitive functioning in 9- to 12-year-olds prenatally exposed to cigarettes and marijuana. Neurotoxicol Teratol 1998;20:293–306. 21. Gerschanick J, Brooks G, Little J: Blood lead values in pregnant women and their offspring. Am J Obstet Gynecol 1974;119:508–511. 22. Graham K, Koren G, Klein J, et al: Determination of gestational cocaine exposure by hair analysis. JAMA 1989;262:3328–3330. 23. Grandjean P, Weihe P, Nielsen JB: Methylmercury: Significance of intrauterine and postnatal exposures. Clin Chem 1994;40:1395–1400.

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24. Grant BF, Harford TC: Concurrent and simultaneous use of alcohol with cocaine: Results of a national survey. Drug Alcohol Depend 1990;25:97–104. 25. Holmes L: Fetal environmental toxins. Pediatr Rev 1992;13:364–370. 26. Jain L, Meyer W, Moore C, et al: Detection of fetal cocaine exposure by analysis of amniotic fluid. Obstet Gynecol 1993;81:787–790. 27. Klein J, Chitayat D, Koren G: Hair analysis as a marker for fetal exposure to maternal smoking. N Engl J Med 1993;328:66–67. 28. Klein J, Forman R, Eliopoulos C, Koren G: A method for simultaneous measurement of cocaine and nicotine in neonatal hair. Ther Drug Monit 1994;16:67–70. 29. Klein J, Karaskov T, Koren G: Clinical application of hair testing for drug abuse. Forensic Sci Int 2000;107:281–288. 30. Koren G: Measurement of drugs in neonatal hair: A window to fetal exposure. Forensic Sci Int 1995;70:77–82. 31. Koren G, Bologa M, Long D, et al: Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the first trimester. Am J Obstet Gynecol 1989;160:1190–1194. 32. Koren G, Pastuszak A, Ito S: Drugs in pregnancy. N Engl J Med 1998;338:1128–1137. 33. Koren G, Klein N: Bias against negative studies in newspaper reports of medical research. JAMA 1991;266:1824–1826. 34. Koren G, Klein J, Forman R, Graham K: Hair analysis of cocaine: Differentiation between systemic exposure and external contamination. J Clin Pharmacol 1992;32:671–675. 35. Koren G, Nulman I: Antenatal visualization of malformations associated with drugs and chemicals. Dev Brain Dysfunct 1993;6:305–316. 36. Koren G, Pastuszak A: Prevention of unnecessary pregnancy terminations by counselling women on drug, chemical, and radiation exposure during the first trimester. Teratology 1990;41:657–661. 37. Kyerematen GA, Vesel E: Metabolism of nicotine. Drug Metab Rev 1991;23:3. 38. Laker M: On determining trace element levels in man: The uses of blood and hair. Lancet 1982;2:260–262. 39. Langer B, Haddad J, Gasser B, et al: Isolated fetal bilateral radial ray reduction associated with valproic acid usage. Fetal Diagn Ther 1994; 9:155–158. 40. Lehninger AL: Principles of Biochemistry. New York, Worth, 1982, pp. 879–886. 41. Lewis DE, Moore CM, Leikin JB: Cocaethylene in meconium specimens. J Toxicol Clin Toxicol 1994;32:697–703. 42. Lombardero N, Casanova O, Behnke M, et al: Comparison of specimens for GC/MS detection of prenatal cocaine exposure. Ann Clin Lab Sci 1993;23:385–394. 43. Longo L: The biological effects of carbon monoxide on the pregnant woman, fetus and newborn infant. Am J Obstet Gynecol 1977;129: 69–103. 44. Mahone PR, Scott K, Sleggs G, et al: Cocaine and metabolites in amniotic fluid may prolong fetal drug exposure. Am J Obstet Gynecol 1994;171:465–469. 45. Marsh DO, Clarkson TW, Cox C, et al: Fetal methylmercury poisoning, relationship between concentrations in single strand of maternal hair and child effects. Arch Neurol 1987;44:1017–1022. 46. Maynard EC, Amuroso LP, Oh W: Meconium for drug testing. Am J Dis Child 1991;145:650–652. 47. Miller EC: Some current perspectives on chemical carcinogenesis: Presidential address. Cancer Res 1978;8:1479–1496. 48. Mitchell AE, Cottler LB, Shapira SP: Effect of questionnaire design on recall of drug exposure in pregnancy. Am J Epidemiol 1986;123: 670–676. 49. Moore MR, McIntosh MJ, Bushnell JWR: The neurotoxicity of lead. Neurotoxicology 1986;7:541–546. 50. Nogaki K: On action of lead on body of lead refinery workers: Particularly conception, pregnancy and parturition in case of females and on vitality of their newborn. Excerpta Med 1958;4:2176. 51. Okey AB: Carcinogenesis and mutagenesis by xenobiotic chemicals. In: Kalant H, Roschlau WHE, eds: Principles of Medical Pharmacology, 5th ed. Toronto, Canada, Decker, 1989; pp. 632–643.

52. Ostrea EM: Testing for exposure to illicit drugs and other agents in the neonate: A review of laboratory methods and the role of meconium analysis. Curr Probl Pediatr 1999;29:37–56. 53. Ostrea EM, Matias O, Keane C, et al: Spectrum of gestational exposure to illicit drugs and other xenobiotic agents in newborn infants by meconium analysis. J Pediatr 1998;133:513–515. 54. Ostrea EM, Knapp DK, Romero A, et al: Meconium analysis to assess fetal exposure to nicotine by active and passive maternal smoking. J Pediatr 1994;124:471–476. 55. Ostrea EM, Romero A, Knapp DK, et al: Postmortem drug analysis of meconium in early gestation human fetuses exposed to cocaine: Clinical implications. J Pediatr 1994;125:477–479. 56. Pilotti A: Biosynthesis and mammalian metabolism of nicotine. Acta Physiol Scand 1980;479(Suppl):13–17. 57. Potter S, Klein J, Valilante G, et al: Maternal cocaine use without evidence of fetal exposure. J Pediatr 1994;125:652–654. 58. Rajegowda BK, Glass L, Evans HE: Lead concentration in newborn infants. J Pediatr 1972;80:116–117. 59. Randall T: Cocaine, alcohol mix in body to form even longer lasting, more lethal drug. JAMA 1992;267:1043–1044. 60. Reynolds WA, Pitkin RM: Transplacental passage of methylmercury and its uptake by primate fetal tissues. Proc Soc Exp Biol Med 1975; 148:523–526. 61. Ripple MG, Goldberger BA, Caplan YH, et al: Detection of cocaine and its metabolites in human amniotic fluid. J Anal Toxicol 1992; 16:328–331. 62. Rosengren S, Longobucco D, Bernstein B, et al: Meconium testing for cocaine metabolite: Prevalence, perceptions, and pitfalls. Am J Obstet Gynecol 1993;168:1449–1456. 63. Ruhle W, Graf von Ballestrem CL, Pult HM, Gnirs J: Correlation of cotinine levels in amniotic fluid, umbilical artery blood and maternal blood (in German). Geburtshilfe und Frauenheilkunde 1995;15: 156–159. 64. Rush D, Callahan KR: Exposure to passive cigarette smoking and child development. Ann N Y Acad Sci 1989;562:74–100. 65. Ryan RM, Wagner CL, Schultz JM, et al: Meconium analysis for improved identification of infants exposed to cocaine in utero. J Pediatr 1994;125:435–440. 66. Sharony R, Garber A, Viskochil D, et al: Preaxial ray reduction defects as part of valproic acid embryo fetopathy. Pregnant Diagn 1993; 13:909–918. 67. Shephard TH: “Proof ” of human teratogenicity. Teratology 1994;50: 97–98. 68. Silva Lima B, Van der Laan JW: Mechanism of nongenotoxic carcinogenesis and assessment of the human hazard. Regul Toxicol Pharmacol 2000;32:135–143. 69. Strickler SM, Dansky LV, Miller MA, et al: Genetic predisposition to phenytoin-induced birth defects. Lancet 1989;2:746–749. 70. Szeto HH, Umans JG, McFarland JW: A comparison of morphine and methadone disposition in the maternal-fetal unit. Am J Obstet Gynecol 1982;143:700–706. 71. Van Maldergem L, Jauniaux E, Gillerot Y: Morphological features of a case of retinoic acid embryopathy. Prenat Diag 1992;12:699–701. 72. Varvarigou A, Beratis NG, Makri M, Vagenakis AG: Increased levels and positive correlation between erythropoietin and hemoglobin concentrations in newborn children of mothers who are smokers. J Pediatr 1994;124:480–482. 73. Viscarello RR, Ferguson DD, Nores J, Hobbins JC: Limb body wall complex associated with cocaine abuse: Further evidence of cocaine’s teratogenicity. Obstet Gynecol 1992;80:523–526. 74. Welch E, Fleming LE, Peyser I, et al: Rapid cocaine screening of urine in a newborn nursery. J Pediatr 1993;123:468–470. 75. Williams GM, Weisburger JH: Chemical carcinogens. In: Amdur MO, Doull J, Klaassen CD, eds: Casarett and Doull’s Toxicology: The Basic Science of Poisons. New York, Macmillan, 1991, pp. 127–200. 76. Ylagan LR, Budorick NE: Radial ray aplasia in utero: A prenatal finding associated with valproic acid exposure. J Ultrasound Med 1994; 13:408–411.

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17

VITAL SIGNS AND TOXIC SYNDROMES Lewis R. Goldfrank / Neal E. Flomenbaum / Neal A. Lewin / Mary Ann Howland / Robert S. Hoffman / Lewis S. Nelson

Normal Vital Signs by Age Age Adult 16 years 12 years 10 years 6 years 4 years 2 years 1 year 6 months 4 months 2 months Newborn

Systolic BP mm Hg

Diastolic BP mm Hg

90–140 120 110 110 100 100 100 95 90 85 80 60

41.1°C; >106°F) from any cause can lead to extensive rhabdomyolysis and myoglobinuric renal failure as well as direct brain injury. Hyperthermia can result from a distinct neurologic response to a signal demanding thermal up-regulation or from an externally imposed hyperthermia as seen in heat stroke, in cancer chemotherapy, or in an infant excessively swaddled in clothing.10 Fevers higher than 41.1°C (106°F) are extremely rare unless normal feedback mechanisms are overwhelmed.1 Hyperthermia of this extreme nature is usually attributed to heat stroke, malignant hyperthermia, or drug-related temperature disturbances. Drug-induced fevers coincide with the administration of a drug and disappear within 48–96 hours of the drug’s discontinuation.6,9 A common drug-related hyperthermia pattern that occurs in the emergency department is defervescence after an acute temperature elevation resulting from agitation or seizure activity. In the case of a seizure, hyperthermia may persist for several hours, even in the

TABLE 17–6. Common Drugs and Important Toxins that Affect Respiratory Rate Bradypnea

Tachypnea

Barbiturates Botulinum toxin Clonidine Ethanol Neuromuscular blockers Opioids Sedative-hypnotics

Carbon monoxide Cyanide Ethylene glycol Hydrogen sulfide Isopropanol Methanol Methemoglobin producing agents Nicotine Organic phosphorus compounds and carbamates Salicylates Sympathomimetics Theophylline

See Chap. 20 for additional agents affecting respiratory rate.

TABLE 17–7. Common Drugs and Important Toxins that Affect Body Temperature Hyperthermia

Hypothermia

Amphetamines Anticholinergics Antihistamines Cocaine Cyclic antidepressants Monoamine oxidase inhibitors Phencyclidine Phenothiazines Salicylates Sedative-hypnotic withdrawal Thyroxine

Carbon monoxide Ethanol and other alcohols Hypoglycemic agents Opioids Phenothiazines Sedative-hypnotic agents

See Chap. 18 for a more complete listing.

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absence of an infectious etiology for the elevation in body temperature. One-third of the patients may still be febrile at 48 hours.11 Table 17–7 is a representative list of toxins that affect body temperature (see Chap. 18 for greater detail). Hypothermia will impair the metabolism of many drugs at both toxic and therapeutic levels, leading to unpredictable delayed effects when the patient is warmed. Most importantly, a hypothermic patient should never be declared dead without both an extensive assessment and a full resuscitative effort, particularly if the body temperature remains less than 95°F (35°C). In addition, many drugs and toxins impair judgment and CNS function, thereby placing patients at great risk for becoming hypothermic from exposure to the cold of northern winter climates. Continuous monitoring of the vital signs is as essential in medical toxicology as in any other type of emergency or critical care medicine. For this reason, the vital signs an essential part of the initial evaluation of every case, and repeated vital sign values are almost always necessary throughout the subsequent case management.

REFERENCES 1. Dubois EF: Why are fever temperatures over 106°F rare? Am J Med Sci 1949;217:361–368.

2. Fiore MC: The new vital signs: Assessing and documenting smoking status. JAMA 1991;266:3183–3189. 3. Gravelyn TR, Weg JG: Respiratory rate as an indicator of acute respiratory dysfunction. JAMA 1980;244:1123–1125. 4. Karajalainen J, Vitassalo M: Fever and cardiac rhythm. Arch Intern Med 1986;146:1169–1171. 5. Lipsitz LA: Orthostatic hypotension in the elderly. N Engl J Med 1989;321:952–957. 6. Lipsky BA, Hirschman JV: Drug fever. JAMA 1981;245:851–854. 7. Mofenson HC, Greensher J: The nontoxic ingestion. Pediatr Clin North Am 1970;17:583–590. 8. Musher DM, Dominguez EA, Bar-Sela A: Edouard Seguin and the social power of thermometry. N Engl J Med 1987;316:115–117. 9. Orringer CE, Eustace JC, Wunsch CD, Gardner LB: Natural history of lactic acidosis after grand mal seizures: A model for the study of an anion gap acidosis not associated with hyperkalemia. N Engl J Med 1977;297:796–799. 10. Styrt B, Sugarman B: Antipyresis and fever. Arch Intern Med 1990; 150:1589–1597. 11. Wachtel TJ, Steele GH, Day JA: Natural history of fever following a seizure. Arch Intern Med 1987;147:1153–1155.

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THERMOREGULATORY PRINCIPLES Susi U. Vassallo / Kathleen A. Delaney

vironments, thermal gradients may be reversed, leading to transfer of heat to the body by radiation, conduction, or convection.135,159

Despite exposure to wide fluctuations of environmental temperature, human body temperature is maintained within a narrow range.14,109 Elevation or depression of body temperature occurs when (a) thermoregulatory mechanisms are overwhelmed by exposure to extremes of environmental heat or cold; (b) endogenous heat production is either inadequate, resulting in hypothermia, or exceeds the physiologic capacity for dissipation, resulting in hyperthermia; or (c) disease processes or drug effects interfere with normal thermoregulatory responses to heat or cold exposure.

PHYSIOLOGY OF THERMOREGULATION In the normal human, stimulation of peripheral and hypothalamic temperature-sensitive neurons results in autonomic, somatic, and behavioral responses that lead to the dissipation or conservation of heat. Thermoregulation is the complex physiologic process that serves to maintain hypothalamic temperature within a narrow range of 37 ± 0.4°C (98.6 ± 0.8°F) known as the set point.262 This hypothalamic set point is influenced by factors such as diurnal variation, the menstrual cycle and others. Maintaining, raising, or lowering the set point results in many outwardly visible physiologic manifestations of thermoregulation such as sweating, shivering, flushing, or panting. In the central nervous system, thermosensitive neurons are located predominantly in the preoptic area of the anterior hypothalamus, although some are found in the posterior hypothalamus. These neurons may be divided into those that are warm-sensitive, cold sensitive, or temperature-insensitive. About 30% of preoptic neurons are warm-sensitive. These increase their firing rate during warming and decrease their firing rate during cooling.22 Warming of the hypothalamus in conscious animals results in vasodilatation, hyperventilation, salivation, and increases in evaporative water loss, as well as a reduction of cold-induced shivering and vasoconstriction.106 Cooling of the hypothalamus in conscious animals causes shivering, vasoconstriction, and increased metabolic rate, even if the environment is hot.98 How these temperature-sensitive neurons of the hypothalamus detect temperature changes and effect neuronal transmission is unclear. Altered action potential initiation and propagation due to temperature-dependent changes in membrane potential, changes in the ratios of Na+ to Ca2+ ions which alter neuronal excitability and neurotransmitter release, or effects on the Na+K+-ATPase (adenosine triphosphatase) pump, may be involved.124 Drugs that increase intracellular cyclic AMP increase the thermosensitivity of warm-sensitive neurons.22 In the brainstem, warm- and cold-sensitive neurons are located in the medullary reticular formation, where information from cutaneous receptors, spinal cord, and preoptic area of the anterior hypothalamus is integrated.109,113,116,185

METHODS OF HEAT TRANSFER Heat is transferred to or away from the body through radiation, conduction, convection, and evaporation. Radiation involves the transfer of heat from a body to the environment, and from warm objects in the environment, for example, the sun, to a body. Conduction involves the transfer of heat to solid or liquid media in direct contact with the body. Water immersion or wet clothing in contact with the body conducts significant amounts of heat away from the body. This effect facilitates cooling in a swimming pool on a hot summer day, or may lead to hypothermia despite moderate ambient temperatures on a rainy day. The amount of heat lost through conduction and radiation depends on the temperature gradient between skin and surroundings, cutaneous blood flow, and insulation such as subcutaneous fat, hair, clothing, or fur in lower animals.124 In the respiratory tract, heat is lost by conduction to water vapor or gas. In animals unable to sweat, this represents the primary method of heat loss. The amount of heat lost through the respiratory tract depends on the temperature gradient between inspired air and the environment, as well as the rate and depth of breathing.124 Convection is the transfer of heat to the air surrounding the body. Wind velocity and ambient air temperature are the major determinants of convective heat loss. Evaporation is the process of vaporization of water, or sweat. Large amounts of heat are dissipated from the skin during this process, resulting in cooling. Ambient temperature, rate of sweating, air velocity, and relative humidity are important factors in determining how much heat is lost through evaporation. On a very humid day, sweat may pour off, rather than evaporate from a person exercising in a hot environment, thereby accomplishing little heat loss. In very warm en-

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The spinal cord also manifests thermosensitivity. Heat- and cold-sensitive ascending spinal impulses are conducted in the spinothalamic tract. As in the hypothalamus, local heating or cooling of the spinal cord results in thermoregulatory responses.106 In addition to the hypothalamus, brainstem, and spinal cord, there is evidence of thermosensitivity in the deep abdominal viscera.94,106,208 Intra-abdominal heating or cooling results in thermoregulatory responses. Cold- and warm-sensitive afferent impulses can be recorded from the splanchnic nerves in animals.94,210 Finally, the skin also contains heat and cold thermosensitive neurons. Cold receptors are free nerve endings that protrude into the basal epidermis, whereas warm-sensitive receptors protrude into the dermis.107,108 Cutaneous thermoreceptor output is affected by the absolute temperature of the skin, rate of temperature change, and area of stimulation.106 Cutaneous cold receptors are A
and C nociceptor afferent fibers. A
fibers are small-diameter thinly myelinated fibers that conduct at 5–30 m/sec, and C-fibers are small-diameter unmyelinated fibers that conduct at 0.5–2 m/sec.122 Afferents from heat receptors are primarily C fibers. Cutaneous thermoreceptive neurons respond to external temperature change as well as rate of temperature change, sending early warning to the central nervous system (CNS) via afferent impulses, allowing rapid and transient thermoregulatory responses before brain temperature changes (Fig. 18–1).

VASOMOTOR AND SWEAT GLAND FUNCTION Vasomotor responses to thermoregulatory input differ according to location. The normal thermoregulatory response to heat stress is mediated primarily by heat-sensitive neurons in the hypothalamus. Increased body-core temperature results in active vasodilatation in the extremities and is under noradrenergic control; increasing sympathetic stimulation results in vasoconstriction, and decreasing sympathetic control results in vasodilatation. Vasodilatation in the head, trunk, and proximal limbs is not a result of decreased sympathetic tone; instead, it is a result of an active process that is under the influence of cholinergic sudomotor nerves and local effects of temperature on venomotor tone. Sweat glands release local transmitters, such as vasoactive intestinal polypeptide (VIP) or bradykinins, and vasodilatation results. Areas of the body such as the forehead, where sweating is most prominent during heat stress, correspond to areas where active vasodilatation is greatest. The neurotransmitters involved in the regulation of relationships between vasodilatation and sweating as a response to heat stress are not fully elucidated, but animal evidence suggests the presence of specific vasodilator nerves.106 Sweat glands are controlled by sympathetic postganglionic nerve fibers, which are cholinergic, and large amounts of acetylcholinesterase as well as other peptides involved in neural transmission.106,107

NEUROTRANSMITTERS AND THERMOREGULATION The neurotransmitters involved in thermoregulation include serotonin, norepinephrine, acetylcholine, dopamine, prostaglandins, -endorphins, and intrinsic hypothalamic peptides such as argi-

Figure 18–1. A schematic representation of the response of cutaneous thermoreceptive neurons to external termperature change as an early warning to the central nervous system.

nine vasopressin, adrenocorticotrophic hormone, thyrotropin releasing hormone, and -melanocyte stimulating hormone.40,195 Studies on the effects of individual neurotransmitters in thermoregulation yield contradictory results, depending on the animal species and the route of administration of the exogenous neurotransmitter. Refinements in techniques of microinjection of neurotransmitters into the hypothalamus of animals, rather than intraventricular instillation, have elucidated microanatomic sites where neurotransmitters are active. However, more research is necessary with regard to stimulation of thermoregulatory responses by individual neurotransmitters. Interspecies variation and theoretic differences in response to exogenous versus endogenous peptides makes this study difficult. Apomorphine is a mixed dopamine agonist that has been shown to cause hypothermia in animals; studies using selective D1- and D2-receptor agonists and antagonists suggest that the hypothermic effect of apomorphine is a result of its effects on D2 receptors, with some modulation by D1 receptors in the hypothalamus.173 Stimulation of D2 receptors appears to mediate the hypothermia induced by the peptide sauvagine.25 Dopamine D3 receptors undoubtedly play a role, as well; stimulation of D3 by

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specific agonists caused hypothermia in an animal model.174,175 There appears to be a link between dopamine D2 receptors and norepinephrine receptors in the hypothalamus, perhaps leading to vasodilatation and hypothermia. The effect of clozapine in producing hypothermia in the rat was demonstrated to be caused by D1 and D3 stimulation.174,219 Lesser-known peptides appear to be involved in thermoregulation. For example, neuropeptide Y is an amino acid neurotransmitter that occurs in high concentrations in the preoptic area of the anterior hypothalamus. Administration of neuropeptide Y caused a reduction in core temperature when administered with adrenoceptor antagonists such as prazosin, an 1 antagonist, propranolol, a -adrenergic antagonist, and clonidine, a central 2-adrenergic agonist.70,218 The administration of synthetic cannabinoids induces hypothermia in animals, an effect that is antagonized by adrenergic agonists and enhanced by adrenergic antagonists.203 Finally, studies on muscarinic receptors suggest the involvement of muscarinic M2 and M3 receptors in the production of hypothermia when agonists to these receptors are administered centrally.220 Blockers of ATP-sensitive K+ channels can reverse the effect of cholinomimetic drugs in producing hypothermia.205

DRUG EFFECTS ON THERMOREGULATION Many drugs and toxins have pharmacologic effects that interfere with thermoregulatory responses157,160,250 (Tables 18–1 and 18–2). -Adrenergic agonist agents prevent vasodilatation in response to heat stress. Increased endogenous heat production in the setting of increased motor activity also occurs in patients poisoned with cocaine or amphetamines. Life-threatening hyperthermia has been associated with the use of these agents. -Adrenergic antagonists and calcium channel blockers diminish the cardiac reserve available to compensate for heat-induced vasodilatation, whereas diuretics decrease cardiac reserve through their effects on intravascular volume.54 -Adrenergic antagonists also interfere with the capacity to maintain normothermia under conditions of cold stress, possibly related to their interference with the mobilization of substrates required for thermogenesis.106,160 Opioids, and diverse sedative-hypnotics, depress hypothalamic function and predispose to hypothermia in the overdose setting.72 Carbon monoxide poisoning must also be considered in the hypothermic patient. Organic phosphorous insecticides and other agents that cause cholinergic stimulation cause hypothermia by stimulation of inappropriate sweating and possibly through depression of the endogenous utilization of calorigenic substrates.160 Drugs with anticholinergic effects decrease sweating and predispose to hyperthermia during environmental heat exposure or exercise. Phenothiazines appear to interfere with normal response to both heat and cold. Severe hyperthermia associated with the absence of sweating has been frequently described in patients on phenothiazines and may be a consequence of their anticholinergic effects.221,264 Effects on cold tolerance are attributed to their -adrenergic antagonist effects, which prevent vasoconstriction in response to cold stress.158 In addition, hyperthermia associated with severe extrapyramidal rigidity may occur in patients on antipsychotic agents.150 This rigidity is attributed to the dopamine-blocking effects of this class of drugs.

THERMOREGULATORY PRINCIPLES

TABLE 18–1. Effects of Drugs and Toxins that Predispose to Hyperthermia I. Impaired cutaneous heat loss A. Vasoconstriction through -adrenergic stimulation Amphetamine and derivatives Cocaine Ephedrine Phenylpropanolamine Pseudoephedrine B. Sweat gland dysfunction by anticholinergic effects Antihistamines Belladonna alkaloids Cyclic antidepressants Phenothiazines II. Myocardial depression A. Decreased cardiac output Antidysrhythmic agents -Adrenergic antagonists Calcium channel blockers B. Reduced cardiac filling by dehydration Diuretics Ethanol III. Hypothalamic depression Antipsychotic agents IV. Impaired behavioral response Ethanol Opioids Phencyclidine Sedative-hypnotics Cocaine V. Uncoupling of oxidative phosphorylation Pentachlorophenol Dinitrophenol Salicylates VI. Increased muscle activity through agitation, seizures, or rigidity Amphetamine derivatives Caffeine Cocaine Isoniazid Lithium Monoamine oxidase inhibitors Phencyclidine Strychnine Sympathomimetic agents VII. Dystonia Butyrophenones Phenothiazines VIII. Withdrawal Dopamine agonist Ethanol Sedative-hypnotic

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TABLE 18–2. Effects of Drugs and Toxins that Predispose to Hypothermia Impaired nonshivering thermogenesis -Adrenergic antagonists Cholinergic agents Hypoglycemic agents Impaired perception of cold Carbon monoxide Ethanol Hypoglycemic agents Opioids Sedative-hypnotics Impaired shivering by hypothalamic depression Carbon monoxide Ethanol General anesthetic agents Opioids Phenothiazines Sedative-hypnotics Impaired vasoconstriction -Adrenergic antagonists Ethanol Phenothiazines

ETHANOL The most common variable related to the occurrence of hypothermia in an urban setting is the use of ethanol.51,257 The mechanism by which ethanol predisposes to hypothermia is said to be by virtue of its effects on CNS depression, vasodilatation, and blunting of behavorial responses to cold. However, thermoregulatory dysfunction associated with ethanol intoxication is undoubtedly more complex. In animal models, ethanol leads to hypothermia, the extent of which is in part dependent on ambient temperature.190,211,212 In mice, as the dose of ethanol increased, body temperature decreased and the rate of this decline in body temperature was faster at higher ethanol doses.184 The decline in body temperature could be reversed by increasing ambient temperature; increasing ambient temperature to 36°C (96.8°F) caused an immediate rise in the body temperature.184 The poikilothermic effect of ethanol was not due to hypoglycemia. Poikilothermia is the variation in body temperature >± 2°C (3.6°F) upon exposure to environmental temperature changes. Rats treated with equipotent amounts of sodium pentobarbital showed the same effects on body temperature as rats treated with ethanol, suggesting a similar central mechanism of central nervous system depression resulting in altered thermoregulation.184 Numerous mechanisms are involved in the “ethanol-induced depression of central nervous system function.”215 Genetic factors influence the role of ethanol in the production of hypothermia. Mouse strains bred for sleep times differed in sensitivity to ethanol’s effect on temperature.83,178,184 Mice can be selectively bred for genetic sensitivity or insensitivity to acute ethanolinduced hypothermia, and the differences appear to be mediated by the serotonergic systems.73 Histidyl-proline dike-topiperazine (cyclo His-Pro or CHP), another neurotransmitter that is found in many animal species, acts at the preoptic-anterior hypothalamus to

modulate body temperature.32,117 Exogenous administration of this neuropeptide produced a dose-dependent decrease in ethanolinduced hypothermia. Attenuation of hypothermia resulted from passive immunization with CHP antibody.32,117 Ethanol effects may be mediated through modulation of endogenous opioid peptides, as high-dose (10 mg/kg) naloxone reverses ethanol-induced hypothermia in animals.200 Pharmacokinetic characteristics of ethanol metabolism change in the presence of hypothermia. Hypothermic piglets infused with ethanol showed slower ethanol metabolism and a smaller volume of distribution and, as a result, higher ethanol levels than normothermic controls. Ethanol elimination and metabolism decreased as temperature fell.141 Tolerance develops to the effect of ethanol in producing hypothermia in all species.74,190 The degree of tolerance is proportional to the dose and duration of treatment with ethanol and is not explained by the increased rate of metabolism with chronic exposure.124 Age is a factor in the development of tolerance; older animals do not display the same degree of tolerance to the hypothermic effects of chronic ethanol administration as do younger animals.182,199,261 The development of tolerance to ethanol-induced hypothermia is affected by genetic factors. Experimentally, tolerance to ethanol-induced hypothermia increases the incorporation of certain amino acids into proteins in the rat brain. The formation of new proteins in ethanol-tolerant rats suggests stimulation of gene expression related to the tolerant state.124,253 Deficits in N-methyl-D-aspartate (NMDA) receptor systems may also be implicated in the development of ethanol tolerance. In addition, altered nicotinamide adenine dinucleotide (NADH) oxidation to NAD+, diminished blood flow to the liver, or slowing of metabolism through the P450 microsomal enzyme system may be involved.215 Hypothermia alters the breath-ethanol partition in the alveolus, and the temperature of expired breath alters breath-alcohol analysis results. In patients with mild hypothermia, ethanol breath analysis results in lower values by 7.3% per degree centigrade (or 1.8°F) decrease in body temperature.77 Whether breath-alcohol analysis is also affected by hyperthermia in the test subject remains to be studied.77

DISEASE PROCESSES AND THERMOREGULATION Many disease processes interfere with normal thermoregulation, limiting an individual’s capacity to prevent hypothermia or hyperthermia. Extensive dermatologic disease or cutaneous burns impair sweating and vasomotor responses to heat stress.27 Patients with autonomic disturbances such as diabetes or peripheral vascular disease also have altered vasomotor responses that impair vasodilatation and sweating.209 Extensive surgical dressings may preclude the evaporation of sweat in an otherwise normal patient. Heat-stressed persons with poor cardiac reserve may not be able to sustain a skin blood flow high enough to maintain normothermia.64,239 Intense motor activity may lead to excessive endogenous heat production in patients with Parkinson disease or hyperthyroidism. Patients with agitated delirium or seizures also have significantly elevated rates of endogenous heat production. Hypothalamic injury caused by cerebrovascular accidents, trauma, or infection may disturb thermoregulation.62,153 Hypothalamic dys-

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function can lead to high, unremitting fevers and insufficient stimulation of heat loss mechanisms such as sweating. Hypothalamic damage may predispose to hypothermia by interference with centrally mediated heat conservation.62,153,222,223 Fever, the normal response to stimulation of the hypothalamus by pyrogens, results in an elevated physiologic temperature set point and is a disadvantage in the heat-stressed individual.106

HYPOTHERMIA Epidemiology Hypothermia is defined as an unintentional lowering of the core body temperature to 25 µg/mL > 129 µmol/L

= = = = =

180.17 daltons 5–15 µg/mL 10 µg/mL 55.5 µmol/L > 20 µg/mL

= = =

> 20 µg/mL > 90 µg/mL > 40 µg/mL

Values greater than or equal to the action level necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical characteristics of the patient.

mg/dL. One liter of normal saline was administered by intravenous bolus and potassium chloride (40 mEq IV) was administered twice by infusion over 1 hour. Electrolytes repeated 3 hours after admission and subsequent to potassium repletion were sodium, 141 mEq/L; potassium, 2.8 mEq/L; chloride, 110 mEq/L; and bicarbonate, 17 mEq/L. The patient continued to have a sinus tachycardia with frequent PVCs, and her blood pressure decreased to 98/50 mm Hg. Two liters of lactated Ringer solution was administered by bolus, and her blood pressure increased to 108/56 mm Hg. Activated charcoal with sorbitol was again orally administered, this time without ensuing emesis. Approximately 4 hours after presentation and 6 hours after ingestion, a serum sample for a quantitative caffeine level was obtained. The treating institution lacked the capability to determine a quantitative caffeine level, and the blood sample was sent to a reference laboratory. Serum electrolytes were repeated at approximately 7 hours postingestion. Although the bicarbonate had increased to 20 mEq/L, the potassium was still 2.8

A 17-year-old girl presented to the Emergency Department reporting that she ingested 35 (200 mg) tablets of caffeine approximately 2 hours earlier. She complained of nausea, vomiting, and palpitations. Her vital signs were blood pressure, 115/66 mm Hg; heart rate, 142 beats/min; respiratory rate, 20 breaths/min; and temperature, 100.2°F (37.9°C). The patient was attached to a cardiac monitor. She was anxious and confused, but cooperative. Significant physical findings included mydriasis, tachycardia, tremor, and diaphoresis. A 12-lead ECG demonstrated a sinus tachycardia with frequent premature ventricular contractions (PVCs). Fifty grams of activated charcoal with sorbitol was given orally, but she immediately vomited. Metoclopramide (10 mg IV) was administered, and activated charcoal with sorbitol was again orally administered, but she again vomited. Serum electrolytes were sodium, 140 mEq/L; potassium, 3.0 mEq/L; chloride, 107 mEq/L; bicarbonate, 16 mEq/L; blood urea nitrogen (BUN), 8 mg/dL; creatinine, 1 mg/dL; and glucose, 248

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mEq/L. The patient again received potassium chloride (40 mEq IV) by infusion over 1 hour. The severity and persistence of hypotension and hypokalemia combined with a lack of intensive care capabilities necessitated transfer to the intensive care unit in a nearby children’s hospital. At the children’s hospital, her vital signs improved and were blood pressure, 110/64 mm Hg; heart rate, 110 beats/min; respiratory rate, 18 breaths/min; and temperature, 99°F (37.2°C). Fifty grams of activated charcoal without sorbitol was administered. The patient experienced anxiety and agitation that responded to lorazepam (3 mg IV). She was awakened during the night to perform a physical examination and to receive another dose of activated charcoal orally. Otherwise, the patient remained sedated through the night. She awoke in the morning with a normal mental status and reported feeling unwell but much improved. Repeat electrolytes were normal except for a potassium of 3.1 mEq/L. A serum caffeine level at that time, approximately 18 hours postingestion, was 88 µg/mL. Caffeine levels were repeated twice that day, with results of 56 µg/mL and 40 µg/mL, at which time further assays were deemed unnecessary. Serum electrolytes repeated that evening and at all subsequent times were normal. The patient was discharged from intensive care and admitted to a psychiatric service. The 6-hour caffeine level drawn at the initial institution was later reported to be 149 µg/mL.

Methylxanthines, which include caffeine (1,3,7-trimethylxanthine), theobromine (3,7-dimethylxanthine), and theophylline (1,3-dimethylxanthine), are so named because they are methylated deriv-

Figure 39-1.

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atives of xanthine (Fig. 39–1). Members of this group of plant-derived alkaloids have very similar pharmacologic properties and cause similar clinical effects. Methylxanthines are used ubiquitously throughout the world, most commonly in beverages imbibed for their stimulant, mood-elevating, and fatigue-abating effects. Coffea arabica and related species, from which coffee beans are obtained, are used to make coffee, a beverage rich in caffeine. Cocoa and chocolate are derived from the seeds of Theobroma cacao, which contains theobromine and, to a lesser extent, caffeine. Thea sinensis, a bush native to China but now cultivated worldwide, produces leaves from which various teas, rich in caffeine and containing small amounts of theophylline and theobromine, are brewed.

EPIDEMIOLOGY From 1991 to 1999, the American Association of Poison Control Centers (AAPCC) reported a noteworthy downward trend of theophylline exposures from 6744 exposures in 1991 to 1641 exposures in 1999. The number of deaths reported from theophylline exposure has decreased progressively, from 38 in 1991 to 10 in 1999. The decrease in theophylline exposures presumably reflects decreased use of theophylline as a therapeutic agent. The number of caffeine exposures, 5639 in 1991 and 6264 in 1999, has essentially remained stable, reflecting steady use of caffeine, particularly caffeine in substances other than coffee, tea, and soft drinks. Deaths from caffeine exposure continue to be uncommon: The

Metabolism of caffeine and other methylxanthines by the hepatic P450 enzyme system.

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maximal number of deaths associated with caffeine exposure in this time period was 3 per year (page XX and Chap. 116). The overwhelming preponderance of caffeine consumed is in beverages, and a lesser portion in foods and tablets or capsules. Users typically seek the stimulant and psychoactive effects of caffeine. The use of guarana, a plant with very high caffeine content, for weight loss and athletic performance enhancement has increased dramatically in recent years. In particular, guarana or caffeine is frequently combined with ephedrine or ma huang, a dietary supplement product containing ephedrine. These combination pills are marketed for use as diet agents, anorectics, “energy” boosters, and athletic-performance-enhancement products. Despite the limited experience with overdose from these combination preparations, formulations containing caffeine/guarana combined with ephedrine/ ma huang cause illnesses such as myocardial infarctions and death.77 Formulations containing phenylpropanolamine and caffeine, also once marketed as an anorexiant diet aid, were removed from US markets because of adverse drug events and a demonstrated lack of benefit from the inclusion of caffeine and a sympathomimetic agent for the purpose of appetite suppression.80 Medicinally, caffeine is used to treat neonatal apnea and bradycardia syndrome; as an analgesic adjuvant, particularly when combined with relatively mild analgesics such as acetaminophen, aspirin, and ibuprofen; and as an adjuvant treatment for migraine headache. Theophylline, or its salt aminophylline, is used to treat varied respiratory conditions. Most prevalently, theophylline is used to treat obstructive airway disease, particularly asthma and chronic obstructive pulmonary disease. Although theophylline was once the mainstay of therapy for such diseases, more selective agents with fewer side effects, such as albuterol and other selective
2adrenergic agonists, are now more commonly utilized. However, because anti-inflammatory and other beneficial effects of theophylline were recently described, its role in the treatment of pulmonary disease may again expand.100 In neonates, theophylline and aminophylline are used similarly to caffeine to treat neonatal apnea and bradycardia syndrome. The result of such treatment is increased respiratory rate, decreased apnea, increased cardiac chronotropy and inotropy, and increased cardiac output.33 Caffeine or theophylline toxicity result from iatrogenic events as well as self-administration, and acute or chronic toxicity may result from either drug or circumstance. Chronic toxicity from caffeine is most typically described as a result of the frequent self-administration of caffeine. A particular syndrome associated with chronic caffeine use consisting of headache, palpitations, tachycardia, insomnia, and delirium is termed caffeinism. Chronic theophylline toxicity results from the use of theophylline as a medicinal therapeutic agent. Neonates receiving caffeine therapy may develop either acute or chronic caffeine toxicity.6,15 Most reported cases of theobromine poisoning occur in animals and typically result from small animals ingesting cocoa or chocolate.29,46,50,78,181 Humans may theoretically experience theobromine poisoning from ingestion of chocolate or cocoa, although evidence of such occurrence is lacking.

PHARMACOLOGY Methylxanthines cause the release of endogenous catecholamines, resulting in stimulation of adrenergic receptors. The resulting adrenergic agonism plays a significant role in their therapeutic ef-

fects and in their untoward effects in cases of toxicity.187 Levels of endogenous catecholamines are extremely elevated in patients with acute methylxanthine poisoning.20 Methylxanthines are also structural analogues of adenosine and function pharmacologically as adenosine antagonists. Adenosine is believed to modulate histamine release and to cause constriction of respiratory smooth muscle, which may explain the efficacy of adenosine antagonists in the treatment of bronchoconstriction. Additionally, adenosine antagonism results in release of norepinephrine, and, to a lesser extent, epinephrine. At supertherapeutic doses, methylxanthines also inhibit phosphodiesterase, the enzyme responsible for degradation of intracellular cyclic AMP. This likely occurs as a result of the structural similarity of cyclic AMP and methylxanthines. Cyclic AMP is involved in the postsynaptic second messenger system of
-adrenergic stimulation. Thus, elevated cyclic AMP levels cause clinical effects similar to adrenergic stimulation including smooth muscle relaxation, peripheral vasodilation, myocardial stimulation, and central nervous system (CNS) excitation. Phosphodiesterase inhibition was long considered to be the primary therapeutic mechanism of the methylxanthines, but clinically significant elevations in cyclic AMP levels are not achieved until serum methylxanthine levels are well above the therapeutic range.

PHARMACOKINETICS AND TOXICOKINETICS Caffeine Caffeine is bioavailable by oral, intravenous, subcutaneous, intramuscular, and rectal routes of administration. Oral administration, which is by far the most common route of exposure, results in nearly 100% bioavailability of the drug. The presence of food in the gut does little to affect peak concentration. However, food in the gut does delay time until the peak serum concentration is reached, which is typically 30–60 minutes in the absence of food. Caffeine rapidly diffuses into the total body water and all tissues and readily crosses the blood-brain barrier and placenta. Caffeine is secreted in breast milk.185 The volume of distribution is 0.6 L/kg, and 36% is protein bound. Caffeine is metabolized via the cytochrome P450 system, primarily by the isozyme CYP1A2. The major pathway involves demethylation to 1,7-dimethylxanthine (paraxanthine) followed by hydroxylation, or repeated demethylation followed by hydroxylation. To a lesser extent caffeine is also metabolized to 3,7dimethylxanthine (theobromine) and to 1,3-dimethylxanthine (theophylline). Neonates demethylate caffeine, producing theophylline, and also possess the unique ability to convert theophylline to caffeine by methylation.2,10 By approximately 4–7 months of age, infants metabolize and eliminate caffeine in a manner similar to adults.9 Less than 5% of caffeine is excreted in the urine unchanged. All patients metabolize some quantity of caffeine to active metabolites including theophylline and theobromine. The degree to which this occurs is dependent on the age, cytochrome P450 enzyme induction status, and other factors. For this reason, there may be a role for assessment of serum theophylline concentration in the management of patients with suspected caffeine overdose, but such role is not clearly defined and obviously limited.

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The half-life of caffeine is highly variable and dependent on several factors. Generally speaking, younger patients, particularly infants, as well as patients with cytochrome P450 inhibition, such as pregnant patients and patients with cirrhosis, have longer caffeine half-lives than the 4.5-hour half-life in healthy, adult, nonsmoking patients.34,45,47,178 Caffeine also exhibits MichaelisMenten kinetics (Chap. 11). Caffeine poisoning is a dose-dependent phenomenon. Unfortunately, the range of toxicity reported in different references varies greatly, and no definite conclusions can be drawn regarding serum levels and symptomatology in overdose. Therapeutic dosing in adults is 100–200 mg orally every 4 hours, and in neonates a typical loading dose is 20 mg/kg, with daily maintenance dosing of 5 mg/kg. Based on case reports and series, lethal dosing in adults is estimated at 150–200 mg/kg, and death was associated with serum levels above 80 µg/mL. Although numerous fatalities occur with serum levels under 200 µg/mL, survival of a patient with an acute caffeine overdose and a serum level over 400 µg/mL has been reported.183 Infants survive toxicity with greater serum concentrations of caffeine than are tolerated by children and adults.

Theophylline Theophylline, or its water-soluble ethylenediethylamine salt derivative aminophylline, is approximately 100% bioavailable by both the oral and intravenous routes. Many of the available oral preparations are sustained-release, designed to provide stable serum concentrations over a prolonged period of time with less frequent dosing. Peak absorption generally occurs 6–10 hours after ingestion of these products. However, following overdose of sustainedrelease preparations, the time to peak absorption may be twice as long as that of the intermediate-release preparations. Like caffeine, theophylline rapidly diffuses into the total body water and all tissues, readily crosses the blood-brain barrier and placenta, and is secreted into breast milk.13,102,179,199 Theophylline’s volume of distribution is 0.5 L/kg, and 56% of it is protein bound. Theophylline is metabolized via the cytochrome P450 system, primarily by the isozyme CYP1A2. The major pathway is demethylation to 3-methylxanthine, in addition to being demethylated or oxidized to other metabolites. Neonates have the unique ability to readily methylate and demethylate methylxanthines, and a portion of theophylline administered to neonates is methylated to form 1,3,7-trimethylxanthine (caffeine).11,31,65 Less than 10% of theophylline is excreted in the urine unchanged. Like caffeine, the half-life of theophylline is highly variable, and is dependent on several factors. In healthy, adult, nonsmoking patients, the half-life is 4.5 hours. Infants and the elderly, as well as patients with cytochrome P450 inhibition, pregnant patients, and patients with cirrhosis, have longer theophylline half-lives than do healthy children and adult nonsmoking patients.59,87,119,177 Factors that induce cytochrome P450, such as cigarette smoking, or others that inhibit cytochrome P450, such as exposure to cimetidine, erythromycin, rifampin, and oral contraceptives, can significantly alter theophylline clearance.73,95,96,103,118,134,135,152,189 Decreased theophylline or caffeine metabolism or reversal of enzyme induction predisposes to the development of chronic toxicity. Like caffeine, theophylline exhibits Michaelis-Menten kinetics. At low doses, it is metabolized by first-order kinetics, and increases in dose result in concomitant increases in elimination.151

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At higher doses and in overdose it undergoes zero-order elimination, and only a fixed amount of the drug can be eliminated in a given time because of saturation of metabolic enzymes.149 Therapeutic serum levels of theophylline are 10–15 µg/mL, and higher levels are considered toxic. Morbidity and mortality occur with relatively lower levels in chronic toxicity. Although morbidity and mortality are not always predictable based on serum levels, life-threatening toxicity, including seizures, ventricular dysrhythmias, and death, are associated with serum levels of 80–100 µg/mL in acute overdoses and serum levels of 40–60 µg/mL in chronic toxicity.

Theobromine As is the case with the other methylxanthines, theobromine is well absorbed from the gut, and is 80% bioavailable when administered in solution. It is bioavailable orally, intravenously, and rectally. Theobromine has 21% protein binding, a volume of distribution of 0.62 L/kg, and a plasma half-life of 6–10 hours.51,146 Theobromine undergoes hepatic metabolism by the CYP450 system similarly to caffeine and theophylline.30 Like the other methylxanthines, theobromine is excreted in breast milk, and consumption of chocolate results in measurable concentrations in breast milk. Toxic concentrations of theobromine in animals are known, but comparable human data are lacking. A serum concentration of 133 µg/mL was reported in a lethal ingestion by a dog.67

PATHOPHYSIOLOGY Caffeine, theobromine, and theophylline affect the same organ systems and cause qualitatively similar effects. For the purposes of this chapter, the adverse effects of all methylxanthines in acute overdose are considered to be similar. It should be noted, however, that there are distinct differences in the activity and effects of the various methylxanthines, particularly in therapeutic dose. The major clinical effects at both therapeutic doses and in overdose result from adenosine antagonism, release of endogenous norepinephrine and consequent
-adrenergic receptor stimulation, and phosphodiesterase inhibition. Toxicity affects the gastrointestinal, cardiovascular, central nervous, and musculoskeletal systems in addition to causing a constellation of metabolic derangements. Polypharmacy poisoning with methylxanthines and other agents that result in adrenergic stimulation, such as ephedrine, amphetamines, or cocaine, may be particularly severe.48,190 Theobromine toxicity is exceedingly rare. There are limited human data and most published cases are actually veterinary. Animals with theobromine poisoning may experience emesis, incontinence, restlessness, excitement, tachycardia, seizures, coma, and death. These characteristic symptoms, as well the pharmacologic similarity between theobromine and other methylxanthines, dictate that management principles for caffeine and theophylline be applied in cases of theobromine toxicity.

Gastrointestinal In overdose, methylxanthines cause nausea and most significant acute overdoses result in severe and protracted emesis. Emesis occurs in 75% of cases of acute theophylline poisoning, whereas only 30% of cases of chronic poisoning are characterized by emesis.169 This emesis is often quite severe and may be difficult to control despite the use of potent antiemetics. In particular, poison-

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ing with sustained-release theophylline preparations may cause particularly severe emesis refractory to treatment.4 Methylxanthines cause an increase in gastric acid secretion and smooth-muscle relaxation. These factors contribute to the gastritis and esophagitis reported in chronic methylxanthine users.42 Gastritis is noted in drinkers of decaffeinated coffee, so some adverse gastric effects associated with coffee drinking may be due to ingredients other than caffeine alone.

Pulmonary Methylxanthines stimulate the CNS respiratory center, causing an increase in respiratory rate. For this reason, caffeine and theophylline are used to treat neonatal apnea syndromes. Caffeine and theophylline overdose may cause hyperventilation, respiratory alkalosis, respiratory failure, respiratory arrest, and acute lung injury.

Neuropsychiatric Cardiovascular Methylxanthines are cardiac stimulants, and result in positive inotropy and chronotropy. Dysrhythmias, particularly tachydysrhythmias, are common in methylxanthine overdose. Considering the adenosine antagonist properties of methylxanthines, it is not surprising that supraventricular tachycardias (SVTs) commonly occur in overdose. Tachydysrhythmias, particularly ventricular extrasystoles, are uncommon following therapeutic doses, whereas they are common in overdose.40,126,164 In the setting of acute poisoning, generally benign sinus tachycardia is nearly universal in patients without antecedent cardiac disease. In any patient, particularly those with underlying cardiac disease, a sinus tachycardia can degenerate to a more severe rhythm disturbance, which is the most common cause of fatality associated with methylxanthine poisoning. Supraventricular tachycardias, atrial fibrillation, atrial flutter, multifocal atrial tachycardia, ventricular tachycardia, and ventricular fibrillation may all result from methylxanthine toxicity.18 Electrolyte disturbances, particularly hypokalemia, may be a contributing factor in the development of dysrhythmias. Dysrhythmias occur more commonly and at lower serum concentrations in cases of chronic poisoning. Consequential dysrhythmias occur in 35% of chronic theophylline poisonings, but in only 10% of acute poisonings.173 These dysrhythmias occur at serum levels of 40–80 µg/mL in chronic theophylline overdoses and most commonly at serum levels greater than 80 µg/mL in acute overdose. Neonates born to mothers who consumed >500 mg/d of caffeine are more likely to have dysrhythmias as compared to cohorts born to mothers consuming less then 250 mg/d of caffeine.74 Myocardial ischemia and myocardial infarction may result from acute caffeine or theophylline poisoning.58,79 At therapeutic doses, and initially in overdose, methylxanthines result in tachycardias and increased blood pressure, both by the effect of adenosine antagonism on the sinoatrial or atrioventricular node, and by causing the release of endogenous catecholamines. Tolerance to these pressor effects develops after several days of use and rapidly disappears after relatively brief periods of abstinence. At elevated serum concentrations, methylxanthines will result in peripheral vasodilation, causing a characteristic widened pulse pressure.
2-Adrenergic agonism is one major mechanism by which hypotension occurs. In cases of acute theophylline overdose, serum levels greater than 100 µg/mL are usually associated with severe hypotension. In therapeutic doses, methylxanthines cause cerebral vasoconstriction, which is a desirable effect when caffeine is used to treat a migraine headache. However, in overdose, this effect likely exacerbates CNS toxicity by diminishing cerebral perfusion.121 Methylxanthines cause renal vasodilation, which, in addition to the increased cardiac output, results in a mild diuresis.136

The stimulant and psychoactive properties of methylxanthines, particularly caffeine, elevate mood and improve performance of manual tasks.24,35,89,111 These stimulant effects are typically considered desirable, and are one reason caffeine is so widely used. CNS stimulation is an effect sought by users of coffee, tea, cocoa, and chocolate, but CNS stimulation resulting from therapeutic use of theophylline is generally considered to be an undesirable side effect. Caffeine is an effective analgesic adjuvant, possibly because of the stimulant properties of the drug.90,91,125,127,160,165 Agitation, insomnia, nervousness, and irritability are common following initial administration of methylxanthines, but tolerance to these effects develops quickly. Although at low doses methylxanthines improve cognitive performance and elevate mood, with increasing doses they result in adverse effects. Headache, anxiety, agitation, insomnia, tremor, irritability, hallucinations, and seizures may result from caffeine or theophylline poisoning. In adults, caffeine doses of 50–200 mg result in increased alertness, decreased drowsiness, and lessened fatigue, and caffeine doses of 200–500 mg produce adverse effects. Children tend to develop CNS symptoms at lower serum theophylline concentrations than do adults, and such excitation is a significant clinical disadvantage of theophylline use. Although not reported, theobromine is probably capable of causing similar CNS symptoms reported with caffeine and theophylline. Seizures are a major complication of methylxanthine poisoning. The additional methyl group possessed by caffeine (1,3,7trimethylxanthine) affords this agent greater CNS penetration relative to theophylline and theobromine, which are dimethylxanthines. Caffeine’s ability to both promote and prolong seizures is well recognized, and caffeine has been used to prolong therapeutically induced seizures in electroconvulsive therapy (ECT).98,174 Seizures resulting from methylxanthine overdose tend to be severe and recurrent, and may be refractory to treatment. Antagonism of adenosine, the endogenous neurotransmitter responsible for halting seizures, contributes to the profound seizures associated with methylxanthine overdose.53,60,171,198 When studied prospectively, chronic theophylline toxicity results in seizures in 14% of patients, whereas 5% of acutely poisoned patients experience seizures. Seizures are more likely to occur in cases of chronic overdose, and in such situations they occur at lower serum levels.138 Patients at extremes of age, younger than 3 years and older than 60 years, are more likely to experience seizure with overdose.

Musculoskeletal Methylxanthines increase intracellular calcium content and increase striated muscle contractility, secondarily decreasing muscle fatigue. They also increase muscle oxygen consumption and increase the basal metabolic rate. These effects are sought by users

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of methylxanthines to enhance or improve athletic performance or to lose weight.8,17,41,54,69,70,116,130 Theobromine has the most potent activity on the muscles, more than 100 times that of caffeine, and theophylline has the least muscle-stimulating activity. All methylxanthines cause smooth-muscle relaxation. Skeletal muscle excitation, which may include tremor, fasciculation, hypertonicity, myoclonus, or even rhabdomyolysis, can all occur with methylxanthine overdose.104,117,142,154,192,196 Mechanisms by which rhabdomyolysis may result include increased muscle activity, particularly from seizures, and direct cytotoxicity from excessive sequestered intracytoplasmic calcium. Interestingly, there are multiple case reports of compartment syndrome resulting from theophylline overdose.115,184 This phenomenon is not described as a result of caffeine or theobromine overdose.

amount of additional theophylline or caffeine. Chronic theophylline poisoning typically occurs in the setting of therapeutic use of theophylline and may occur with iatrogenic administration of caffeine or from frequent, chronic consumption of caffeinated products. Patients often manifest subtle signs of illness, such as anorexia, nausea, palpitations, or emesis. However, the initial presentation in these patients, even with levels in the 40–60 µg/mL range, may be a seizure. In children chronically overdosed with theophylline, the peak serum theophylline concentration may fail to identify those who will progress to life-threatening toxicity. In the absence of protracted emesis or seizures, the initial electrolytes and blood gases are expected to be normal in patients with chronic methylxanthine toxicity.

Metabolic

CHRONIC METHYLXANTHINE USE

Numerous metabolic derangements may result from acute methylxanthine toxicity, and are similar to other states of excess adrenergic agonism or increased metabolism.75,76,159,170 Transient hypokalemia resulting from
-adrenergic agonism occurs in 85% of patients with acute theophylline overdose, and typically the serum potassium falls to approximately 3 mEq/L.5,167 Stimulation of Na+/K+ ATPase results in a shift of serum potassium to the intracellular compartment of skeletal muscle. This hypokalemia is only a shift of potassium from the extracellular to the intracellular compartment rather than a loss of potassium, and total body potassium stores are unchanged. The significance of hypokalemia in patients with methylxanthine overdose is unclear. Vomiting and renal losses contribute significantly to true total body hypokalemia. Hyperkalemia may result from overly aggressive repletion of potassium or as a result of rhabdomyolysis. Metabolic acidosis with increased serum lactate levels is commonly noted as a complication of theophylline overdose.23,108 Tachypnea and respiratory alkalosis secondary to stimulation of the respiratory center are common. Hyperglycemia, with serum glucose of approximately 200 mg/dL, is common and occurs in 75% of acute theophylline overdoses. Hypophosphatemia, hypomagnesemia, hypocalcemia, hypercalcemia, and ketosis may also result from methylxanthine toxicity.156 Hyperthermia caused by increased metabolic activity and increased muscle activity may result from caffeine and theophylline overdose. Leukocytosis, probably secondary to the high levels of circulating catecholamines, results from acute methylxanthine overdose. This phenomenon apparently lacks clinical significance. In the absence of seizures or protracted emesis, chronic methylxanthine poisoning does not typically lead to metabolic derangements because such toxicity is an ongoing, compensated process.

An inconclusive link to cancer, heart disease, osteoporosis, hyperlipidemia, and hypercholesterolemia is associated with caffeine use.57,61,72,110,131,150,193,194 Excessive consumption of caffeine-containing beverages can cause hypokalemia.153 A substantial debate centers on the psychiatric and cognitive effects of chronic theophylline use, particularly in children.114 To date, evidence suggests that although theophylline may acutely result in excessive CNS stimulation and hyperactivity, chronic use of methylxanthines does not adversely affect children’s cognitive development.19,180

CAFFEINISM Caffeinism is a syndrome of chronic toxicity resulting from excessive caffeine consumption. It may involve anxiety, palpitations, tremulousness, tachycardia, diuresis, headache, and diarrhea.188 Patients suffering caffeinism also experience withdrawal symptoms upon abstinence. The chronic toxicity from excessive caffeine use, caffeinism, is a distinctly different entity from caffeine withdrawal.

CAFFEINE WITHDRAWAL Caffeine is habit-forming and a withdrawal syndrome, including headache, yawning, nausea, drowsiness, rhinorrhea, lethargy, irritability, nervousness, a disinclination to work, and depression, may result upon abstinence.25,182 Caffeine withdrawal symptoms are described in neonates born to mothers with consequential caffeine use.123 The onset of caffeine withdrawal symptoms begins 12–24 hours after cessation, and lasts up to 1 week.71 In a doubleblind trial, 52% of adults with moderate caffeine intake developed a withdrawal syndrome upon caffeine abstinence.175

Chronic Methylxanthine Toxicity The major difference between acute and chronic toxicity is the duration of exposure to the drug. Patients with chronic toxicity may manifest subtle signs such as anorexia, nausea, palpitations, or emesis, although they may also present with seizures or dysrhythmias. The patient chronically receiving theophylline or caffeine has higher total body stores, and may develop toxicity with a smaller

REPRODUCTION Massive doses of methylxanthines are teratogenic, but the doses of typical use are not associated with birth defects. Decreased fecundity and adverse fetal outcome are noted in animals with chronic exposure to methylxanthines.62,66,122 Human studies of fertility, fetal loss, and fetal outcome produce divergent results, and

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the effects of methylxanthine use during gestation are unclear.1,21,55,86,94,128,133

DIAGNOSTIC TESTING An electrocardiogram (ECG) and serum electrolytes, as well as a serum caffeine or theophylline level as appropriate, are indicated in cases of suspected methylxanthine toxicity. Some degree of methylation and demethylation of methylxanthines may occur in patients of all ages, and methylxanthine poisoning may result in elevation in the serum level of other methylxanthine metabolites. Overdose of caffeine may cause a spuriously elevated serum measurement for theophylline.56,93 The utility of a serum theophylline level in cases of caffeine toxicity is undemonstrated, and at this time, obtaining such levels should only be considered an academic exercise. Theophylline levels, and to a lesser extent caffeine levels, may be used to guide management of poisoning with the respective agents. For these levels to be maximally useful it is important to know whether they reflect acute or chronic poisoning. In the setting of acute toxicity, serum methylxanthine levels should be obtained immediately and then serially every 1–2 hours until a downward trend is evident. Acute poisoning by caffeine and theophylline is well described. Because toxicity is dose related, serum concentrations of caffeine and theophylline may be loosely applied as a correlate with toxicity. Unfortunately, serum caffeine concentrations are usually readily available only in institutions in which neonates are therapeutically treated with caffeine. Serum theophylline concentration is a more readily available laboratory assay, and the greater clinical experience with theophylline in therapeutic dose and in overdose provides an established correlation between serum theophylline concentration and symptomatology. Likewise, serum electrolytes, particularly potassium, should be monitored serially as long as the poisoned patient remains symptomatic and such values are in a range that may warrant treatment. Cardiac monitoring should continue until the patient is free of any dysrhythmia other than sinus tachycardia, the patient has a decreasing serum methylxanthine level, and the patient is not systemically ill. In patients with systemic illness, hyperthermia, or increased muscle tone, assessing serum creatine phosphokinase (CPK) and urinalysis to detect rhabdomyolysis are also indicated.

MANAGEMENT General Principles and Gastrointestinal Decontamination After assuring adequacy of airway, breathing, and circulation, supportive care and maintenance of vital signs within acceptable limits are the mainstay of therapy for methylxanthine overdose. Decisions regarding gastrointestinal decontamination including orogastric lavage, induction of emesis with syrup of ipecac, administration of activated charcoal, or whole-bowel irrigation depend on the dosage and type of preparation of theophylline or caffeine involved, time since exposure, and the patient’s physical condition.

Emesis Emesis with syrup of ipecac should only be rarely considered for minimally symptomatic patients whose ingestions occurred less than 1 hour previously. A simulated overdose controlled volunteer study with sustained-release theophylline was unable to demonstrate reduction of absorption of theophylline in patients treated with syrup of ipecac.129 Seizures are possible with any significant methylxanthine poisoning, and emesis in a patient experiencing a seizure is an obvious danger. Because the benefits of emetics are undemonstrated and emesis interferes with administration of activated charcoal, syrup of ipecac is rarely indicated for methylxanthine poisoning.3,63

Orogastric Lavage Orogastric lavage may be considered for patients with potentially toxic methylxanthine ingestions, particularly those who are ill enough to require endotracheal intubation. Orogastric lavage may not be effective in removing theophylline tablets, probably because of the large size of the tablets relative to the lumen of the orogastric tube. Ingestion of sustained-release theophylline tablets is associated with the formation of bezoars that may be difficult to remove or dislodge.26 Treatment in such cases has included endoscopic removal.38

Whole-Bowel Irrigation Treatment of patients with significant ingestions of sustainedrelease pills may include whole-bowel irrigation (WBI) with a balanced electrolyte solution to enhance gastrointestinal elimination. (Antidotes in Depth: Whole-Bowel Irrigation) Polyethylene glycol solution used for WBI may displace theophylline already bound to charcoal.83 This may be a particular problem in patients who have taken several doses of activated charcoal prior to WBI, in which desorption of methylxanthine from activated charcoal may result in a bolus of methylxanthine available for gastrointestinal absorption. Also, WBI is experimentally demonstrated to provide no additional benefit to activated charcoal in treatment of sustainedreleased theophylline ingestion.37 Despite these data, WBI remains the preferred and recommended treatment of an ingestion of sustained-release theophylline.

Activated Charcoal Activated charcoal plays an important role in the treatment of methylxanthine poisoning. Activated charcoal can bind methylxanthines present in the gastrointestinal (GI) tract prior to absorption of the methylxanthine, limiting the absorption of a given methylxanthine dose. Multiple-dose activated charcoal (MDAC) also plays a significant role in the management of methylxanthine toxicity. MDAC enhances elimination of theophylline by gut dialysis. Such enhanced elimination by gut dialysis is not demonstrated, experimentally or otherwise, for caffeine or theobromine toxicity. Because caffeine is to some extent metabolized to theophylline, MDAC in cases of caffeine poisoning would, at the very least, enhance elimination of theophylline metabolites. The pharmacologic similarity of the methylxanthines and the relative safety of MDAC therapy warrant the use of such treatment for any methylxanthine toxicity. MDAC is for the purpose of enhanced elimination and is discussed in depth later in this chapter.

CHAPTER 39

Selecting a Method of Decontamination The use of decontamination methods that involve more than minimal risk, specifically emesis with syrup of ipecac or orogastric lavage, should only occur after careful consideration of the indications. Acute ingestion occurring not more than 1 hour previously in a patient without CNS depression or contraindicating factors may be treated with syrup of ipecac, and potentially life-threatening acute ingestions may be treated with orogastric lavage.

Treatment of Gastrointestinal Toxicity Phenothiazine antiemetics are relatively contraindicated in methylxanthine poisoning because they are typically ineffective and may lower the seizure threshold. Metoclopramide may be used, but a more potent antiemetic such as ondansetron or granisetron may be required.44,147,157 Histamine (H2) blockers or proton-pump inhibitors may be administered to any patient with hematemesis. Use of such agents should be reserved for cases in which they are certainly needed, because some H2 blockers (cimetidine) may inhibit CYP450, delaying clearance of methylxanthines.

Treatment of Cardiovascular Toxicity Hypotension should initially be treated by administration of an isotonic intravenous fluid, such as 0.9% sodium chloride or lactated Ringer solution, in bolus volumes of 20 mL/kg. If acceptable blood pressure cannot be maintained despite several fluid boluses, or if there are contraindications to fluid bolus, vasopressor therapy should be considered. Methylxanthine toxicity typically results in excessive
-adrenergic agonism; therefore, administration of vasopressors with
adrenergic agonist effects, such as epinephrine, dobutamine, or isoproterenol, are not preferred. A strictly -adrenergic agonist such as phenylephrine is the first-line pressor of choice in such a situation, although norepinephrine is also acceptable (Table 39–1). Hypotension may be refractory to treatment with intravenous fluid and pressor therapy, and in such cases the administration of a
-adrenergic antagonist may be warranted.49 This approach may seem counterintuitive. Methylxanthine-induced hypotension is to a significant extent mediated by
2-adrenergic vasodilation, and a nonselective
-adrenergic antagonist suppresses
2-adrenergic stimulation. In addition,
1-adrenergic antagonism treats tachycardia and any decreased cardiac output that may result from inefficient cardiac activity. In canines with aminophylline-induced tachycardia and hypotension, administration of esmolol results in a return to normal heart rate and blood pressure, and does not exacerbate hypotension.63 Propranolol, esmolol, and metoprolol have been used successfully to treat methylxanthine-induced hypotension in humans.27,144,161,186 It is more appropriate to use a
-adrenergic antagonist with a brief duration of action, such as esmolol or metoprolol, at least initially, in such circumstances. In the event of an adverse reaction or side effect such as hypotension or bronchospasm, the duration of such will be relatively brief. Any
adrenergic antagonist therapy should ideally be preceded and accompanied by measurement of cardiac output and central venous blood pressure with a device such as a pulmonary artery catheter.99 In most other situations, adenosine or electrical cardioversion is the preferred treatment for SVT, but this is not so for SVT resulting from methylxanthine toxicity. Although adenosine or elec-

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trical cardioversion may be effective, neither is likely to be effective. Because of the adenosine antagonist effects of methylxanthines, administration of adenosine should not be expected to convert an SVT. However, even if adenosine is successfully used to convert an SVT, the effect is likely to be transient. Because methylxanthine toxicity has a global effect on the myocardium, cardioversion, which is effective in electrically “reorganizing” depolarization, is unlikely to work because this SVT does not result from a single locus of aberrant electrical activity. Primary treatment for methylxanthine-induced SVT includes administration of benzodiazepines, which work to abate CNS stimulation and concomitant release of catecholamines. More focused pharmacologic therapy to treat SVT is through administration of a conduction-attenuating calcium channel blocker such as diltiazem. In rat and dog models, treatment of acute theophylline toxicity with calcium channel blockers verapamil, diltiazem, or nifedipine results in decreased cardiac-related deaths and prevented dysrhythmias, hypotension, myocardial necrosis, and seizures.91 In addition to the cardiovascular benefit of calcium channel blockers, they also afford some neurologic protection and prevention of seizure. In the nonasthmatic patient, methylxanthine-induced supraventricular tachycardia and other tachydysrhythmias may be treated by administration of
-adrenergic antagonist. Correction of hypokalemia may be crucial in methylxanthine poisoning associated with ventricular dysrhythmias. Hypokalemia is a well-described consequence of excess adrenergic agonism, including poisoning from methylxanthines as well as sympathomimetic agents. In the absence of associated dysrhythmia, the clinical significance of such hypokalemia is unclear. Such hypokalemia has been experimentally demonstrated to respond to treatment with
-adrenergic antagonists.

Treatment of Central Nervous System Toxicity Administration of a benzodiazepine such as diazepam or lorazepam is appropriate treatment for anxiety, agitation, or seizure. The seizures associated with methylxanthine toxicity are severe and often refractory to treatment. Seizures not controlled with 1 or 2 therapeutic doses of a benzodiazepine should be treated with a barbiturate such as pentobarbital or phenobarbital, or a suitable sedative-hypnotic such as propofol. No delay should occur before administering such medications. Unsuccessful treatment of methylxanthine-induced seizures with any particular agent should quickly be abandoned in favor of treatment with an additional or more efficacious anticonvulsant. The administration of barbiturates may result in or exacerbate hypotension. Treatment of any aforementioned problem with benzodiazepines, barbiturates, or other sedative-hypnotic may require repeated dosing until clinical effect is achieved. Administration of phenobarbital to prevent seizures in theophylline-poisoned rabbits and mice increases survival by decreasing the incidence of seizures.43,68 Patients at increased risk for seizures should be prophylactically administered a benzodiazepine such as lorazepam. These patients include those identified earlier in this chapter: patients older than 60 years or younger than 3 years of age, those with chronic overdose and a serum level of 40–60 µg/mL, and acutely overdosed patients with serum levels greater than 100 µg/mL. Phenytoin and fosphenytoin are of no benefit in controlling methylxanthine-induced seizures and they have no role in such

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY TABLE 39–1.

Therapeutic Agents for Methylxanthine Poisoning

System

Indication

Therapeutic agent

Cardiovascular

Hypotension

Fluids Vasopressors Phenylephrine Norepinephrine β-Adrenergic antagonist Esmolol Metoprolol Propranolol Calcium channel blocker Diltiazem Verapamil

Supraventricular dysrhythmias

Ventricular dysrhythmias

Gastrointestinal

Emesis

Hematemesis

CNS

Anxiety Agitation Seizure and seizure prophylaxis

Metabolic

Metabolic acidosis Hypokalemia

β-Adrenergic antagonist Esmolol Metoprolol Propranolol Antidysrhythmic Lidocaine β-Adrenergic antagonist Esmolol Metoprolol Propranolol Antiemetic Metoclopramide Ondansetron Granisetron Proton pump inhibitor Omeprazole Histamine H2 antagonist Ranitidine Famotidine Benzodiazepine Diazepam Lorazepam Benzodiazepine Diazepam Lorazepam Sodium bicarbonate Potassium chloride β-Adrenergic antagonist Esmolol Metoprolol Propranolol

treatment.82,120 Retrospective review of human cases demonstrated phenytoin to be ineffective in treating seizures in 21 of 22 cases.88 In a rabbit model, phenytoin is ineffective in the treatment of seizures, results in the occurrence of seizures at an earlier time after overdose, and results in higher mortality when administered to theophylline-poisoned mice.28

Treatment of Metabolic Disorders Patients with symptomatic hypokalemia, hyperkalemia, or hypocalcemia should be treated accordingly. Most cases of hyperkalemia are well tolerated, but any patient with symptomatic hypokalemia, particularly those associated with ECG changes of T waves or QTc prolongation, should be treated. The frequency of

Comments

Relatively contraindicated in asthmatic patients

Dihyrdopyridine agents such as nifedipine and amlodipine are not indicated Relatively contraindicated in asthmatic patients

Relatively contraindicated in asthmatic patients

Cimetidine may decrease clearance of methylxanthines and prolong toxicity

Not routinely recommended for this purpose; relatively contraindicated in asthmatic patients

ventricular dysrhythmias in methylxanthine poisoning, which may be the exacerbated by hypokalemia coupled with increased intrinsic catecholamine release, prompts the recommendation that otherwise asymptomatic hypokalemia below 2.7 mEq/L be treated. Cautious administration of potassium to treat symptomatic hypokalemia may be indicated, but this is distinct from higher doses of potassium used in total body potassium repletion. In cases of hypokalemia secondary to
-adrenergic agonism, after the
adrenergic agonism returns to baseline level an efflux of potassium from the intracellular compartment occurs. Concomitant rise of the serum potassium concentration occurs at that time. Overly aggressive attempts to correct hypokalemia may result in hyperkalemia after the
-adrenergic agonist effects abate. Acute methylxanthine-induced hypokalemia may be treated with potas-

CHAPTER 39

sium supplementation, but because of the nature of the problem— excess
-adrenergic agonism—potassium supplementation is typically ineffective. Experimentally, administration of propranolol to theophyllinepoisoned dogs prevented or partially reversed hypokalemia, hypophosphatemia, hyperglycemia, and metabolic acidosis, as well as hypotension.97 Prevention or correction of the metabolic derangements associated with theophylline toxicity by administration of a
-adrenergic antagonist is congruent with the fact that these derangements, particularly hypokalemia, are the consequence of
-adrenergic agonism. The efficacy of
-adrenergic antagonists as therapy for hypokalemia resulting from acute methylxanthine poisoning in humans is unstudied. However, the pathophysiology of acute methylxanthine-induced hypokalemia and available animal data suggest that therapy with a
-adrenergic antagonist is probably the optimal treatment of such hypokalemia. As mentioned previously, this is relatively contraindicated in an asthmatic patient, and any such treatment should initially be with a short-acting
-adrenergic antagonist such as esmolol or metoprolol to afford greater safety in the event of untoward effects. The importance of treating hypomagnesemia, hypophosphatemia, and hypocalcemia is not evident, and these disorders should be treated as they would for other patients experiencing them. As with hypokalemia, QTc prolongation is an absolute indication to treat these derangements. Hyperglycemia, likely resulting from increased circulating catecholamines, is common. This hyperglycemia does not necessitate treatment with any type of hypoglycemic agent, both because it is a transient effect and because in other situations of hyperglycemia resulting from adrenergic agonism a rebound hypoglycemia may occur.

Treatment of Musculoskeletal Toxicity The use of benzodiazepines is appropriate treatment for fasciculation, hypertonicity, myoclonus, or rhabdomyolysis. Rhabdomyolysis necessitates aggressive intravenous fluid therapy, possibly with sodium bicarbonate (Antidotes in Depth: Sodium Bicarbonate).

Enhanced Elimination Fortunately, methylxanthine toxicity lends itself well to several methods of enhanced elimination, including gut dialysis with MDAC, charcoal hemoperfusion, and hemodialysis, as well as less used methods such as continuous arteriovenous hemoperfusion (CAVHP) and plasmapheresis.14,105,113 Infants with methylxanthine poisoning may be too ill, too unstable, or too small to be treated with hemodialysis or hemoperfusion. Both MDAC and exchange blood transfusion are effective methods of enhanced elimination in infants, and may be the preferred method of treatment in these patients.16,81,92,139,143,166,168 MDAC is extremely effective at enhancing elimination of theophylline.22,64,112,137,140 Experimentally in dogs, rabbits, and human volunteers, activated charcoal administered after IV aminophylline administration results in increased systemic clearance and decreased half-life of theophylline.32,85,101,124,145 The therapeutic effects of activated charcoal in such cases are much greater than simply limiting absorption of ingested methylxanthine. Activated charcoal, particularly MDAC, enables elimination of theophylline by way of gastrointestinal dialysis.12 Gut dialysis works to eliminate a drug by virtue the drug diffusing across the

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gut mucosa. Activated charcoal in the gut lumen acts to adsorb that drug, after which it is eliminated in stool. The pharmacologic similarity of the methylxanthines suggests that MDAC may be effective in gut dialyzing caffeine or theobromine, and MDAC certainly will be effective in eliminating any theophylline generated from metabolism of caffeine or theobromine. The extreme efficacy of MDAC combined with the safety and ease with which this therapy can be administered make MDAC the mainstay of enhanced elimination in methylxanthine toxicity. Severe emesis associated with methylxanthine poisoning may result in intolerance of MDAC, and in case series, has been shown to necessitate abandonment of MDAC for definitive enhancement of methylxanthine elimination by charcoal hemoperfusion162 (Antidotes in Depth: Activated Charcoal). Charcoal hemoperfusion is the single most effective method of enhanced elimination of methylxanthines, decreasing theophylline’s half-life to 2 hours, and increasing its clearance possibly up to 6-fold.36,52,132,141,155,158,195 Variations of charcoal hemoperfusion, including albumin colloid hemoperfusion, resin hemoperfusion, and charcoal hemoperfusion, in series with hemodialysis are reported.39,84,106,148,179 Charcoal hemoperfusion in series with hemodialysis may be superior to either method alone, because it extends the life of the charcoal perfusion cartridge, increases overall methylxanthine extraction and clearance, and allows fluid and electrolyte abnormalities to be corrected. Charcoal hemoperfusion is typically less readily available and somewhat more complicated than hemodialysis, and this may influence selection between charcoal hemoperfusion and hemodialysis as therapeutic options. Combined hemodialysis and MDAC are an easily performed regimen that provides superior theophylline clearance to hemodialysis alone. Although employed as an effective treatment modality, hemodialysis has always been less efficient than hemoperfusion in the extracorporeal removal of methylxanthines.7,107,109,176 Traditionally, hemodialysis was not preferred because methylxanthine elimination rates by hemodialysis were much lower than that those achieved by charcoal hemoperfusion, and even lower than a much safer, easier, noninvasive method—MDAC. Improvement of hemodialysis equipment allows blood flow rates as much as 2 times faster than in the recent past, and has tremendously increased the potential rates of methylxanthine clearance by hemodialysis. As a result, the difference in elimination achieved by hemoperfusion and hemodialysis is less. This fact, in combination with the ability of hemodialysis to correct fluid and electrolyte imbalances, the greater availability of hemodialysis, its greater technical ease, and its lower complication rates, has resulted in a paradigm shift from considering charcoal hemoperfusion to be the definitive treatment for significant methylxanthine toxicity to one in which charcoal hemoperfusion and hemodialysis are considered fairly equivalent treatment options172 (Chap. 6). In the treatment of methylxanthine poisoning, the specific indications for therapy to enhance elimination are not agreed upon. Several studies and clinical experience are the basis for the following suggested indications for extracorporeal elimination by charcoal hemoperfusion, hemodialysis, combined charcoal hemoperfusion/hemodialysis, or combined hemodialysis and MDAC. Most cases of methylxanthine toxicity and overdoses occur with theophylline, and theophylline levels tend to be both readily available and correlate with toxicity. Therefore, many recommendations regarding hemoperfusion and/or hemodialysis for theo-

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phylline toxicity use serum theophylline concentration as a guideline. Serum levels may not be available in instances of caffeine poisoning and do not exist for theobromine poisoning. The clinical aspects of theophylline management guidelines can probably be generalized to all methylxanthine toxicities. When indicated, charcoal hemoperfusion and/or hemodialysis should be initiated while the patient is still hemodynamically stable, or considered alternatively, before the patient becomes unstable. Charcoal hemoperfusion and/or hemodialysis therapy should be employed for chronic theophylline poisoning associated with a serum theophylline concentration above 40–60 µg/mL or with a deteriorating clinical status. Our recommendation is that charcoal hemoperfusion and/or hemodialysis be performed any time a methylxanthine exposure results in a serum theophylline or caffeine concentration of greater than 90 µg/mL and symptoms, regardless of clinical stability (Table 39–2). Any methylxanthine exposure resulting in a serum theophylline or caffeine concentration greater than 40 µg/mL that is associated with ventricular dysrhythmias, seizures, hypotension unresponsive to fluids, or emesis unresponsive to antiemetics should also be treated with charcoal hemoperfusion and/or hemodialysis. A patient who experiences a seizure or dysrythmias or who becomes extremely ill remains a candidate for extracorporeal drug removal. To the contrary, these events make administration of such therapy more critical to ensure survival of the patient. TABLE 39–2. Indications for Charcoal Hemoperfusion and/or Hemodialysis 1. Theophylline or caffeine serum level >90 µg/mL 2. Acute theophylline or caffeine overdose with seizures or cardiovascular compromise 3. Chronic theophylline or caffeine serum level >40 µg/mL and A. Seizures or B. Hypotension unresponsive to intravenous fluid or C. Ventricular dysrhythmias

Treatment of Chronic Methylxanthine Toxicity Treatment of chronic methylxanthine toxicity is determined by the patient’s clinical status and by the efficacy of MDAC. The precise serum theophylline or caffeine concentration at which patients with chronic theophylline or caffeine toxicity should receive charcoal hemoperfusion or hemodialysis is controversial. For a hemodynamically stable patient without signs of life-threatening methylxanthine toxicity such as ventricular dysrhythmias or seizure, therapy with MDAC may be sufficient. If the serum theophylline or caffeine concentration does not decline following the administration of activated charcoal, or if the patient’s clinical status deteriorates, charcoal hemoperfusion or hemodialysis is indicated.

Treatment of Acute-on-Chronic Methylxanthine Toxicity Patients chronically receiving theophylline or caffeine who acutely overdose should be initially managed in the same manner as patients with acute overdose. The clinical presentation of such patients resembles that of acute poisoning, and the initial management issues of gastrointestinal decontamination are the same as for

acute poisoning. Such issues include gastrointestinal decontamination, emesis and other gastrointestinal toxicity, and metabolic derangement. Because total body stores of the methylxanthine are higher in patients who are chronically exposed, the threshold for toxicity may be reached at lower serum concentrations. After issues of gastrointestinal decontamination and control of emesis are addressed, acute-on-chronic methylxanthine poisoning is managed similarly to chronic poisoning. Seizure prophylaxis indications are the same as those for chronic methylxanthine poisoning, and enhanced elimination is indicated at the lower serum methylxanthine concentrations applied in chronic methylxanthine poisoning.

SUMMARY Methylxanthines are ubiquitously used by cultures throughout the world. Toxicity results from both the use of medicinal and therapeutic agents, as well as from consumption of methylxanthinecontaining foods and beverages. There are significant differences in the clinical presentation and management of patients with acute and chronic poisoning. Supportive care and treatment of gastrointestinal, cardiovascular, CNS, metabolic, and musculoskeletal toxicities are the mainstay of therapy. The unique properties of methylxanthines necessitate specific therapies for the gastrointestinal, cardiovascular, and CNS toxicities of methylxanthines. Methods of enhanced elimination, particularly extracorporeal elimination by charcoal hemoperfusion, hemodialysis, or charcoal hemoperfusion and hemodialysis in series, as well as gut dialysis with MDAC are effective treatments.

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132. Nagesh RV, Murphy KA: Caffeine poisoning treated by hemoperfusion. Am J Kidney Dis 1988;4:316–318. 133. Nehlig A, Debry G: Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: A review on human and animal data. Neurotoxicol Teratol 1994;16:531–543. 134. Nicot G, Charmes JP, Lachatre G, et al: Theophylline toxicity risks and chronic renal failure. Int J Clin Pharmacol Ther Toxicol 1989; 27:398–401. 135. Nix DE, DiCicco RA, Miller AK, et al: The effect of low-dose cimetidine (200 mg twice daily) on the pharmacokinetics of theophylline. J Clin Pharmacol 1999;39:855–865. 136. Nobel PA, Light GS: Theophylline-induced diuresis in the neonate. J Pediatr 1977;90:825–826. 137. Ohning BL, Reed MD, Blumer JL. Continuous nasogastric administration of activated charcoal for the treatment of theophylline intoxication. Pediatr Pharmacol 1986;5:241–245. 138. Olson KR, Benowitz NL, Woo OF, Pond SM: Theophylline overdose: Acute single ingestion versus chronic repeated overmedication. Am J Emerg Med 1985;3:386–394. 139. Osborn HH, Henry G, Wax P, et al: Theophylline toxicity in a premature neonate—Elimination kinetics of exchange transfusion. J Toxicol 1993;31:639–644. 140. Park GD, Radomski L, Goldberg MJ, et al: Effects of size and frequency of oral doses of charcoal on theophylline clearance. Clin Pharmacol Ther 1983;34:663–666. 141. Park GD, Spector R, Roberts RJ, et al: Use of hemoperfusion for the treatment of theophylline toxicity. Am J Med 1983;74:961–966. 142. Parr MJA, Willatts SM: Fatal theophylline poisoning with rhabdomyolysis. Anaesthesia 1991;46:557–559. 143. Perrin C, Debruyne D, Lacotte J, et al: Treatment of caffeine intoxication by exchange transfusion in a newborn. Acta Paediatr Scand 1987;76:679–681. 144. Price KR, Fligner DJ: Treatment of caffeine toxicity with esmolol. Ann Emerg Med 1990;19:44–46. 145. Radomski L, Park GD, Goldberg MJ, et al: Model for theophylline overdose treatment with oral activated charcoal. Clin Pharmacol Ther 1984;35:402–408. 146. Resman BH, Blumenthal HP, Jusko WJ. Breast milk distribution of theobromine from chocolate. J Pediatrics 1977;91:477–480. 147. Roberts JR, Carney S, Boyle SM, Lee DC: Ondansetron quells drugresistant emesis in theophylline poisoning. Am J Emerg Med 1993; 11:609–610. 148. Rongved G, Westlie L: Hemoperfusion/hemodialysis in the treatment of acute theophylline poisoning: Description of a fatal case. Int J Clin Pharmacol Ther Toxicol 1986;24:85–87. 149. Rosenberg J, Benowitz NL, Pond S: Pharmacokinetics of drug overdose. Clin Pharacokinet 1981;6:161–192. 150. Ross PC: Osteoporosis frequency, consequences and risk factors. Arch Intern Med 1996;156:1399–1411. 151. Rovei V, Chanoine F, Strolin Benedetti M: Pharmacokinetics of theophylline: A dose-range study. Br J Clin Pharmacol 1982;14: 769–778. 152. Roy AK, Cuda MP, Levine RA: Induction of theophylline toxicity and inhibition of clearance rates by ranitidine. Am J Med 1988; 85: 525–527. 153. Rudy DR, Lee S: Coffee and hypokalemia. J Fam Pract 1988;26: 679–680. 154. Rumpf DW, Wagner H, Criee CP, et al: Rhabdomyolysis after theophylline overdose. Lancet 1985;1:1451–1452. 155. Russo ME: Management of theophylline intoxication with charcoalcolumn hemoperfusion. N Engl J Med 1979;300:24–26. 156. Ryan T, Coughlan G, McGing P, Phelan D: Ketosis, a complication of theophylline toxicity. J Intern Med 1989;226:277–278. 157. Sage TA, Jones WN, Clark RF: Ondansetron in the treatment of intractable nausea associated with theophylline toxicity. Ann Pharmacother 1993;27:584–585.

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158. Sahney S, Abarzua J, Sessums L: Hemoperfusion in theophylline neurotoxicity. Pediatrics 1983;71:615–619. 159. Sawyer WT, Caravati EM, Ellison MJ, Krueger KA: Hypokalemia, hyperglycemia, and acidosis after intentional theophylline overdose. Am J Emerg Med 1985;3:408–411. 160. Sawynok J, Yaksh TL: Caffeine as an analgesic adjuvant: A review of pharmacology and mechanisms of action. Pharmacol Rev 1993; 45:43–85. 161. Seneff M, Scott J, Friedman B, Smith M: Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability. Ann Emerg Med 1990;19:671–673. 162. Sessler CN, Glauser FL, Cooper KR: Treatment of theophylline toxicity with oral activated charcoal. Chest 1985;87:325–329. 163. Sessler CN: Poor tolerance of oral activated charcoal with theophylline overdose. Am J Emerg Med 1987;5:492–495. 164. Sessler CN, Cohen MD: Cardiac arrhythmias during theophylline toxicity: A prospective continuous electrocardiographic study. Chest 1990;98:672–678. 165. Schaftel BP, Fillman JM, Lane AC, et al: Caffeine as an analgesic adjuvant. Arch Intern Med 1991;151:733–737. 166. Shannon M, Amitai Y, Lovejoy FH Jr: Multiple-dose activated charcoal for theophylline poisoning in young infants. Pediatrics 1987; 80:368–370. 167. Shannon M, Lovejoy FH Jr: Hypokalemia after theophylline intoxication. The effects of acute vs chronic poisoning. Arch Intern Med 1989;149:2725–2729. 168. Shannon M, Wernovsky G, Morris C: Exchange transfusion in the treatment of severe theophylline poisoning. Pediatrics 1992;89: 145–147. 169. Shannon M: Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993;119:1161–1167. 170. Shannon M: Hypokalemia, hyperglycemia and plasma catecholamine activity after severe theophylline intoxication. Clin Toxicol 1994;32:41–47. 171. Shannon MW, Maher TJ: Anticonvulsant effects of intracerebroventricular adenosine in theophylline-induced seizures. Ann Emerg Med 1995;26:723–724. 172. Shannon MW: Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication. Acad Emerg Med 1997;4: 674–678. 173. Shannon M: Life-threatening events after theophylline overdose: A 10-year prospective analysis. Arch Intern Med 1999;159:989–994. 174. Shapira B, Lerer B, Gilboa D, et al: Facilitation of ECT by caffeine pretreatment. Am J Psychiatry 1987;144:1199–1202. 175. Silverman K, Evans SM, Strain EC, Griffiths RR: Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 1992;327:1109–1114. 176. Slaughter RL, Green L, Kohli R: Hemodialysis clearance of theophylline. Ther Drug Monit 1982;4:191–193. 177. Staib AH, Schuppan D, Lissner R, et al: Pharmacokinetics and metabolism of theophylline in patients with liver disease. Int J Clin Pharm Ther Toxicol 1980;18:500–502. 178. Statland BE, Demas TJ: Serum caffeine half-lives. Healthy subjects vs. patients having alcoholic hepatic disease. Am J Clin Pathol 1980; 73:390–393.

179. Stegmayr BG: On-line hemodialysis and hemoperfusion in a girl intoxicated by theophylline. Acta Med Scand 1988;223:565–567. 180. Stein MA, Krasowski M, Leventhal BL, et al: Behavioral and cognitive effects of methylxanthines. A meta-analysis of theophylline and caffeine. Arch Pediatr Adolesc Med 1996;150:284–288. 181. Strachan ER, Bennett A: Theobromine poisoning in dogs. Vet Rec 1994;134:284. 182. Strain EC, Mumford GK, Silverman K, Griffiths RR: Caffeine dependence syndrome. JAMA 1994;272:1043–1048. 183. Tisdell R, Iacobucci M, Snodgrass WR: Caffeine poisoning in an adult—Survival with a serum concentration of 400 mg/L and need for adenosine agonist antidotes. Vet Human Toxicol 1986;28:492. 184. Titley OG, Williams N: Theophylline toxicity causing rhabdomyolysis and acute compartment syndrome. Intensive Care Med 1992;18: 129–130. 185. Tyrala EE, Dodson WE: Caffeine secretion into breast milk. Arch Dis Child 1979;54:787–800. 186. Vanden Hoek T, Murphy C, Aks S, et al: The use of esmolol to reverse unstable supraventricular tachycardia in a theophylline toxic patient. Vet Hum Toxicol 1991;33:390. 187. Vestal RE, Eiriksson CE Jr, Musser B, et al: Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 1983;67: 162–171. 188. Victor BS, Lubetsky M, Greden JF: Somatic manifestations of caffeinism. J Clin Psychiatry 1981;42:185–188. 189. Vozeh S, Powell R, Riegelman S, et al: Changes in theophylline clearances during acute illness. JAMA 1978;240:1882–1884. 190. Weinberger M, Bronsky E, Bensch GW, et al: Interaction of ephedrine and theophylline. Clin Pharmacol Ther 1975;291: 151–153. 191. Whitehurst VE, Joseph X, Vick JA, et al: Reversal of acute theophylline toxicity by calcium channel blockers in dogs and rats. Toxicology 1996;110:113–121. 192. Wight JP, Laurence S, Holt S, Forrest AR: Rhabdomyolysis with hyperkalaemia after aminophylline overdose. Med Sci Law 1987;27: 103–105. 193. Willett WC, Stampfer MJ, Manson JE, et al: Coffee consumption and coronary heart disease in women. JAMA 1996;275:458–462. 194. Wilson PW, Garrison RJ, Kannel WB, et al: Is coffee consumption a contributor to cardiovascular disease? Arch Intern Med 1989;149: 1169–1172. 195. Woo OF, Pond SM, Benowitz NL, Olson KR: Benefit of hemoperfusion in acute theophylline intoxication. J Toxicol Clin Toxicol 1984; 22:411–424. 196. Wrenn KD, Oschner I: Rhabdomyolysis induced by caffeine overdose. Ann Emerg Med 1989;18:94–97. 197. Yeh TF, Pildes R: Transplacental aminophylline toxicity in a neonate. Lancet 1977;1:9–10. 198. Young D, Dragunow M: Status epilepticus may be caused by a loss of adenosine anticonvulsant mechanisms. Neuroscience 1994;58: 245–261. 199. Yurchak AM, Jusko WJ: Theophylline secretion into breast milk. Pediatrics 1976;57:518–520.

CHAPTER

40

ANTIDIABETIC AND HYPOGLYCEMIC AGENTS George M. Bosse

Glucose MW Normal range (blood)

= 180 daltons = 60–110 mg/dL = 3.3–6.1 mmol/L Values less than or equal to the action level necessitate clinical intervention. Values greater than this level may necessitate intervention based on the clinical characteristics of the patient.

His pretreatment serum glucose was 18 mg/dL. Although the patient’s blood sugar remained elevated in the ED, he was admitted to the hospital so that he could be observed, and if necessary treated, for recurrent hypoglycemia. An IV line was maintained for 24 hours until the patient began to eat regularly. No neurologic sequelae were observed. Diabetic education and alcoholism counseling were initiated during his 2-day hospitalization, which was uneventful. He was discharged to the care of his private physician and the chlorpropamide was discontinued.

Five police officers entered the Emergency Department (ED) with an obese, middle-aged man whose arms were handcuffed behind his back. He was extremely agitated, diffusely diaphoretic, bleeding from the mouth, and had several small lacerations and multiple contusions. His respirations were labored. The police stated that the man’s family had called them after he had “gone berserk.” When they arrived at the apartment, several pieces of furniture had been broken, and it took all five police officers to restrain the man. In a few minutes, the family arrived in the ED. They related that the patient had been despondent recently; they suspected he had been drinking. In addition, they reported, he was taking various unknown medications, “because he’s been sick.” Shortly after the handcuffs were removed to permit physical examination, the patient developed a focal seizure that began in his right hand and progressed to become a typical generalized tonic-clonic seizure lasting 2 minutes. Postictal vital signs were: blood pressure, 120/80 mm Hg; pulse, 120 beats/min; respiration, 24 breaths/min; and temperature, 36.8°C (98.4°F). The patient was lethargic but oriented. The remainder of the neurologic examination revealed a right hemiparesis, right conjugate gaze, right central facial paralysis, and right-sided plantar extension. The pupils were equal and reactive to light, and the fundi were unremarkable. He had no evidence of significant head trauma. His chest was clear to percussion and auscultation, and heart sounds were normal except for tachycardia. Multiple contusions were clearly visible on his extremities, but there were no overt fractures and there was no edema. Within 5 minutes of empiric administration of 100 mL of D50W and 100 mg thiamine IV, the right-sided neurologic findings disappeared, the lethargy cleared, and the patient was sufficiently alert to relate a history. The patient stated that his private physician had placed him on chlorpropamide for “mild diabetes.” Because his mother had died of diabetes, he thought he knew the type of complications he might expect. He became despondent, he said, because of his “inevitable fate” and began to drink. The alcohol, however, only led to more frequent episodes of despondency.

Although various pharmacologic agents and medical conditions may cause hypoglycemia, the focus of this chapter is on the drugs used in the treatment of diabetes mellitus. This includes the various forms of insulin and several oral agents: the sulfonylureas, biguanides,
-glucosidase inhibitors, thiazolidinediones, and meglitinides. This chemically heterogeneous group of drugs has the potential to cause various unique toxic effects in addition to hypoglycemia. Most patients with diabetes mellitus are classified as either insulin-dependent (IDDM) (Type 1) or noninsulin-dependent (NIDDM) (Type 2). This classification scheme for diabetes mellitus is not perfect. For example, patients with NIDDM may be managed with insulin therapy. Early in the course of IDDM, patients may enter a remission period during which insulin is not required. In general, neurohormonal control of glucose production in healthy individuals maintains a serum glucose level in the range of 60–110 mg/dL. Hypoglycemia is the failure to maintain serum glucose above a level that does not cause signs or symptoms of glucose deficit. The glycemic threshold is the plasma glucose concentration below which clinical manifestations develop. This threshold level for symptoms to occur is quite variable. In one study, the mean glycemic threshold for hypoglycemic symptoms was 78 mg/dL in poorly controlled diabetics as compared to 53 mg/dL in nondiabetics.11

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HISTORY AND EPIDEMIOLOGY Insulin first became available for use in 1922.7 Since its introduction, several forms with varying kinetic properties have become available. In an attempt to more closely simulate physiologic conditions, newer, designer insulins have been developed, including an ultrashort-acting preparation known as lispro.49,97 Research into an oral form of insulin with resistance to the protein degradation effects of the gut is ongoing and of particular interest.36 Emphasis on tighter diabetic control as a means of preventing microvascular effects of diabetes mellitus carries with it an increased risk of hypoglycemia.22,23 Insulin-induced hypoglycemia may be used therapeutically in alternative medicine practices and psychiatrists use this therapy for patients with severe depression. The hypoglycemic activity of a sulfonamide derivative used for typhoid fever in World War II was noted by the French physician Janbon.51 This discovery was subsequently verified in animals. The sulfonylureas in use today are all chemical modifications of that original sulfonamide compound. In the mid-1960s, the first-generation sulfonylureas were widely used. The newer, second-generation agents differ from those early first-generation agents primarily in their potency. Although insulin is widely used, overdose with the sulfonylureas is more commonly reported than is insulin overdose, based on 10 years of data from the 1989 through 1998 reports of the American Association of Poison Control Centers Toxic Exposure Surveillance System (Chap. 116 and page 1752). However, insulin-induced hypoglycemia probably occurs more frequently than reported. The biguanides metformin and phenformin were developed as derivatives of Galega officinalis, the French lilac which was recognized in medieval Europe as a treatment for diabetes mellitus.4 Phenformin was used in the United States until 1977, when it was banned because of its association with life-threatening lactic acidosis (64 cases/100,000 patient-years). However, it is still available in certain countries, including Spain and Italy.57 Travelers and immigrant patients who continue to receive medication from their native countries may still present here with phenformin-induced lactic acidosis. Metformin became available in the United States in 1995. Its use is also associated with lactic acidosis, but to a much lesser degree than with phenformin (only 3 cases/100,000 patientyears).20 Several newer agents have been introduced in the treatment of diabetes mellitus. Although overdose data are limited, some of these drugs have unique toxicity related to therapeutic use. These include the thiazolidinedione derivatives (troglitazone, rosiglitazone, pioglitazone), acarbose and miglitol (α-glucosidase inhibitors), and repaglinide and nateglinide (meglitinides). Hypoglycemia and its secondary effects on the central nervous system are the most common adverse effects related to insulin and the sulfonylureas. Ethanol is also a common cause of hypoglycemia and is discussed in depth in Chapter 64. Although this classically occurs in alcoholics with decreased carbohydrate intake and depleted hepatic glycogen stores, other populations, such as children, are also particularly vulnerable to ethanol-induced hypoglycemia. Various other drugs, including -adrenergic antagonists and salicylates, as well as various medical conditions, such as sepsis and insulin-secreting tumors, may cause hypoglycemia (see Table 40–1). Certain plant products may be implicated as well. Although not a particular problem in the United States, ingestion of the unripe fruit of the Ackee tree (Blighia sapida) in countries

TABLE 40–1.

Causes of Hypoglycemia

Endocrine Disorders Addison disease Glucagon deficiency Panhypopituitarism (Sheehan syndrome) Neoplasms Carcinomas (diverse extrapancreatic) Hematologic Insulinoma Mesenchymal Multiple endocrine adenopathy type 1 (Werner syndrome) Reactive Hypoglycemia Hepatic Disease Acute hepatic atrophy Alcoholism Cirrhosis Galactose or fructose intolerance Glycogen storage disease Neoplasia Renal Disease Chronic hemodialysis Chronic renal insufficiency Miscellaneous Acquired immunodeficiency syndrome (AIDS) Anorexia nervosa Autoimmune disorders SLE

Rheumatoid arthritis Graves disease Burns Diarrhea (childhood) Leucine sensitivity Muscular activity (excessive) Postgastric surgery Pregnancy Protein calorie malnutrition Septicemia Shock Wasting syndrome Exogenous Ackee (hypoglycin) Alloxan β-Adrenergic antagonists Cocaine Disopyramide Ethanol Hypoglycemic agents (insulin, sulfonylureas) Opioids Pentamidine Quinine Quinidine Ritodrine Salicylates Streptozocin Sulfonamides Vacor Valproic acid Artifactual Chronic myelogenous leukemia Polycythemia vera

where food is in short supply may result in significant hypoglycemia due to the compound hypoglycin.

PHARMACOLOGY Insulin is synthesized in the  cells of the pancreas as a prohormone, which upon release is cleaved, resulting in a C-peptide and insulin itself, a double-chain molecule containing 51 amino acid residues. Glucose concentration plays a major role in the regulation of insulin release. The activation of insulin secretion by glucose is complex and not well understood. Likely steps in the triggering process include the activation of signal transduction pathways, ATP production via glucose metabolism, closure of adenosine triphosphate (ATP)-sensitive potassium channels, cellular depolarization, and calcium entry into the  cell. Insulin binds to specific receptors on cell surfaces in insulin-sensitive tissues, particularly liver, muscle, and adipose. The action of insulin on these tissues is complex and involves various phosphorylation and dephosphorylation reactions.86 Chapter 26 has a detailed discussion of the endocrine principles of insulin and other antidiabetic agents. Figure 40–1 depicts the chemical structures of representative oral agents. The sulfonylureas stimulate the  cells of the pancreas to produce insulin; as such, they are ineffective in IDDM

CHAPTER 40

Figure 40–1.

ANTIDIABETIC AND HYPOGLYCEMIC AGENTS

595

The chemical structures of representative oral antidiabetic and hypoglycemic agents.

where the patient is insulinopenic (Fig. 40–2). This stimulatory effect diminishes with chronic therapy. All the sulfonylureas have molecular mechanisms that involve binding to high-affinity receptors on the pancreatic -cell membrane, with subsequent closure of potassium channels sensitive to adenosine triphosphate (KATP channels).27,31,32 This inhibition of potassium ion efflux from pancreatic  cells causes membrane depolarization, calcium influx, and activation of the secretory machinery independent of glucose concentration. High-affinity sulfonylurea receptors are also present within pancreatic  cells and are postulated to be either on granular membranes or part of a regulatory exocytosis kinase. Binding to these receptors promotes exocytosis by direct interaction with secretory machinery not involving closure of the plasma membrane KATP channels.27,31,32 Repaglinide is a new oral agent that is structurally different from the sulfonylureas. However, it also binds to ATP-sensitive potassium channels on  cells of the pancreas, resulting in increased insulin secretion.61 The linkage of two guanidine molecules forms the biguanides. In the process, an amino group is eliminated. Metformin, the only biguanide available in the United States, is an oral compound used in the treatment of NIDDM. Its glucose-lowering effect is caused by several underlying mechanisms. The most important mechanism appears to involve the inhibition of gluconeogenesis and subsequent decreased hepatic glucose output. Enhanced peripheral glucose uptake also plays a significant role. Other contributing factors include decreased fatty acid oxidation and increased intestinal use of glucose.5,99 In skeletal muscle and adipose cells, metformin causes enhanced activity and translocation of glucose transporters. Although the details are unclear, the mechanism by which this occurs involves an interaction between metformin and

Glucose

β-Islet Cell

Glucose

ATP

Pyruvate

Kinases Inactive

K+

Ca 2+

X

Kinases Active

ATP Insulin

Sulfonylurea receptor site on ATP sensitive K+ channel

Somatostatin receptor

ATP sensitive K+ channel

Ca 2+

Voltage-gated Ca 2+ channel

Figure 40–2. Under normal conditions, cells release insulin in response to an elevation of intracellular ATP levels. Sulfonylureas potentiate the effects of ATP at its “sensor” on the ligand gated K+ channels and prevent efflux of K+. The subsequent rise in intracellular potential opens voltage-gated Ca2+ channels, which sets in action a series of phosphorylation reactions culminating in fusion of the insulin-containing vesicle with the cell membrane and release of insulin.

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tyrosine kinase on the intracellular portion of the insulin receptor. Figure 40–3 depicts the mechanism of action of metformin. Insulin resistance is common in NIDDM. Resistance may occur because of abnormal -cell secretory products, circulating insulin antagonists, and target tissue defects in insulin action.66 The thiazolidinedione derivatives decrease insulin resistance by the potentiation of insulin sensitivity in the liver, adipose tissue, and skeletal muscle. Uptake of glucose into adipose tissue and skeletal muscle is enhanced, while hepatic glucose production is reduced.13,41 Acarbose and miglitol are oligosaccharides that inhibit
-glucosidase enzymes in the brush border of the small intestine, mainly glucoamylase, sucrase, and maltase. As a result, postprandial elevations in blood glucose levels after carbohydrate ingestion are blunted.105 Delayed gastric emptying may be another mechanism for their antihyperglycemic effect.76

PHARMACOKINETICS AND TOXICOKINETICS Some of the pharmacokinetic parameters of the hypoglycemic agents are outlined in Tables 40–2 and 40–3. Insulin is a peptide that is degraded in the gut and is therefore not active by the oral

pho

} Tyrosine kinase

METFORMIN

sph ory la PC-1 tion -

Glucose

Glucose

Skeletal Muscle/Adipocyte

METFORMIN

Glucose Gluconeogenesis

Hepatocyte = GLUT

route. The duration of action in therapeutic doses varies considerably from less than 5 hours with the ultrashort-acting lispro to as long as 36 hours with protamine zinc (NPH) and Ultralente insulin. Insulin overdose usually occurs by the subcutaneous or intramuscular route. As might be predicted based on the duration of action of some of the preparations, insulin overdose may result in prolonged hypoglycemia. However, this may also occur with short-acting forms because of some unusual toxicokinetic features. Insulin overdose of any type presents the potential for unusually delayed and profound hypoglycemia as well. Some of these unpredicted responses may be caused by a depot effect, and poor absorption may be further potentiated by the poor perfusion that can occur in hypoglycemia.62,96 The clinical course after insulin overdose can also vary quite widely and is often unpredictable based on the dose injected. Delayed release of insulin from adipose tissue at the injection site(s) and in diabetics the presence of insulin antibodies may explain a victim’s recovery in spite of massive overdoses.80 As there are a finite number of insulin receptors, insulin overdoses of varying size are probably equivalent in terms of the degree of hypoglycemia but not its duration once receptor saturation occurs. A comparison can be made with the current treatment of diabetic ketoacidosis, in which lower doses of insulin are as effective as the higher doses used in the past.48 Many of the sulfonylureas have a long duration of action, and this may explain the unusually long period of hypoglycemia that may occur with therapeutic use and in the overdose setting. The first-generation sulfonylureas (acetohexamide, chlorpropamide, tolazamide, and tolbutamide) reduce hepatic clearance of insulin, and produce active hepatic metabolites. These agents are dependent on their effective urinary excretion to maintain euglycemia and avoid hypoglycemia. The second-generation sulfonylureas (glimepiride, glipizide, and glyburide) have half-lives that approach 24 hours and are associated with substantial fecal excretion of the parent drug. These agents are associated with frequent episodes of hypoglycemia (Table 40–2). The sulfonylureas, like insulin, may cause delayed onset of hypoglycemia in the overdose setting.68,75 The reason for the potential delayed onset of effects with sulfonylureas is unclear and cannot be explained by known kinetic principles. The kinetics of acarbose are notable for minimal systemic absorption and metabolism that occurs in the gut. As a result, serious systemic toxicity would not be expected.81 Related symptoms are usually gastrointestinal in nature.

Glycolysis ATP

Pyruvate

= Insulin receptor

Figure 40–3. Under normal conditions, insulin binding to its receptor on myocytes and adipocytes activates tyrosine kinase, resulting in phosphorylation, and activation, of the membrane bound glucose transporter, GLUT. NIDDM is causally associated with an increased activity of PC-1, a glycoprotein that inhibits tyrosine kinase activity and thus reduces myocyte and adipocyte glucose uptake. Metformin reduces PC-1 activity in these cells, enhancing peripheral glucose utilization. In addition, gluconeogenesis in hepatic cells is reduced through interference with pyruvate carboxylase, the enzyme responsible for the conversion of pyruvate to oxaloacetate (Chap. 13).

PATHOPHYSIOLOGY Hypoglycemic agents are a diverse group of drugs, all of which, with the possible exception of metformin, the thiazolidinedioness and acarbose, may produce a nearly identical clinical condition of hypoglycemia. The etiologies of hypoglycemia are divided into three general categories:29 physiologic or pathophysiologic conditions (Table 40–1), direct effects of various hypoglycemic agents (Tables 40–2 and 40–3), and the potentiation of hypoglycemic agents by interactions with other pharmacologic agents (Table 40–4). The most common cause of severe hypoglycemia resulting in an emergency department visit is excessive insulin use or insulin use that is relatively excessive for the caloric intake or exercise level of the individual. Central nervous system symptoms predominate in hypoglycemia because the brain relies almost entirely on glucose as an

CHAPTER 40

TABLE 40–2

ANTIDIABETIC AND HYPOGLYCEMIC AGENTS

597

Characteristics of Orally Administered Hypoglycemic Agents Active Hepatic Metabolite

Active Urinary Excretory Product (% of dose)

Fecal Excretion (% of dose)

Frequency of Severe Hypoglycemia (other complications)

12–18

Hydroxyhexamide (+++)

Hydroxyhexamide (65%) Acetohexamide (2%)

Negligible

~1%

24–72

2-Hydroxychlorpropamide (+) 3-Hydroxychlorpropamide (+)

Negligible

4–6%

16–24

Hydroxytolazamide (++)

Negligible

~1%

6–12

Hydroxytolbutamide (+)

Chlorpropamide (20%) 2-Hydroxychlorpropamide (55%) 3-Hydroxychlorpropamide (2%) Hydroxytolazamide (35%) Tolazamide (7%) Hydroxytolbutamide (30%) Tolbutamide (2%)

Negligible

82 d 17 d — >11 mo 100 d >150 d

9 >8 >4 4 9 >12 >12 8 10 >4 >4 >5

*Denotes possible repeat ingestion.

summarizes these cases. These patients’ clinical courses are characterized by a severe coagulopathy that may last weeks to months, often accompanied by consequential blood loss. The most common sites of bleeding include the gastrointestinal and genitourinary tracts. Although initial parenteral vitamin K1 doses as high as 400 mg have been used,32 daily oral vitamin K1 requirements may be in the range of 50–100 mg. Recent experience in both animals and humans suggests that parenteral vitamin K1 therapy may not be required30,184 (Antidotes in Depth: Vitamin K). Patients with unintentional ingestions must be distinguished from those with intentional ingestions, because the former individuals demonstrate a low likelihood of producing coagulation abnormalities and rare morbidity or mortality. Actually, with a single, small ingestion of a superwarfarin rodenticide, prolongation of the PT or INR is unlikely. Clinically significant anticoagulation is even rarer. In the combined pediatric case series, prolongation of the PT occurred in only 8 of 142 children (5.6%) reported with

single small ingestions of long-acting anticoagulants.15,87,89,156 Only 1 child in this group was reported to have “abnormal prolonged bleeding,” but this required no medical attention.156 In a single case report, a 36-month-old child developed a coagulopathy manifested by epistaxis and hematuria with anticoagulation persisting for over 100 days after a presumed, but unwitnessed, single unintentional ingestion of brodifacoum.170 Clinically significant coagulopathy can result, however, following small repeated ingestions. Two children reportedly became unintentionally poisoned by repeated ingestions of a long-acting anticoagulant. One child presented with a neck hematoma that compromised his airway; the other child presented with a hemarthrosis.64 Similarly, a 7-year-old girl required multiple hospitalizations over a 20-month period following an unintentional chronic ingestion of brodifacoum.177 Finally, a 24-month-old child who presented with unexplained bruising and a PT >125 seconds, was the victim of brodifacoum poisoning caused by a Munchausen syndrome by proxy.6

CHAPTER 42

Following an acute unintentional exposure, most patients (usually children) are entirely asymptomatic and have a normal coagulation profile. Knowing that the risk of coagulopathy is low and that it will occur over days, most authors recommend nonintervention.88,156 Despite the fact that significant toxicity from superwarfarins is rare, it should be recognized that the reported benign courses of pediatric exposures may be misleading. Multiple retrospective studies suggest that children with unintentional acute exposures do not require any followup coagulation studies.31,117,132,151 This conclusion and approach to management are an unjustified attempt to decrease the cost of “unnecessary” coagulation studies. However, there are clearly insufficient data to justify this conclusion as many of these “exposed” children were never documented to have actually ingested long-acting anticoagulants (Chap. 116). We recommend that clinicians continue to manage these children as possible ingestions and that all children be followed up with daily INR studies for at least 48 hours.

Laboratory Assessment Established screening tests are helpful for diagnosis. Four studies —PT(INR), PTT, thrombin time, and fibrinogen concentration— are available. Prothrombin time is calculated by adding standardized thromboplastin reagent (phospholipid and tissue factor) to a sample of the patient’s citrated plasma (the citrate removes calcium). Calcium is then introduced and the time to clotting measured. The PT is unaffected by the presence or absence of factors VIII to XIII (with the exception of X), platelets, prekallikrein, and HMWK. An individual’s PT was formerly expressed as a ratio (PT observed/PT control). Because both laboratory methodology and the source of the thromboplastin reagent used directly affect this ratio, the results generated suffered from significant variability. A new standard, the international normalized ratio (INR) was developed in an attempt to limit interlaboratory variability.74,121 The INR is derived by raising the PT ratio to a power value known as the international sensitivity index (ISI): (PT ratio)ISI. The ISI is a measure of responsiveness of the particular thromboplastin to warfarin. Although the use of the INR does not completely eliminate variability,76,120 it does improve the potential for standardized interpretation and limits interinstitutional variations. Partial thromboplastin time is measured by adding kaolin or celite to citrated plasma in order to activate the “contact” components of the intrinsic system. This mixture is then recalcified and the time to clotting observed. Some tests use phospholipids in the reagent to activate the remaining coagulation factors, thereby giving rise to the term activated PTT (aPTT). Because the PTT and aPTT are essentially interchangeable, the term PTT is used hereafter to represent the concept. The PTT is not affected by factors VII, XIII, or platelets. The thrombin time, which is determined by adding exogenous thrombin to citrated plasma, evaluates the ability to convert fibrinogen to fibrin, and is thus unaffected by factors II, V, VII to XIII, platelets, prekallikrein, or HMWK. Finally, either a fibrinogen level or a determination of fibrin degradation products helps to distinguish between problems with clot formation and consumptive coagulopathy. An evaluation of the combination of normal and abnormal results of these tests determines the patient’s abnormality (Table 42–3). Inhibitors can be diagnosed by “mixing studies,” because only a small percentage of the coagulation factor levels present in normal plasma are necessary to have a normal PTT. If the patient with

TABLE 42–3.

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Evaluation of Abnormal Coagulation Times

INR Normal, PTT Prolonged, Bleeding Deficiencies of factors VIII, IX, XI Von Willebrand disease Heparin therapy (low dose) INR Normal, PTT Prolonged, No Bleeding Deficiencies of factor XII, prekallikrein, high-molecular-weight-kininogen Inhibitor syndrome INR Prolonged, PTT Normal Deficiency of factor VII Warfarin therapy (early) Vitamin K deficiency (mild) Liver disease (mild) INR and PTT Prolonged, Thrombin Time Normal, Fibrinogen Normal Deficiencies of factors II, V, IX, vitamin K (severe) Warfarin therapy (late) INR and PTT Prolonged, Thrombin Time Abnormal, Fibrinogen Normal Heparin effect Dysfibrinogenemia INR and PTT Prolonged, Thrombin Time Abnormal, Fibrinogen Abnormal Liver disease Disseminated intravascular coagulation Fibrinolytic therapy Crotaline envenomation

an abnormal PTT suffers from even a severe factor deficiency, restoration of that factor activity to 50% of normal will completely normalize the PTT. Thus, the presence of an abnormal PTT that will not correct by incubation of the patient’s plasma with an equal volume of normal plasma is diagnostic of an inhibitor of coagulation. More sophisticated studies can be used to identify specific coagulation factor deficiencies. The reader is referred to one of several standard references for a more detailed discussion of the approach to patients with abnormal coagulation studies.2,70 Although warfarin levels may be useful to confirm the diagnosis in unknown cases and to study drug kinetics,67,122 the routine use of simple and inexpensive measures such as INR determination seems more appropriate.

Evaluation of Long-Acting Anticoagulants For patients who have known ingestions of long-acting anticoagulants and are considered likely to develop a coagulopathy, baseline coagulation studies are not usually helpful, but they may provide information about chronic exposures. If the history is reliable and the patient is healthy, baseline studies can be avoided. Serial INRs at 24 and 48 hours should identify all patients at risk of coagulopathy.156 These studies can be obtained while the patient remains in the home setting, depending on the social situation. In contrast, all patients with intentional ingestions of longacting anticoagulants should be presumed to be at risk for a severe coagulopathy. In fact, most patients do not seek medical care until bruising or bleeding is evident.9,30,32,36,51,73,77,86,87,89,92,100,119,142,165 These events often occur many days after ingestion, which obviates the need for gastric decontamination unless there is a suggestion of repetitive ingestion. These patients should be managed as described below.

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For patients who have a suspected long-acting anticoagulant overdose, daily or twice-daily INR evaluations should be adequate to identify most patients at risk for coagulopathy. Early detection (through coagulation factor analysis) may be preferred,67 however, and levels of long-acting anticoagulants can now be measured.54,94,122 Emphasis has been placed on determining a critical superwarfarin level below which anticoagulation does not occur,32 and in one case report, brodifacoum was observed to follow zeroorder elimination kinetics.30 If this type of toxicokinetics is consistent in the analysis of other long-acting anticoagulants, these laboratory measurements may prove more reliable than the current empiric endpoints of therapy.

months to be 3%, 12%, and 53% in low-risk (0 risk factors), intermediate-risk (1–2 risk factors), and high-risk (3–4 risk factors) patients, respectively. Physicians had little ability to accurately estimate the probability of bleeding and use of the Outpatient Bleeding Risk Index would therefore seem appropriate to improve awareness and treatment of these high-risk patients. In a study of 32 patients who developed life-threatening hemorrhage while on warfarin therapy, most patients had multiple risk factors for hemorrhage, including excessive anticoagulation.182 The gastrointestinal tract was identified as the source of bleeding in two-thirds of the patients.182 Sixty-six percent of patients were given vitamin K1, 50% were given FFP, and 7% were given both therapies.182

Clinical Manifestations Typical warfarin-containing rodenticides contain only small concentrations of anticoagulant, such as 0.025% (or 25 mg of warfarin per 100 g of product). Using the data previously listed, a 10-kg child requires a dose of 1 mg of warfarin (4 g of rodenticide) and a daily dose of about 1.2 mg of warfarin (5 g of rodenticide) to remain anticoagulated. These quantities are far greater than those that occur in typical “tastes.” Thus, single unintentional ingestions of warfarin-containing rodenticides pose virtually no threat to either normal or anticoagulated patients.88 In contrast, intentional and large unintentional ingestions of pharmaceutical-grade anticoagulants have the potential to produce a coagulopathy and consequential bleeding. In one study describing 12 patients with surreptitious ingestion of oral anticoagulants, 9 were healthcare professionals.124 These patients presented with typical manifestations of impaired coagulation: bruising, hematuria, hematochezia, and menorrhagia. Rare but life-threatening complications, such as hemorrhage into the neck with resultant airway compromise, are reported.23 Although intentional ingestions of warfarin-containing products are uncommon, adverse drug events resulting in excessive anticoagulation and bleeding occur frequently. The risk of hemorrhage during oral anticoagulant therapy depends upon a myriad of factors, including the intensity of anticoagulation, patient characteristics and comorbid conditions (ie, hypertension, renal insufficiency, malignancy, etc), length of anticoagulant therapy, and indications for anticoagulation (ie, cerebral vascular disease, prosthetic heart valves, atrial fibrillation, ischemic heart disease, and venous thromboembolism). The significance of each of these clinical conditions varies among different reports; however, most studies demonstrate that there is a greater incidence of bleeding complications with increasing INR,39 increasing intensity (or variation) of coagulation, advanced age, a history of previous bleeding episodes while on therapeutic warfarin, drug interactions, impaired liver function, and dietary changes.55,57,66,71,135,182 Clearly, the most serious complication of excessive anticoagulation is intracranial hemorrhage, reported to occur in as many as 2% of patients on long-term therapy.57 This complication is associated with a fatality rate as high as 77%.109 Recently, an Outpatient Bleeding Risk Index was created and shown to be more accurate than physician’s judgment in classifying patients according to the risk of major bleeding.19 The index was based on 4 independent risk factors: age ≥65 years; history of cerebrovascular accident; history of gastrointestinal bleeding; and either history of recent myocardial infarction, hematocrit 1.5 mg/dL, or diabetes mellitus. The sum of the number of risk factors successfully predicted major bleeding at 48

GENERAL MANAGEMENT Gastrointestinal decontamination should be performed on patients who are believed to have potentially significant life-threatening ingestions, but for patients who present a few hours after ingestion, gastric decontamination with either orogastric lavage or syrup of ipecac-induced emesis is not indicated (Chap. 5). Although convincing data on the efficacy of either single- or multiple-dose activated charcoal (possible enterohepatic circulation) are lacking, at least a single dose should be administered unless it is contraindicated. Oral cholestyramine can also be used to enhance warfarin elimination,137 but no studies are available that compare these two therapies or that evaluate the role of combined activated charcoal and cholestyramine therapy. Although phenobarbital also enhances elimination in animal models, it would be contraindicated in humans because of the decreased ability to reliably monitor the mental status of a patient who had the possibility of spontaneous intracranial hemorrhage. In addition to general supportive measures, the patient should be placed in a supportive medical and psychiatric environment that offers protection against external or self-induced trauma, and permits observation for the onset of coagulopathy. Blood is required for any patient with a history of blood loss or active bleeding who is hemodynamically unstable, has impaired oxygen transport, or is expected to become unstable. Although a transfusion of packed red blood cells is ideal for replacing lost blood, it cannot correct a coagulopathy, and thus patients will continue to bleed. Whole blood contains not only the cellular elements the patient is losing, but the necessary coagulation factors to reverse the coagulopathy. Although transfusion of whole blood should be considered in severe cases, whole blood contains many components (platelets, white blood cells, and nonvitamin K–dependent factors) that might benefit other patients, and relatively small amounts of vitamin K–dependent factors. Thus, selective use of specific blood products is generally preferred. Packed red blood cells should be given to correct the anemia and fresh-frozen plasma (FFP) or other factor concentrates (cryoprecipitate, Konyne) to correct the coagulopathy. FFP is rich in active vitamin K–dependent coagulation factors and will reverse oral anticoagulant– induced coagulopathy in most patients. Multiple FFP transfusions may be required, however, because of the rapid degradation of coagulation factors in the absence of vitamin K. Although vitamin K administration is required to reverse the blockade of coagulation factor activation, it cannot be relied upon for the patient with acute and consequential hemorrhage (Antidotes in Depth: Vitamin K).

CHAPTER 42

Treatment with vitamin K takes several hours to activate enough factors to reverse the patient’s coagulopathy,107,131 and this delay may potentially be fatal.

Antidotal Treatment Several issues influence the decision to treat a patient with a suspected overdose of a warfarinlike anticoagulant. Answers to the following questions should always be considered: Does the ingestion involve a warfarin-containing rodenticide or a pharmaceutical preparation? Is the ingestion unintentional or intentional? Does the patient require maintenance of therapeutic anticoagulation? Life-threatening hemorrhage should immediately be reversed with FFP and vitamin K1. The amount of FFP to adequately replace the vitamin K–dependent clotting factors to a level of 25% is equivalent to approximately 10–25 mL/kg.159 In most cases, this should be adequate to reverse any coagulopathy. However, the specific factor quantities and volume of each unit may be varied, leading to an unpredictable response.106 A recent study comparing the efficacy of FFP and clotting factor concentrates in rapid reversal of anticoagulation showed that despite significant reduction in the INR, FFP had an extremely varied effect on factor IX repletion. Clotting factor concentrates not only significantly decreased the INR, but completely corrected it and factor IX replacement was much more consistent.106 Repetitive, large doses of vitamin K1 (on the order of 60 mg/d) may be required in some patients.23,67,124 If complete reversal of the PT prolongation occurs or is desirable (as in most cases of lifethreatening bleeding) and the patient’s underlying medical condition still requires some degree of anticoagulation, they can then receive controlled anticoagulation with heparin until the bleeding is controlled and they are otherwise stable. This approach was used in 25% of patients in one study.182 Vitamin K1 is the preferred form of vitamin K because the other forms of vitamin K are ineffective86,119,123,171 and potentially toxic.8 Parenteral administration of vitamin K1 (AquaMEPHYTON) is traditionally preferred as initial therapy by many authors, but success can be achieved with early oral therapy as well.30 In most cases reviewed, the patient was switched to oral vitamin K1 preparations for long-term care. Vitamin K1 can be administered intramuscularly, subcutaneously, intradermally, or intravenously. Although intravenous therapy has the most rapid onset of action of all routes of delivery, its use as the sole therapeutic agent is still associated with a delay of several hours107,131 and carries the added risk of anaphylactoid reactions.138 The use of low doses and slow rates of administration reduces this risk,153 but we generally prefer that vitamin K1 be administered by other than the intravenous route (Antidotes in Depth: Vitamin K). For patients with non-life-threatening hemorrhage, the clinician must consider whether anticoagulation is required for longterm care. In patients not requiring chronic anticoagulation, even small elevations of the PT may be treated (with vitamin K1 alone) to prevent a deterioration in coagulation status and reduce the risk of bleeding. Because in most cases, coagulopathy persists only for several days, there may be a rationale for prophylactic vitamin K1 administration in known warfarinlike anticoagulant ingestions in patients not requiring anticoagulation. In contrast to ingestions of warfarin, prophylactic vitamin K1 should never be given to asymptomatic children with unintentional ingestions of long-acting anticoagulants, for several reasons: (a) if the child develops a coagulopathy it will last for weeks, and the one or two doses of vi-

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tamin K1 given will not prevent complications; (b) because a gradual decline in coagulation factors occurs over the first day of anticoagulation, no child would be expected to develop a lifethreatening coagulopathy in a single day; and (c) after vitamin K1 is administered, the onset of an INR abnormality will be delayed, which could impair the clinician’s ability to diagnose any coagulation abnormality, or, more likely, require an unnecessarily prolonged observation period. For patients requiring chronic anticoagulation, The American College of Chest Physicians has issued guideline for management of patients with elevated INR values2 (Table 42–4). Moreover, a recent study investigated the use of a regression formula to calculate the amount of oral vitamin K1 necessary to partially correct the INR without completely discontinuing the oral anticoagulant. If validated, it would be extremely useful prior to minor surgery or dental procedures in patients requiring chronic anticoagulation while theoretically decreasing the likelihood of thromboembolism.179

Treatment of Long-Acting Anticoagulant Overdoses The goal of therapy is to reverse the coagulopathy and to replace lost blood. Patients should have large-bore venous access established at the first sign of bleeding and have a blood type and crossmatch available for packed red blood cells and FFP. FFP is the initial treatment of choice for patients with active blood loss. It should be infused as needed, based on clinical symptoms and sequential PT or INR determinations. Vitamin K1 is required, however, for long-term control of the INR. Long-acting anticoagulants are metabolized by the hepatic mixed-function oxidase system (cytochrome P450).7,123 In a rat model, the duration of coagulopathy was shortened by administering phenobarbital, a CYP3A4 inducer.7 Although a phenobarbital effect has never been systematically studied in humans, this approach was employed by several authors in isolated human cases of long-acting anticoagulant toxicity.32,86,100,170,177 Although these

TABLE 42–4. American College of Chest Physicians Consensus Conference 2001 Guidelines for Management of Excessive INR with and without Bleeding in Patients Requiring Chronic Anticoagulation.2 INR

Recommendations

Below 5.0 Between 5.0–9.0

Lower dose or omit next dose of warfarin Low risk: a Discontinue warfarin for several doses or High risk: a Omit next dose and give oral vitamin K1 (1–2.5 mg) If cannot be treated with oral medication then give parenteral vitamin K1 (0.5–1 mg) Higher dose of oral vitamin K1 (3–5 mg) Vitamin K1 10 mg slow parenteralb infusion with fresh-frozen plasma or prothrombin complex concentrate; vitamin K1 administration may need to be repeated q12 h

Between 9.0–20.0 Greater than 20.0 (or rapid reversal of anticoagulation needed) a

Low and high risk are determined by assessing parameters associated with potential hemorrhage such as recent hemorrhage, alcohol abuse, hepatic or renal impairment, and use of aspirin or other nonsteroidal anti-inflammatory agents. b Although parenteral infusion of vitamin K is recommended, we urge caution when this route of administration is used because there may not be an appreciable difference in onset of therapeutic effect and, although rare, severe anaphylactoid reactions may occur.

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anecdotal reports suggest some improvement with phenobarbital therapy, the risks of producing sedation in a patient who might be prone to bleeding complications appear consequential.77 Patients should be followed until their coagulation studies remain normal while off therapy for several days. This usually requires daily or even twice-daily INR measurements until the INR is at the lower limit of the therapeutic range. Monitoring of serial INR measurements should allow for a gradual decrease in vitamin K1 requirement over time. Periodic coagulation factor analysis, however, may provide an early clue to the resolution of toxicity.77 The patient may require weeks to months of close observation for both psychiatric and medical reasons.

PARENTERAL ANTICOAGULANTS

ommended for anticoagulation in pregnant women. These factors also eliminate oral administration as a therapeutic route, and heparin must be administered by either deep subcutaneous injection or by continuous intravenous infusion. Following parenteral administration heparin remains in the intravascular compartment, in part bound to globulins, fibrinogen, and low-density lipoproteins, thus resulting in a volume of distribution of 0.06 L/kg in humans.50,125 Heparin has a short duration of effect, as a result of its rapid metabolism in the liver by a heparinase and by the reticuloendothelial system.105 Although the half-life of elimination is dose dependent and ranges from 1 to 2.5 hours,105,110,125 the duration of anticoagulant effect is usually reported as 1–3 hours.105 Dosing errors or drug interactions with thrombolytic agents, antiplatelet drugs, or nonsteroidal antiinflammatory drugs may increase the risk of hemorrhage.71

Heparin

Clinical Manifestations

Conventional or unfractionated heparin is a heterogeneous group of molecules within the class of glycosaminoglycans.85 The heparin precursor molecule is composed of long chains of mucopolysaccharides, a polypeptide, and carbohydrates. The main carbohydrate components of heparin molecules include uronic acids and amino sugars in polysaccharide chains. Heparin for pharmaceutical use is extracted from bovine lung tissue and porcine intestines.146 As a therapeutic agent, heparin inhibits thrombosis by accelerating the binding of the protease inhibitor antithrombin III to thrombin and other serine proteases involved in coagulation.105,140 Thus, factors IX to XII, kallikrein, and thrombin are inhibited. Heparin also affects plasminogen activator inhibitor, protein C inhibitor, and other components of coagulation. Heparin’s therapeutic effect is usually measured through the activated PTT. The activated blood coagulation time (ACT) may be more useful for monitoring large therapeutic doses or in the overdose situation.94 Low-molecular-weight heparins are 4000–6000-dalton fractions obtained from conventional (unfractionated) heparin.58 As such, they share many of the pharmacologic and toxicologic properties of conventional heparin.24 The major differences between low-molecular-weight heparins and conventional heparin are greater bioavailability, longer half-life, more predictable anticoagulation with fixed dosing, and targeted activity against activated factor X, and less against activated factor II.24,58 As a result of this targeted factor X activity, low-molecular-weight heparins have minimal effect on the activated PTT, thereby eliminating either the need for or the utility of monitoring. As such, they are administered on a fixed-dose schedule. Low-molecular-weight heparins have been investigated for prevention of thromboembolic disease after hip surgery and trauma, in patients with stroke or deep venous thrombosis, in pregnancy, and in other conditions where anticoagulation with heparin would otherwise be indicated. Although these drugs are presumed to have a minimal risk in pregnancy113 because they do not cross the placenta,56,161 they are not approved for treatment or prophylaxis of thromboembolic disease. Most studies demonstrate a lower incidence of embolization; however, there is still a trend toward increased bleeding.17,65,99

Intentional overdoses with heparin are rare.67,108 Most reported cases involve unintentional poisoning in hospitalized infants.60,63,108,145 One neonate received 8000 U (2666 U/kg) of heparin. Bleeding from injection sites and intra-abdominal hemorrhage occurred after 17 hours despite administration of a total of 25.4 mg of protamine sulfate, and the infant died.60 Similarly, the inadvertent administration of 8620 U/kg of heparin over 4 hours to a neonate via an umbilical catheter resulted in excessive bleeding from all skin puncture sites.63 Another 3 cases of toxicity in infants related to flushing an indwelling catheter with heparin instead of saline.145 These infants received 500–50,000 U of heparin and presented with respiratory distress, hypotension, bleeding from puncture sites and umbilical stumps, and gross hematuria. Finally, following the unintentional intramuscular administration of 20,000 U of heparin to an 8-month-old girl, a hematoma formed, bleeding from injection sites began within 2 hours, and her hemoglobin fell to 5.5 g/dL. Capillary coagulation times remained abnormal for 31 hours.128 Although no overdoses of low-molecular-weight heparins are reported, similar adverse effects to unfractionated heparins have been reported to include epidural/spinal hematoma, intrahepatic hemorrhage,80 abdominal wall hematomas,3 psoas hematoma after lumbar plexus block,90 and intracranial hemorrhage in patients with malignancy in the brain.48 These complications were all reported in patients who received the low-molecular-weight enoxaparin.

Pharmacology Because of heparin’s large size and negative charge, it is unable to cross cellular membranes. For this reason, heparin is usually rec-

Evaluation and Treatment After stabilization of the airway, breathing, and circulation are assured, the physician should be prepared to replace blood loss and reverse the coagulopathy, if indicated. Because of the relatively short duration of action of heparin, observation alone may be indicated if significant bleeding has not occurred. For the patient requiring anticoagulation, serial PTT determinations will indicate when it is safe to resume therapy. If significant bleeding occurs, either removal of the heparin or reversal of its anticoagulant effect is indicated. Because heparin has a very small volume of distribution, it can be effectively removed by exchange transfusion.145 Although this technique has been used successfully in neonates, it is not generally applicable to older children and adults. When severe bleeding occurs, heparin may be effectively neutralized by protamine sulfate. Protamine is a low-molecularweight protein found in the sperm and testes of salmon, which

CHAPTER 42

forms ionic bonds with heparin and renders it devoid of anticoagulant activity.105 One milligram of protamine sulfate injected intravenously neutralizes 100 U of heparin.105 The dose of protamine should be calculated from the dose of heparin administered and heparin’s approximate half-life, such that the amount of protamine does not exceed the amount of heparin expected to be found intravascularly at the time of infusion. As with other foreign proteins, protamine administration is associated with numerous adverse effects. Because approximately 0.2% of patients receiving protamine experience anaphylaxis, a complication that carries a 30% mortality rate, most authors commonly recommend that protamine be reserved for patients with life-threatening hemorrhage78 (Antidotes in Depth: Protamine). Because of the severe adverse effects associated with protamine, current research is focusing on safer methods to reverse heparin anticoagulation. These experimental agents include heparinase,114 designer protamine variants,173,174 and platelet factor 4.46 If life-threatening bleeding occurs following low-molecularweight heparin administration, patients should be treated supportively. The newer (safer) experimental protamine variants appear to be effective against low-molecular-weight heparins but as of yet are unavailable.173,174

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syndrome results from heparin-induced platelet aggregation, a more severe form of thrombocytopenia occurs in 1–5% of patients between days 7 and 14 of therapy (Heparin-induced thrombocytopenia and thrombosis, or HITT).5,104,105,185 Heparin stimulates platelets to release platelet factor 4, which subsequently complexes with heparin to provoke an IgG response. These antibodies against the heparin-platelet factor 4 complex activate platelets, leading to platelet-fibrin thrombotic events known as the white clot syndrome. Because low-molecular-weight heparins do not stimulate the release of platelet factor 4, their use is not associated with either severe thrombocytopenia or the white clot syndrome.176 However, once HITT occurs, low-molecular-weight heparins are not recommended as alternative therapy. In patients previously treated with heparin these events can occur earlier than 7 days. Patients may present with either hemorrhagic or thromboembolic complications. Necrotizing skin lesions134 and hyperkalemia from aldosterone suppression126 are rarely reported in patients receiving heparin therapy. Some additional complications of heparin use include osteoporosis, which mostly occurs in patients on long-term therapy with unfractionated heparin.81 A small percentage of these patients may develop bone fractures if treated continuously for more than 3 months. Data for low-molecular-weight heparins are limited and the incidence of osteoporosis may be less as compared to unfractionated heparin.81

NONBLEEDING COMPLICATIONS OF ANTICOAGULANTS Warfarin therapy is associated with three nonhemorrhagic lesions of the skin: urticaria,144 purple toe syndrome,53 and warfarin skin necrosis.42,91,95,112,172 Although skin necrosis was once thought to be a rare and idiosyncratic reaction,91,95 more recent evidence suggests a link between this disorder and protein C deficiency.95,172 Protein C is also dependent on vitamin K.38 Patients who are homozygotes for protein C deficiency have an increased incidence of thrombosis and embolic events, such that they often require longterm anticoagulant therapy.38 Because the half-life of protein C is shorter than that of many of the vitamin K–dependent coagulation factors, protein C levels fall rapidly during the first hours of warfarin therapy. In the protein C–deficient patient, protein C levels fall dramatically prior to a reduction in coagulation factors. This results in an imbalance that actually favors coagulation, and skin necrosis results.112,172 Although warfarin skin necrosis is more common in patients with protein C deficiency, this disorder is also described in patients with protein S and antithrombin III deficiencies.42 Unfortunately, these deficiencies are neither necessary nor sufficient to account for the incidence of warfarin necrosis.42 If necrosis occurs, warfarin should be discontinued and heparin should be initiated to decrease thrombosis of postcapillary venules. Some patients may also require surgical debridement.168 The purple toe syndrome, in contrast to warfarin-induced skin necrosis, is presumed to result from small atheroemboli that are no longer adherent to their plaques by clot. An additional major nonhemorrhagic complication of warfarin therapy relates to its use in pregnant women. Most warfarininduced fetal abnormalities occur during weeks 6 to 12 of gestation, but central nervous system (CNS) and ocular abnormalities can develop at any time during gestation.69,158 Heparin therapy is associated with a transient and mild heparin-induced thrombocytopenia (HIT) that occurs in about 25% of patients during the first few days of therapy. Although this

OTHER ANTICOAGULANTS Snake Venoms A detailed discussion of snake envenomations is found in Chapter 101; only a few specific issues are discussed here. Snake venoms may be composed of a vast number of complex proteins and peptides that interact with components of the human hemostatic system. Their functions may be thought of in general as being procoagulant, anticoagulant, fibrinolytic, vessel wall interactive, platelet active, or as protein inactivators. Additionally, they may more specifically also be classified based on their specific biologic activity and some of the various mechanisms include individual factor activating, inhibition of protein C and thrombin, fibrinogen degradation, platelet aggregation, and inhibitors of serine protease inhibitors (SERPINS). Currently, there are more than 100 different snake venoms that affect the hemostatic system;83,84 Figure 42–2 provides an overview of their multiple interactions with the coagulation and fibrinolytic systems.102 Some of these venom proteins are used as therapeutic agents for human diseases. Ancrod, a purified derivative of the Malaysian pit viper, Calloselasma rhodostoma, is used in the treatment of deep-vein thrombosis, myocardial infarction, pulmonary embolus, and acute cerebrovascular thrombosis because of its defibrinogenating property.13 In a multicenter study of 500 patients with acute or progressing ischemic neurologic events, ancrod showed a favorable benefit-risk as compared to placebo.152 As expected, an increased risk of hemorrhage was observed; however, the risk appears to be less than that with thrombolytic agents.152 Monitoring of fibrinogen levels is essential to avoid potential complications and no specific antidote exists. For envenomation of other snake venoms (such as from the Crotalidae family) that induce hemorrhage, antivenin treatment may be required.

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Hirudin Hirudin, a 65-amino-acid polypeptide produced by the salivary glands of the medicinal leech (Hirudo medicinalis), irreversibly blocks thrombin without the need for antithrombin III.148 Unlike heparin, the small size of hirudin allows it to enter clots and inhibit clot-bound thrombin, offering the distinct advantage of restricting further thrombus formation. Hirudin demonstrates enhanced bioavailability and a longer half-life than unfractionated heparin. In addition, there are no known natural inhibitors of hirudin, such as platelet factor 4. Desirudin is a recombinant hirudin that is used in acute coronary syndromes, in the prevention of thromboembolic diseases, and in patients with heparininduced thrombocytopenia.21,143,148 Both of these compounds appear to be at least as effective as unfractionated heparin, and without increased bleeding or thrombocytopenia. However, in the GUSTO IIb study of patients with unstable angina/non-Q-wave myocardial infarction, there was an increase in the number of blood transfusions in patients who received desirudin as compared to those who received heparin.62

rhage occur in 0.30–0.58% of patients receiving anistreplase, 0.42–0.73% of patients receiving alteplase, and 0.08–0.30% of patients receiving streptokinase.181 The frequency of bleeding events is essentially equal regardless of the thrombolytic agent used even with the newer agents, with the exception of lanoteplase.47 Currently, no agents exist to reverse thrombolysis, and prevention is best practiced with the use of weight-based doses of thrombolytic agents and heparin. Only supportive care is indicated for patients with bleeding complications.

SUMMARY The ever-increasing frequency of anticoagulant therapeutic use is associated with complications and adverse outcomes. A complete understanding of the normal mechanisms of coagulation, anticoagulation, and thrombolysis combined with an understanding of the pharmacology of the agents and the patient’s clinical needs allows the clinician to better choose among the complex therapies currently available.

Thrombolytic Agents The fibrinolytic system is designed to remove unwanted clots and leave those clots protecting sites of vascular injury intact. Plasminogen exists as a proenzyme and is converted to the active form, plasmin, by various plasminogen activators.40,41 t-PA is released from the endothelium, and is under the inhibitory control of two inactivators known as tissue plasminogen activator inhibitors 1 and 2 (t-PAI-1 and t-PAI-2).40,41,105,115 Plasmin’s actions are nonspecific in that it degrades not only fibrin clots but also some plasma proteins and coagulation factors.105 Inhibition at the level of plasmin occurs through 2-antiplasmin. With their diverse indications in acute myocardial infarction, unstable angina, arterial and venous thrombosis and embolism, and cerebrovascular disease, the thrombolytic agents (streptokinase, urokinase, alteplase, reteplase, tenectaplase, and anistreplase) are used commonly.14 The reader is referred to one of a number of reviews for specific indications and dosing regimens.43,96,105,133,155,181 Although all agents enhance fibrinolysis, they differ in their specific sites of action and durations of effect. Alteplase (t-PA), reteplase, and tenectaplase are specific for clot (they do not increase fibrinolysis in the absence of a thrombus), whereas streptokinase, urokinase, and anistreplase are not clotspecific. Alteplase has the shortest half-life and duration of effect (5 minutes and 2 hours, respectively), and anistreplase has the longest (90 minutes and 18 hours, respectively).133,155 Streptokinase has the additional risk of severe allergic reaction on rechallenge, limiting its use to once in a lifetime. Newer thrombolytic drugs such as monteplase, lanoteplase, pamiteplase, and staphylokinase are being evaluated for therapeutic use. These agents have a longer half-life in plasma and may be administered via single or repeated bolus injections. Although they also have increased fibrin selectivity, no improvement in long-term mortality has been demonstrated.4 Although the incidence of bleeding requiring transfusion may be as high as 7.7% following high-dose (150 mg) alteplase and 4.4% following lowdose alteplase,43 the incidence of life-threatening hemorrhage is much lower.181 The addition of heparin to the thrombolytic regimen increases the risk of bleeding. Reviews of multiple trials suggest that life-threatening events such as intracranial hemor-

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170. Travis SF, Warfield W, Breenbaum BH, et al: Spontaneous hemorrhage associated with accidental brodifacoum poisoning in a child. J Pediatr 1993;122:982–984. 171. Udall JA: Don’t use the wrong vitamin K. West J Med 1970;112: 65–67. 172. Vigano D’Angelo S, Comp PC, Esmon CT, et al: Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states. J Clin Invest 1984;77: 416–425. 173. Wakefield TW, Andrews PC, Wrobleski SK, et al: Effective and less toxic reversal of low-molecular-weight heparin anticoagulation by a designer variant of protamine. J Vasc Surg 1995;21:839–849. 174. Wakefield TW, Andrews PC, Wrobleski SK, et al: A protamine variant for nontoxic and effective reversal of conventional heparin and low-molecular-weight heparin anticoagulation. J Surg Res 1995;63: 280–286. 175. Wallace S, Paull P, Worsnop C, Mashford ML: Covert self-poisoning with brodifacoum, a “superwarfarin.” Aust N Z J Med 1990;20: 713–715. 176. Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330–1335. 177. Watts RG, Castleberry RP, Sadowski JA: Accidental poisoning with a superwarfarin compound (brodifacoum) in a child. Pediatrics 1990; 86:883–887.

178. Weitzel JN, Sadowski JA, Furie BC, et al: Surreptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brodifacoum: Clinical and metabolic studies in three cases. Blood 1990;76:2555–2559. 179. Weintzen TH, O’Reilly RA, Kearns PJ: Prospective evaluation of anticoagulant reversal with oral vitamin K1 while continuing warfarin therapy unchanged. Chest 1998;114:1546–1550. 180. Wessler S, Gitel SN: Warfarin: From bedside to bench. N Engl J Med 1984;311:645–652. 181. White HD: Comparative safety of thrombolytic agents. Am J Cardiol 1991;67:30E–37E. 182. White RH, McKittrick T, Takakuwa J, et al: Management and prognosis of life-threatening bleeding during warfarin therapy. National Consortium of Clinical Anticoagulation. Arch Intern Med 1996;156: 1197–1201. 183. Whitlon DS, Sadowski JA, Suttie JW: Mechanisms of coumarin action: Significance of vitamin K epoxide reductase inhibition. Biochemistry 1978;17:1371–1377. 184. Woody BJ, Murphy MJ, Ray AC, Green RA: Coagulopathic effects and therapy of brodifacoum toxicosis in dogs. J Vet Intern Med 1992;6:23–28. 185. Young MA, Ehrenpreis ED, Ehrenpreis M, et al: Heparin-associated thrombocytopenia and thrombosis syndrome in a rehabilitation patient. Arch Phys Med Rehabil 1989;70:468–470.

CHAPTER 42

ANTICOAGULANTS

647

ANTIDOTES IN DEPTH

Vitamin K1

Mary Ann Howland

Vitamin K1 (phytonadione) is indicated for the reversal of elevated prothrombin times and international normalized ratios (INRs) in patients with xenobiotic-induced vitamin K deficiency states. Vitamin K deficiency states are typically induced following the therapeutic administration of warfarin or following the ingestion of warfarin or the long-acting anticoagulant rodenticides (LAARs) such as brodifacoum. The optimal dosage regimen of vitamin K1 to treat patients who overdose on either is not adequately studied. Oral administration of large doses of vitamin K1 is used safely and successfully. Intravenous administration of vitamin K1 is associated with anaphylactoid reactions and should be avoided if possible. Subcutaneous administration is an acceptable route as initial therapy and when oral administration is not feasible.

HISTORY It was noted in 1929 that chickens fed a poor diet developed spontaneous bleeding. In 1935, Dam and coworkers discovered that incorporating a fat-soluble substance in the chickens’ diet could correct the bleeding. They named this substance a “koagulation factor,” vitamin K.15,24

CHEMISTRY OF THE NATURAL VITAMINS K1 AND K2 Vitamin K, an essential fat-soluble vitamin, is actually a broad term that encompasses at least two distinct natural forms. Vitamin K1 (phytonadione, phylloquinone) is the only form synthesized by plants and algae. Vitamin K2 (menaquinones) is actually a series of compounds with the same 2-methyl-1,4-naphthoquinone ring structure as phylloquinone but with a variable number (1–13) of repeating 5 carbon units on the side chain. Bacteria synthesize the menaquinones. Most of the vitamin K ingested in the diet is phylloquinone.

PHARMACOLOGY Activation of the coagulation factors II, VII, IX, and X requires γcarboxylation of the glutamate residues, a vitamin K–dependent process. Only the reduced (quinol, hydroquinone) form of vitamin K manifests biologic activity (Fig. 42–3). The quinone form of vitamin K can be activated to the quinol form directly by an NADPH-dependent pathway that is relatively insensitive to warfarin.24,28 During the carboxylation step, the K quinol form is converted to an epoxide. This 2,3-epoxide is reduced and recycled to the active K quinol in a two-step process that is inhibited by warfarin. An in-depth model of the chemical basis of this reaction was recently proposed.7

DAILY REQUIREMENT The human daily requirement for vitamin K is small; the Food and Nutrition Board set the recommended daily allowance at 1 µg/kg/d of phylloquinone for adults, although 10 times that amount is required for infants to maintain normal hemostasis. This value is determined to meet the coagulation function.23 Extrahepatic enzymatic reactions that are vitamin K–dependent relate to carboxylation of proteins in the bone, kidney, placenta, lung, pancreas, and spleen, and include the synthesis of osteocalcin, matrix Gla protein, plaque Gla protein, and one or more renal Gla proteins. 23,24,28

VITAMIN K DEFICIENCY AND MONITORING Vitamin K deficiency can result from inadequate intake, malabsorption, or interference with the vitamin K cycle. Malnourishment and any condition in which bile salts or fatty acids are inadequate, such as extrahepatic cholestasis or severe pancreatic insufficiency, can lead to vitamin K deficiency. Newborns are at risk for hemorrhage because: (a) phylloquinone does not readily cross the placenta; (b) breast milk contains less phylloquinone than vitamin K–fortified formula; (c) fetal hepatic stores of phylloquinone are low; and (d) maternal anticonvulsant therapy may lead to increased vitamin K metabolism.24,28 Although menaquinones are produced in the colon by bacteria, it is unlikely that enteric production contributes significantly to vitamin K stores or that eradication of the bacteria with antibiotics, without a coexistent dietary deficiency of vitamin K, results in deficiency.24 Determination of vitamin K deficiency is usually established on the basis of a prolonged prothrombin time (PT) or INR, an indirect measure. Measurement of the vitamin K–dependent factors, II, VII, IX, and X, appears to be an effective way to determine the ad-

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equacy of vitamin K1 dosing.12 Serial measurements of factor VII, the factor with the shortest half-life, allows for the early detection of inadequate vitamin K1 in the diet or a therapeutic regimen.5 Direct measurement of serum vitamin K plasma levels is done by high-performance liquid chromatography (HPLC) analysis. The human plasma vitamin K concentration required for adequate production of activated clotting factors in the presence of LAAR is still unclear. One study in a patient who overdosed on brodifacoum suggested that a plasma vitamin K concentration of 0.2–0.4 µg/mL as opposed to the 1 µg/mL reported in rabbits was sufficient.5,19

MECHANISM OF ACTION FOR XENOBIOTIC-INDUCED VITAMIN K–DEFICIENT STATES Oral anticoagulants are vitamin K antagonists that interfere with the vitamin K cycle, causing the accumulation of vitamin K 2,3epoxide, an inactive metabolite. Warfarin is a strong irreversible inhibitor of the dithiol-dependent vitamin K reductases (epoxide reductase and quinone reductase), which maintain vitamin K in its active (quinol, hydroquinone) form.2 The superwarfarins are even more potent vitamin K reductase inhibitors. Without exogenous interference vitamin K is recycled and only 1 µg/kg in the adult is required to maintain adequate coagulation. Nicotinamide adenine dinucleotide phosphate (NADPH)-dependent quinone reductase is a warfarin-insensitive enzyme capable of reducing vitamin K1 to its active hydroquinone form, but it is incapable of regenerating vitamin K from vitamin K epoxide following carboxylation of the coagulation factor2 (Fig. 42–3). It is presumed that additional vitamin K1 must be administered to supply this active cofactor for each and every carboxylation step.5 The minimum vitamin K1 requirement in the presence of LAAR is unknown. Other compounds have varying degrees of vitamin K antagonistic activity and include the N-methyl-thiotetrazole side chain containing antibiotics (moxalactam, cefamandole) and salicylates.24

TABLE 42–5.

PHARMACOKINETICS OF DIETARY VITAMIN K Dietary vitamin K in the form of phylloquinone and menaquinones is solubilized with the bile salts, free fatty acids, and monoglycerides to enhance absorption. Vitamin K, bound to chylomicrons, enters the circulation via the lymphatic system and then is taken up by the liver.24 Plasma vitamin K is primarily in the form of phylloquinone, whereas liver stores are 90% menaquinones and 10% phylloquinone.24 Following 3 days of low vitamin K intake, a group of surgical patients showed a 4-fold lowering of liver vitamin K concentrations.27 Rats given a vitamin K–deficient diet developed severe bleeding within 2–3 weeks.

AVAILABILITY OF DIFFERENT FORMS OF VITAMIN K Table 42–5 lists the currently marketed vitamin K products. Vitamin K1 (phylloquinone, phytonadione) is the only vitamin K preparation that should be used to reverse anticoagulant-induced vitamin K deficiency or to treat infants, pregnant women, or patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Vitamin K1 is superior to other no longer commercially available vitamin K preparations because it is more active, thus requiring comparatively smaller doses, and because it works more rapidly (6 vs. 12 hours).10,26 Vitamins K3 (menadione) and K4 (menadiol sodium diphosphate) may produce hemolysis, hyperbilirubinemia, and kernicterus in neonates and hemolysis in G6PD-deficient patients. The only advantage of menadione and menadiol sodium diphosphate is that these preparations are absorbed directly from the intestine by a passive process that does not require the presence of bile salts. Therefore, these agents may be advantageous for patients with cholestasis or severe pancreatic insufficiency. They are neither interchangeable with vitamin K1, nor a substitute for vitamin K1, when anticoagulants such as warfarin or LAAR are re-

Vitamin K Products

Vitamin K1 (phylloquinone, phytonadione)

Commercial Preparation

Route of Administration

Mephyton AquaMEPHYTON

Oral SC, IM, IV

Strength

Comments

5 mg 2 mg/mL 10 mg/mL

Best for anticoagulant-induced prolonged prothrombin time. Oral route preferred; divided doses may be necessary for large requirements; IV reserved for life-threatening situations. Must be carefully diluted and slowly infused (IV) to avoid anaphylactoid reactions; SC for small doses; IM should be avoided; may be used for infants, pregnant women, G6PD deficiency; oral absorption requires presence of bile salts.

CHAPTER 42

sponsible for coagulation deficits. For a patient deficient in bile salts who requires vitamin K1, exogenous bile salts (ie, ox bile extract 300 mg or dehydrocholic acid 500 mg) should be given with each dose of vitamin K1.20

PHARMACOKINETICS AND PHARMACODYNAMICS OF VITAMIN K1 There are only a limited number of pharmacokinetic studies of vitamin K1.5,11,19,30 One study evaluated the pharmacokinetics of vitamin K1 in healthy volunteers, brodifacoum-anticoagulated rabbits, and a patient poisoned with brodifacoum.19 In the volunteers and the poisoned patient, a 10-mg IV dose of vitamin K1 had a half-life of 1.7 hours. After oral administration of doses of 10 and 50 mg of vitamin K1, peaks of 100–400 ng/mL and 200–2000 ng/mL, respectively, occurred at 3–5 hours. Bioavailability varied significantly between patients (10–65%) for both doses and in individual patients with the 50-mg dose. Oral vitamin K1 (phytonadione, phylloquinone) is absorbed in an energy-dependent saturable process in the proximal small intestine, and this likely contributes to the variability.19 In maximally brodifacoum-anticoagulated rabbits, IV vitamin K1 (10 mg/kg) increased prothrombin complex activity (PCA) from 14 to 50% by 4 hours and to 100% by 9 hours, after which it declined with a half-life of 6 hours. The minimum effective concentration of vitamin K1 was approximately 1 µg/mL. High doses of oral vitamin K1 were used to treat a patient anticoagulated with brodifacoum.5 In this patient, a serum vitamin K1 concentration as low as 200 ng/mL (0.2 µg/mL) was effective in maintaining a normal coagulation profile.5 The pharmacokinetics of oral and IM vitamin K1 were compared in 8 healthy female volunteers. Baseline plasma vitamin K levels were 0.23 ng/mL. Following the oral administration of 5 mg of vitamin K, peak plasma levels of 90 ng/mL were achieved between 4 and 6 hours. These levels dropped to a steady state of 3.8 ng/mL and exhibited a halflife of about 4 hours. The pharmacokinetics were distinctly different after IM administration and quite variable. IM administration of 5 mg of vitamin K, resulted in peak plasma levels of only 50 ng/mL with delays from 2 to 30 hours following administration and with the maintenance of a plateau for about 30 hours.11

ROUTES OF ADMINISTRATION AND ADVERSE EFFECTS Although vitamin K1 may be administered orally, subcutaneously, intramuscularly, or intravenously, the oral route is preferred when possible for maintenance therapy. When administered orally, vitamin K1 is virtually free of adverse effects, except for overcorrection of the INR in the setting of a patient who requires maintenance anticoagulation. Subcutaneous administration is limited to about 5 mL, which is the amount that can be physically injected at any one administration site. The intramuscular route is best avoided in patients who are anticoagulated and at risk for hematoma formation. The only preparation available for intravenous administration is AquaMEPHYTON, which is associated with rare anaphylactoid reactions. This preparation is not available in solution but as an aqueous colloidal suspension of a polyoxyethylated fatty acid– derivative dextrose and benzyl alcohol. AquaMEPHYTON is for-

ANTICOAGULANTS

649

mulated as a colloidal suspension because of the vitamin’s lipid solubility. Intravenous administration has resulted in death secondary to anaphylactoid reactions, probably as a result of the preparation’s colloidal formulation.3,6,16 More than 57 anaphylactoid reactions have been reported, even when properly diluted and administered slowly.18

ONSET OF EFFECT The time necessary for PT or INR to return to a safe or normal range is very variable and depends on the rate of absorption of vitamin K1, the plasma concentration achieved, and the time necessary for the synthesis of activated clotting factors. A decrease in the INR can often be seen within several hours, while it may take 8–24 hours to reach target values.4,9,17,21 Maintenance of a normal PT or INR depends on the half-life of the vitamin K1, maintenance of an effective plasma concentration, and the half-life of the anticoagulant involved. The IV route is only slightly faster than the oral route in restoring the INR to a safe range.11 The subcutaneous route has never been studied in the management of overdoses nor has it ever been compared to the oral route even in the therapeutic setting. One study compared subcutaneous (SC) to IV for patients chronically on warfarin with markedly elevated INRs.17 The warfarin dose was stopped in each group. SC doses of vitamin K1 were slightly less effective than IV doses at 24 hours, but there were no differences between the 2 regimens at 72 hours.17 It is presumed that the SC route is more rapidly effective than the oral route and is appropriate for initial administration. If the oral route is not feasible and the dose requirements exceed the 5 mL of SC administration (ie, >50 mg), then the IV route may be used for an initial dose.

DOSING AND ADMINISTRATION The optimal dosage regimen for vitamin K1 remains unclear. Variables include the vitamin K1 pharmacokinetics, as well as the amount and type of anticoagulant ingested.22 Reported cases of LAAR poisoning have required as much as 50–250 mg of vitamin K1 daily for weeks to months.1,5,8,13,14,25,29 A reasonable starting approach for a patient who has overdosed on warfarin or LAAR is 25–50 mg of vitamin K1, orally 3–4 times a day for 1–2 days. This oral dose may be preceded by a SC dose of 10–25 mg of vitamin K1 if desired. The INR should be monitored and the vitamin K1 dose adjusted accordingly. Once the INR is 15 µg/mL > 46.2 µmol/L Late = > 10 µg/mL > 30.8 µmol/L Values greater than or equal to the action level necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical condition of the patient. =

Blood samples were drawn and an electrocardiogram (ECG) was obtained. An IV line was established with 5% dextrose in water (D5W), and 1 g/kg body weight of activated charcoal and 50 g of sorbitol were given orally. The initial laboratory data revealed a hematocrit of 37.6%; hemoglobin, 12.1 g/dL; and white blood cell count (WBC), 8600/mm3 with 80% polymorphonuclear cells, 18% lymphocytes, 1% monocytes, and 1% eosinophils. The platelet count and international normalized ratio (INR) were normal. The electrolyte analysis revealed sodium, 143 mEq/L; potassium, 4.4 mEq/L; chloride, 106 mEq/L; bicarbonate, 29 mEq/L; blood urea nitrogen (BUN), 9 mg/dL; and glucose, 65 mg/dL. The creatine phosphokinase (10,250 IU/L), lactic dehydrogenase (700 IU/L), and aspartate aminotransferase (75 IU/L) were all elevated. The urinalysis was normal with a negative urine ferric chloride test for salicylates. The ECG showed a normal sinus rhythm at 96 beats/min, an axis of 90°, and inverted T waves in leads II, III, and aVF. Peaked T waves were present in V2 to V4. The QRS and QTc intervals were both normal. The chest radiograph was normal. The patient was admitted to the intensive care unit. Without any additional specific therapy the ophthalmic and auditory symptoms rapidly abated. Ophthalmic findings returned to normal. The fundi showed normal vasculature and color within 24 hours. Blood pressure returned to normal by the second day. The abnormal auditory and visual findings entirely resolved within 48 hours. The patient’s mother subsequently revealed that he had taken ten 300-mg quinine tablets, originally intended for the treatment of the Plasmodium falciparum malaria.

A 30-year-old man stumbled into Emergency Department (ED) appearing to be intoxicated and agitated. However, he was quite coherent. He complained of inability to see, difficulty in hearing, with a continuous ringing in his ears, and the sensation of “a train rushing through his head.” He stated that he had taken “a bunch of pills,” drunk some wine, and went off to sleep about 7 hours before coming to the ED. On awakening approximately 6 hours later, he was unable to keep his balance. His mother related an extensive family, medical, and social history: The patient was an asthmatic taking many drugs. In addition, he took “water pills,” later identified as furosemide, to control hypertension. The patient, she said, took aspirin “for arthritis,” and “some other pills for malaria.” She insisted that he used no illicit drugs and seldom drank, but did smoke 2 packs of cigarettes per day. She further noted that he had been extremely depressed recently, after his loss of unemployment benefits. In addition, he had had a quarrel on the day of admission. Physical examination revealed a well-developed, talkative, anxious man, with blood pressure, 100/40 mm Hg; pulse, 100 beats/ min; respiration, 18 breaths/min; and temperature, 97.2°F (36.2°C). The skin was warm, dry, anicteric, and without pallor or cyanosis. Ophthalmic examination revealed fixed, widely dilated pupils (OD 7 mm, OS 8 mm) unresponsive to light and accommodation. Assessment of visual acuity demonstrated some perception of distant shadows but no perception of close objects. The fundi were easily visualized. The optic discs were pale and flat. There was severe arteriolar constriction starting at the disc border with threadlike vessels. The veins appeared normal in diameter. The arteriovenous ratio was 1:7. Extraocular movements were intact. Examination of the ears revealed normal tympanic membranes. The patient was able to hear a tuning fork on each side, but could not hear the ticking of a watch. The remainder of the examination was normal except for a systolic ejection murmur.

The malaria parasite has caused untold grief throughout human history. Today, 40% of humanity lives in areas of endemic malaria. One-half billion people suffer infection and 2 million die each year.62 Included in those at risk are 50,000,000 travelers from

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industrialized countries who visit the developing world each year. In spite of prophylactic medications, 30,000 will acquire malaria (Table 44–1). 76 The battle against malaria and its vectors is also responsible for much of the DDT used in the developing world in the mid-20th century and currently (Chap. 89).

QUININE In addition to its use as an antimalarial, quinine is also available in small amounts in tonic water. It has been used for muscle cramps and, because of its extremely bitter taste (like heroin), as an adulterant in drugs of abuse.

HISTORY AND EPIDEMIOLOGY The bark of the cinchona tree, the first effective remedy for malaria, was introduced to Europeans more than 350 years ago.86 The toxicity of the active ingredient, quinine, was noted from the beginning. In this century, the need to fight wars in malaria-infested areas and the toxicity of quinine led to pharmaceutical advances, funded by the military during WWII (chloroquine, proguanil, amodiaquine, pyrimethamine) and the Vietnam conflict (mefloquine, halofantrine).86,87 Chloroquine, hydroxychloroquine, primaquine, amodiaquine, mefloquine, and halofantrine are related to quinine, but have different patterns of toxicity. Other agents include the folate inhibitors proguanil and pyrimethamine; which are frequently utilized in combination with the sulfonamide, sulfadoxine, or the sulfone, dapsone, and other antibiotics; such as the tetracyclines, clindamycin, and azithromycin (Chap. 46). As each new agent has been introduced, resistance has developed, particularly in Oceania, Southeast Asia, and Africa.86,87 In some places, quinine has again become the first-line therapy for severe malaria.87 In the last two decades, the search for active agents has returned to a natural product, the Chinese herb qinghaosu.49,93 Artemisinin, the active ingredient, is widely used in areas with multidrug-resistant malaria.93 With increased leisure travel, a greater number of North Americans are taking ever more toxic prophylactic agents. Some return with unused medications.

TABLE 44–1.

Those who acquire malaria abroad may return with medications unavailable in the United States.

Pharmacokinetics and Toxicodynamics Quinine is rapidly and relatively completely absorbed orally (Table 44–2). Peak plasma levels are achieved within 3 hours, and 85 to 95% of quinine is protein bound, primarily to human serum albumin and
1 acid glycoprotein.81,90 The apparent volume of distribution is 1.8 L/kg. Peak myocardial concentrations are achieved at 3 to 6 hours. The average therapeutic plasma half-life of quinine is 9 to 15 hours. In overdose, the elimination half-life is approximately 25 to 26 hours.7 The liver, kidneys, and muscles metabolize 80% of the ingested dose. Approximately 20% is excreted unaltered in urine. Quinine passes transplacentally as well as via breast milk. In pregnant women, high doses of cinchona alkaloids exhibit oxytocic activity that may induce abortion or premature labor. For this reason, despite its known dangers, quinine was once used commonly as an abortifacient (Chap. 30).60 Quinine and quinidine are optical isomers and share similar pharmacologic effects as antidysrhythmics and antimalarials. Because of the tissue toxicity of quinine, intravenous quinidine is used in the United States when a parenteral form is needed to treat severe or resistant malaria. Quinine has direct irritant properties on

Common Doses of Antimalarial Drugs Used Worldwide

Drug

Prophylactic Dose (Adult)

Upper Dose Range, Treatment (Adult)

Quinine sulfate Chloroquine phosphate

Not used 500 mg/wk as single dose

Hydroxychloroquine sulfate Primaquine phosphate

Artemisinin

400 mg/wk as single dose 30 mg/d × 14 days after leaving P. vivax or P. ovale area Not used 250 mg/wk as single dose Not used 12.5 mg & 100 mg/wk single dose Not used

650 mg tid × 6–12 days 1000 mg stat then 500 mg at 6 hours, 24 hours, and 48 hours Rarely used 15 mg/d × 14–21 days

Artesunate

Not used

Artemether

Not used

Doxycycline Proguanil Atovaquone

100 mg/d 100 mg once per day§ 250 mg once per day#

Halofantrine Mefloquine Pyrimethamine/sulfadoxine Pyrimethamine/dapsone*

500 mg po q6h × 3 doses, repeat in 7 days 750 mg stat, then 500 mg q6–8h × 3–5 days 75 mg & 1500 mg as single dose Rarely used 25 mg/kg po on day 1 then 12.5 mg/kg on days 2** and 3 5 mg/kg po on day 1 then 2.5 mg/kg on days 2** and 3 3.2 mg/kg IM on day 1 then 1.6 mg/kg/d until po treatment tolerated 100 mg bid^ Rarely used Rarely used

*with chloroquine; ** often with mefloquine 15 mg/kg; ^with quinine sulfate for chloroquine-resistant cases; § usually with chloroquine or atovaquone; #usually with proguanil.

CHAPTER 44

TABLE 44–2.

ANTIMALARIAL AGENTS

673

Pharmacokinetic Properties of Antimalarial Agents

Bioavailability (%) Time to peak (oral) Plasma bound (%) Volume of distribution (L/kg) Half-life Urinary excretion (20%)

Quinine

Chloroquine

Mefloquine

Halofantrine

Pyrimethamine

Dapsone

76 1–3h 93

80 2–5h 50–65

>85 3.8h 98

Low, varies 4–7h —

>95 2–6h 87

90 3–6h 70–80

1.8–4.6 9–15h

>100 40–55d

15–40 15–27d

>100 1–5d

3 3–4d

0.5–1 21–30h

20

50

440 msec.82 Given the long half-life of mefloquine, a drug that also prolongs the QT interval, the use of halofantrine is contraindicated within 4 weeks of mefloquine use.

Clinical Manifestations The primary toxicity in therapeutic and supertherapeutic doses is torsades de pointes and ventricular fibrillation associated with prolongation of the QTc.17,31,62,88 Palpitations, hypotension, and syncope may occur. Because the QTc duration is related to serum concentration, dysrhythmias would be expected in overdose.62 Dysrhythmias are also likely in the context of combined overdose or combined/serial therapeutic use with other drugs that cause QTc prolongation, particularly mefloquine.44 Other side effects, including nausea, vomiting, diarrhea, abdominal cramping, headache, and lightheadedness, which are frequently seen in therapeutic use, are expected in overdose.49 Less frequently described side effects—pruritus, myalgias, and rigors— may occur. In a very few patients, seizures, minimal liver enzyme elevation, and hemolysis are described.49,58,89 Whether these manifestations are related to halofantrine or to the underlying malaria is not clear.

Management Management of halofantrine overdose should focus on decontamination as for quinine, supportive care, and monitoring for QTc prolongation and associated dysrhythmias. Treatment of prolonged QTc and torsades de pointes is discussed above under quinine (Chap. 21).

PROGUANIL, PYRIMETHAMINE, SULFADOXINE, AND DAPSONE Pharmacokinetics and Toxicodynamics These four agents all interfere with folate metabolism and are usually used in combination with each other. Proguanil (chlorguanide) may be used alone, but is often used with dapsone, chloroquine, or the antiparasitic atovaquone for prophylaxis. Pyrimethamine is used in combination with sulfadoxine (Fansidar) or with dapsone (Maloprim). Genetic polymorphism is described in the metabolism of proguanil and dapsone.40,71 This may be the cause of the significant hypersensitivity reactions noted with dapsone.71

Clinical Manifestations Information on proguanil overdose is limited. Proguanil’s side effects during prophylaxis include nausea, diarrhea, and mouth ulcers.49 Because of folate interference, megaloblastic anemia is a rare complication. Folate supplementation may be required in

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pregnancy and renal failure.19 Rarely, neutropenia, thrombocytopenia, rash, and alopecia are also noted.19 In a single case report, hypersensitivity hepatitis was described.19 Dapsone and the sulfonamides have a long history of causing idiosyncratic reactions including neutropenia, thrombocytopenia, eosinophilic pneumonia, aplastic anemia, neuropathy, and hepatitis.49 The rare occurrence of life-threatening erythema multiforme major associated with pyrimethamine/sulfadoxine prophylaxis has limited the use of this combination for prophylaxis. Acute ingestion of dapsone may result in nausea, vomiting, and abdominal pain.37 Following overdose, dapsone produces RBC oxidant stress leading to methemoglobinemia and, to a much lesser extent, sulfhemoglobinemia (Chap. 94).50 The onset may be both immediate and delayed hemolysis.97 Other symptoms, particularly cardiac and neurologic symptoms, resulting from end-organ hypoxia, may occur.37 In addition, in overdose, hepatitis and neuropathy are also described. Overdose of pyrimethamine alone is rare. In children, it results in nausea, vomiting, rapid onset of seizures, fever, and tachycardia.1,37 Blindness, deafness, and mental retardation have followed.1,37 Chronic high-dose use may be associated with a megaloblastic anemia requiring folate replacement (Chap. 25 and Antidotes in Depth: Folic Acid and Leucovorin).1

Management Folate supplementation should be considered after overdose of proguanil or pyrimethamine (Antidotes in Depth: Folic Acid and Leucovorin). Other efforts should include supportive care. Following dapsone ingestion, significant methemoglobinemia should be treated with methylene blue (Chap. 94 and Antidotes in Depth: Methylene Blue). Sulfhemoglobinemia is irreversible, but constitutes an insignificant portion of total hemoglobin. Both hemodialysis and repeat dose activated charcoal are associated with enhanced elimination of dapsone during therapy.61,97 Multidose activated charcoal is recommended in the treatment of dapsone overdose.3 Required support may include RBC transfusion and urinary alkalinization if hemolysis is extensive (Antidotes in Depth: Sodium Bicarbonate).

ARTEMISININ DERIVATIVES: ARTEMETHER, ARTEETHER, AND ARTESUNATE Artemisinin and its derivatives—artemether, arteether, and artesunate—come from the Chinese herb qinghaosu. They were introduced in the 1980s in China for the treatment of malaria. Millions of doses of artemisinin derivatives have been used in Asia and Africa.

No neurologic difference was noted in long-term follow up. In an artemether/quinine comparative trial of adults with severe malaria, recovery from coma was also prolonged in the artemether group.35 A small number (15 cm) Pruritus (urticaria), generalized Asthma, angioedema, nausea, vomiting Airway (asthma, tongue swelling, dysphagia, respiratory distress, laryngeal edema) Cardiovascular (hypotension, may progress to cardiovascular collapse)

Treatment is supportive with careful attention to airway, breathing, and circulation. If the penicillin was ingested orally, the patient may theoretically benefit from activated charcoal 1 g/kg orally. Initial drug therapy includes epinephrine at 0.01 mL/kg (up to 0.5 mL) of 1:1000 dilution SC every 10–20 minutes. Epinephrine, through
-receptor stimulation, results in bronchodilation and increased cardiac output. In addition, its -receptor stimulation results in increased peripheral vascular tone. Oxygen and inhaled
2-adrenergic agonists are warranted in severe cases, as are corticosteroids and H1-receptor antagonists. H2-Receptor antagonism as a treatment for anaphylaxis is controversial. H2-Receptors, when stimulated in the peripheral vasculature, cause vasodilation; in the heart, cause positive inotropy, positive chronotropy, and coronary vasodilation; and in the lung, cause increased mucus production.188 Theoretically, H2-receptor antagonists can lead to a decrease in myocardial activity at a time when H1-receptor stimulation is causing hypotension, coronary vasoconstriction, and bronchospasm. In vitro and animal models demonstrate decreases in coronary circulation and decreases in the overall anaphylactic response following H1 blockers.15,20 In humans, cimetidine and ranitidine are useful for the treatment of pruritus and flushing after acute allergic skin reactions.130,143 Cimetidine, used following anaphylaxis, may result in clinical improvement, particularly hypotension and tachycardia.57,239 However, in one case, chronic ranitidine administration was postulated to result in heart block after an anaphylactic response to latex.166 Treatment using H2-receptor antagonists should only be considered when other therapies have failed and the patient is adequately H1-receptor blocked. Aminophylline, although mentioned in some references for the treatment of anaphylaxis, is not adequately studied and should not be routinely employed. Lastly, glucagon may be of some benefit, particularly in patients who are maintained on
-adrenergic antagonists. Dosing of specific therapy, along with information on side effects, is found in Chapter 15. Amoxicillin/Clavulanic Acid and Hepatitis. Intrahepatic cholestatic hepatitis occurs after treatment with amoxicillin/ clavulanate.40,129,155,177,208 The incidence of hepatotoxicity that typically occurs 1–6 weeks after initiation of therapy is estimated at 1.1–2.7/100,000 prescriptions.74 The mechanism of hepatotoxicity is not clear, but may include toxicity of clavulanate or one of its metabolites. Treatment is supportive with symptoms typically resolving after the discontinuation of therapy. However, prolonged hepatitis, ductopenia, and pancreatitis may rarely occur.40,177 Penicillin G. The most common adverse effects occurring after administration of intramuscular procaine penicillin G are

CHAPTER 46

the Hoigne syndrome and the Jarisch-Herxheimer reaction.11,50,98,106,139,207,245 Both occur after the administration of large intramuscular or intravenous doses of penicillin G.73,84 Hoigne syndrome is characterized by extreme apprehension and fear, illusions, or hallucinations; changes in auditory and visual perception; tachycardia; systolic hypertension; and, occasionally, seizures that begin within minutes of injection.228 These effects occur in the absence of signs or symptoms of anaphylaxis. The cause of this syndrome is unknown. Procaine is implicated as the causative agent because of this syndrome’s similarity to events that occur after the administration of other pharmacologically similar local anesthetics.190,201,225 Hoigne syndrome is 6 times more common in males than females.206 The reason for this increased prevalence is unclear, but autosomal dominance and influences of prostaglandin and thromboxane A2 activity in this population may be responsible.11 The Jarisch-Herxheimer reaction is a self-limited reaction that develops within a few hours of treatment of early syphilis. Symptoms include myalgias, chills, headache, rash, and fever. Symptoms spontaneously resolve within 18–24 hours, even with continued antibiotic therapy.144,184 The pathogenesis of this reaction is unclear, but some authors hypothesize that the reaction is caused by an acute antigen response to lysed bacteria. Similar reactions are reported after treatment of other spirochetal and bacterial infections such as Lyme disease.30

Cephalosporins

Cephalosporins are semisynthetic derivatives of cephalosporin C produced by the fungus Acremonium, previously called Cephalosporium. Cephalosporins have a similar ring structure to penicillins. Cephalosporins are generally divided into first, second, third, and fourth generations based on their antimicrobial spectrum. First-generation cephalosporins include cefadroxil, cefazolin, cephalexin, cephapirin, and cephadrine. Second-generation cephalosporins include cefaclor, cefamandole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime. Third-generation cephalosporins include cefdinir, ceftazidime, cefixime, ceftibuten, cefoperazone, ceftizoxime, cefotaxime, ceftriaxone, and cefpodoxime. Finally, of the fourth-generation cephalosporins, cefepime is the first to be marketed. Acute Overdose. Effects occurring after acute overdose of cephalosporins resemble those occurring after penicillin exposure. Some cephalosporins have similar epileptogenic potential to penicillin in the animal model.77,231 Management guidelines for cephalosporin overdose are similar to those of penicillin overdose. Table 46–1 lists the pharmacologic mechanism of cephalosporins and Table 46–2 lists their pharmacokinetic properties.

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Adverse Effects After Therapeutic Use. Cephalosporins are also capable of causing an immune-mediated acute hemolytic crisis.21,63 Cefaclor is the most common cephalosporin reported to cause serum sickness, although it can occur with other cephalosporins.114,133 Also, like penicillins, cephalosporins are associated with chronic toxicity, including interstitial nephritis and hepatitis with first-generation agents.150,151,237 Cross-Hypersensitivity. The cephalosporins contain a 6-member dihydrithiazine ring instead of the 5-member thiazolidine penicillin ring. The incidence of allergy after cephalosporin use is approximately 4% in the general population and 8% in those with prior penicillin allergy. The incidence of anaphylaxis to cephalosporins is less than 0.02%, with an increase to less than 0.04% in those patients with previous penicillin allergy. Crossreactivity may be greater with agents that are structurally similar to penicillin or that are contaminated by penicillin.6 Antibody binding after cephalosporin exposure occurs at the determinants located on the side chain groups of the cephalosporin.13 These determinants are quite distinct between cephalosporins, which causes the pattern of cross-hypersensitivity between cephalosporins to be much less well defined than between the penicillins. Caution should be used when considering cephalosporins in penicillin- or cephalosporin-allergic patients; however, if a riskbenefit analysis demonstrates a clear benefit to the patient without equivalent alternatives, the cephalosporin should be given. nMTT Side Chain Effects. Cephalosporins containing an N-methylthiotetrazole (nMTT) side chain (moxalactam, cefazolin, cefoperazone, cefmetazole, cefamandole, cefotetan) have toxic effects unique to their group structure. These cephalosporins are metabolized spontaneously and release free nMTT, which is responsible for their effects (Fig. 46–1).140 Free nMTT inhibits the enzyme aldehyde dehydrogenase similarly to disulfiram, and in conjunction with ethanol can cause a disulfiramlike reaction (Chap. 65).31 Patients report flushing, nausea, and vomiting after even small doses of ethanol as a result of the accumulation of acetaldehyde. Those experiencing more severe manifestations may present with hypotension and shock. Treatment is supportive, with careful attention to hemodynamic

Figure 46–1. Characteristic structures of cephalosporins emphasizing the nMTT side chain.

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status. Activated charcoal may be useful if the cephalosporin is recently ingested or has enterohepatic recirculation (ie, cefazolin). The nMTT side chain is also associated with hypoprothrombinemia, although a causal relationship is controversial.85 It is thought that nMTT depletes vitamin K–dependent clotting factors by inhibition of vitamin K epoxide reductase.160 Treatment of patients suspected of hypoprothrombinemia caused by these cephalosporins consists of fresh-frozen plasma, if bleeding is evident, and vitamin K1 in doses required to resynthesize vitamin K cofactors (Chap. 42). The amount of nMTT formed per dose of cephalosporin is variable among the cephalosporins. In a study involving healthy humans, cefoperazone produced the greatest amount of nMTT, followed by cefotetan and cefmetazole.236

Cross-Hypersensitivity. Aztreonam is a monobactam that does not contain the antigenic components required for cross-allergy with penicillins. Therefore, generalized cross-allergenicity is not expected.191 However, aztreonam cross-reacts in vitro with ceftriaxone, thought to be the result of the similarity in their side chain structure.170 Cross-allergenicity has also been noted between imipenem and penicillin, although the incidence has yet to be determined.

Other
-Lactam Antibiotics

Chloramphenicol

activity, providing a structural relationship between imipenem and the development of seizures.218 Treatment for patients with seizures after imipenem use is supportive. GABA agonists such as benzodiazepines or barbiturates should be used if pharmacologic therapy is required for termination of seizure activity.

Chloramphenicol was originally derived from Streptomyces venezuelae and is now produced synthetically. Antimicrobial activity exists against many gram-positive and gram-negative aerobes and anaerobes. Table 46–1 lists the pharmacologic mechanism of chloramphenicol, and Table 46–2 lists its pharmacokinetic properties.

Included in this group are monobactams such as aztreonam and carbapenems such as imipenem and meropenem. Table 46–1 lists the pharmacologic mechanism of these drugs, and Table 46–2 lists their pharmacokinetic properties. Acute Overdose. Effects occurring after acute overdose of other
-lactam antibiotics resemble those occurring following penicillin exposure. Imipenem has clear epileptogenic potential (Adverse Effects After Therapeutic Use). Management guidelines for other
-lactam overdoses are similar to those of penicillin overdoses. Adverse Effects After Therapeutic Use. Imipenem, a member of the class of carbapenem compounds, can cause seizures in therapeutic doses.37,113,125,165,212 The risk factors for seizures include central nervous system disease, prior seizure disorders, or abnormal renal function.167 The mechanism for seizures appears to be GABA antagonism (similar to the penicillins) in conjunction with enhanced activity of excitatory amino acids. In mice, the addition of both excitatory amino acid antagonists and GABA agonists increases the threshold required to provoke carbapenem-induced seizure activity.55 In animals, the C-2 side chain of imipenem provoked seizure

Acute Overdose. Acute overdose of chloramphenicol commonly causes nausea and vomiting. Effects are caused by its ability to inhibit protein synthesis in rapidly proliferating cells. Metabolic acidosis occurs due to the inhibition of mitochondrial enzymes, oxidative phosphorylation, and mitochondrial biogenesis.70 Infrequently, sudden cardiovascular collapse may occur 5–12 hours after acute overdoses. In case series, cardiovascular compromise was more frequent in patients with elevated serum concentrations (>50 µg/mL).70,115,148,168,222 Because levels are not readily available, all poisoned patients should receive close observation for at least 12 hours after exposure. Orogastric lavage may be useful for recent ingestions in which the patient has not vomited, and activated charcoal 1 g/kg should be given orally. Extracorporeal means of eliminating chloramphenicol are not usually required because of its rapid metabolism (Table 46–2). However, it may be of benefit in patients with large overdoses, or in patients with severe hepatic or renal dysfunction. Both hemodialysis and charcoal hemoperfusion decrease elevated plasma chloramphenicol levels.69,142,209 Exchange transfusion also lowers chloramphenicol serum concentrations in neonates.115,216 Surviving patients should be closely monitored for signs of bone marrow suppression. Adverse Effects After Therapeutic Use. Chronic toxicity of chloramphenicol is similar to that seen after acute poisoning. A classic description of the chronic toxicity of chloramphenicol is the “gray baby syndrome.”69,70,142,216 Children with this syndrome exhibit vomiting, anorexia, respiratory distress, abdominal distension,

CHAPTER 46

green stools, lethargy, cyanosis, ashen color, metabolic acidosis, hypotension, and cardiovascular collapse. The majority (90%) of a dose of chloramphenicol is metabolized via glucuronyl transferase forming a glucuronide conjugate. The remainder is excreted renally unchanged. Infants, in particular, are predisposed to the gray baby syndrome because they have a limited capacity to conjugate chloramphenicol and to excrete unconjugated chloramphenicol in the urine.80,235 Dose-dependent bone marrow depression occurs with high serum concentrations of chloramphenicol.102,103,199 Clinical manifestations usually occur after several weeks of therapy and include anemia, thrombocytopenia, and leukopenia. Bone marrow suppression is reversible with discontinuation of therapy. Chloramphenicol causes bone marrow suppression by inhibiting protein synthesis in the mitochondria of marrow cell lines.152,153 Rarely, aplastic anemia occurs after topical application.1 The development of aplastic anemia after chloramphenicol use is not dose related and generally occurs in susceptible patients within 5 months of treatment (Chap. 25).61,242 Although the exact mechanism is unknown, it is theorized that the p-nitrosulfathiazole group on chloramphenicol inhibits DNA synthesis in marrow stem cells.241 Other adverse effects associated with chloramphenicol include peripheral neuropathy;112,174 neurologic abnormalities, including confusion and delirium;127 optic neuritis;46,112 nonlymphocytic leukemia;205 and contact dermatitis.120

Fluoroquinolones

The fluoroquinolones are a structurally similar, synthetically derived group of antibiotics that may exhibit a diverse spectrum of activity. The fluoroquinolones include balofloxacin, ciprofloxacin, clinafloxacin, enoxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, and trovafloxacin. Table 46–1 lists the pharmacologic mechanism of fluoroquinolones, and Table 46–2 lists their pharmacokinetic properties. Acute Overdose. Like other antimicrobials, the fluoroquinolones are rarely life-threatening after acute overdose, and most patients can be safely managed with minimal intervention.10 Rarely, acute overdose of a fluoroquinolone results in renal failure or seizures.48 The mechanism of renal failure after fluoroquinolone exposure is controversial. In animals, ciprofloxacin and norfloxacin cause pathologic changes in the kidney, especially in the setting of neutral or alkaline urine.195 In humans, renal failure is reported after both acute and chronic exposure to fluoroquinolones. A hypersensitivity reaction is postulated to explain pathologic changes con-

ANTIBIOTICS

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sistent with interstitial nephritis.101,150,151,179,240 Treatment is supportive with discontinuation of the fluoroquinolone. Improvement in renal function is usually noticed within several days. Seizures are reported with ciprofloxacin and may be a result of the inhibition of GABA.211,224 Others postulate that the ability of fluoroquinolones to bind efficiently to cations, particularly magnesium, results in seizure activity. This hypothesis is related to magnesium’s inhibitory role at the excitatory NMDA-gated ion channel (Chap. 10).56,196 Treatment is supportive, using benzodiazepines and, if necessary, barbiturates to increase GABAergic activity. Adverse Effects After Therapeutic Use. Several fluoroquinolones are substrates and/or inhibitors of cytochrome P450 isoenzymes. This can result in drug interactions, especially important with drugs that have a narrow therapeutic index. See Chapter 11 for clinical implications. Serious adverse effects related to fluoroquinolone use consist of central nervous system toxicity as discussed, cardiovascular toxicity, hepatotoxicity, and articular/tendon toxicity. Fluoroquinolones cause prolongation of the QTc complex duration that may cause torsades de pointes.54,109,189 Although the mechanism of this effect is unclear, sequestering of magnesium resulting in clinical hypomagnesemia is postulated.196 Treatment of patients presenting with widening of the QTc interval duration is supportive with careful attention to magnesium supplementation if necessary. The fluoroquinolones rarely result in potentially fatal hepatotoxicity.41,42,71,81,92,123,135,181 This adverse effect is most notable with trovafloxacin, although the reason for an increased risk with this particular fluoroquinolone is not clear. As a result, trovafloxacin (Trovan) is now reserved only for the treatment of patients with life-threatening infections in whom the benefits are thought to outweigh the risks. In addition, the manufacturer has initiated a limited distribution system that allows drug shipment only to pharmacies within inpatient healthcare facilities. Fluoroquinolones should be used with caution in children and pregnant women because of their potential adverse effects on developing cartilage and bone. Damage to articular cartilage is demonstrated in young dogs and rats although it was variable with different fluoroquinolones.34,220 There are very limited data in humans; however, children given ciprofloxacin on a compassionate basis developed complaints of swollen, painful, and stiff joints after 3 weeks of therapy.111 All signs and symptoms abated within 2 weeks of discontinuation of therapy. However, 29 additional children treated with ofloxacin or ciprofloxacin showed no differences with respect to cartilage thickness, cartilage structure, edema, cartilage-bone borderline, or synovial fluid. Women who received quinolones during pregnancy had larger babies and more caesarean deliveries because of fetal distress than did controls.17 However, there were no congenital malformations, delay to developmental milestones, or musculoskeletal abnormalities found. Fluoroquinolones are also implicated as a cause of tendon rupture, which is reported to occur for up to 120 days after the start of treatment and even after the discontinuation of therapy.169 The fluoroquinolone should be discontinued in patients, particularly athletes who complain of symptoms consistent with painful and swollen tendons. Other adverse effects include acute psychosis, rash, tinnitus, eosinophilia, serum sickness, and, commonly, photosensitivity.32,86,215,149

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Macrolides

The macrolide antibiotics include various forms of erythromycin (base, estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycin, troleandomycin, and dirithromycin. Table 46–1 lists the pharmacologic mechanism of macrolides, and Table 46–2 lists their pharmacokinetic properties. Acute Overdose. Acute oral overdoses of macrolide antibiotics are usually not life-threatening and symptoms are generally confined to the gastrointestinal tract. Treatment is similar to acute oral penicillin overdoses. Erythromycin lactobionate causes QT prolongation and torsades de pointes after intravenous use.161 In vitro models demonstrate erythromycin’s ability to slow repolarization in a concentration-dependent manner.156 The cause for widened QT was once thought to result from hypokalemia-induced promotion of intracellular efflux of potassium.175 Current data, however, demonstrate that the QT prolongation results from blockade of delayed rectifier potassium currents (Chap. 21).183 QTc prolongation and torsades de pointes are common after intravenous erythromycin lactobionate.161 More pronounced widening occurs in patients with underlying heart disease and correlates with the infusion rate.89 Epidemiologic studies associate an increased incidence of ventricular dysrhythmias in females treated with erythromycin.59 The implications of this finding are unknown. Adverse Events After Therapeutic Use Drug Interactions. Erythromycin is the prototypical macrolide and as such has received the most attention with respect to potential and documented drug interactions. Clarithromycin, erythromycin, and troleandomycin are all potent inhibitors of the cytochrome CYP3A4 enzyme system, whereas azithromycin provides little to no inhibition.51 Erythromycin inhibits P450 after metabolism to a nitroso intermediate, which then forms an inactive complex with the iron (II) of cytochrome P450. Chapter 11 lists some substrates for the CYP3A4 system. Clinically significant interactions occur with erythromycin and astemizole, carbamazepine, cisapride, and terfenadine.35,83,95,100,173 Inhibition of terfenadine, astemizole, and cisapride metabolism results in increased concentrations of the parent drug, all of which are capable of causing a widening of the QTc interval and torsades de pointes.24,164 Cases of carbamazepine toxicity are documented with erythromycin use.95 Erythromycin also inhibits CYP1A2,

producing clinically significant interactions with clozapine, theophylline, and warfarin.180 Macrolides may also interact with the absorption and renal excretion of drugs that are amenable to intestinal p-glycoprotein excretion, or interfere with normal gut flora responsible for metabolism. This may be part of the underlying mechanism of cases of macrolide-induced digoxin toxicity159 (Chap. 48). End-Organ Effects. The most common toxic effect of macrolides after chronic use is hepatitis, which may be immune mediated.38 Erythromycin estolate is the agent most frequently implicated in causing cholestatic hepatitis.79,107 Large doses of macrolide antibiotics are also associated with high-frequency sensorineural hearing loss.28,198 A review of 11 patients who experienced hearing loss following erythromycin therapy showed that the therapy employed a dose greater than 4 g/d or that the patient had prior renal impairment as a potential risk factor.185 The hearing loss was reversible in all 11 cases after dosage reduction or discontinuation. A similar case-control study found that 5 of 30 patients treated with erythromycin therapy experienced ototoxicity, while none of the 15 controls had any manifestations.219 Ototoxicity occurred only with doses of 4 g/d or more, and was found to correlate with higher serum concentrations. Ototoxicity resolved in all patients 6–14 days after discontinuation of therapy. However, there are rare case reports in which ototoxicity did not resolve following discontinuation of therapy.62,126 There are insufficient data concerning the ototoxic potential of the other macrolide antibiotics. Other, rare toxic effects associated with macrolides include cataracts after clarithromycin use in animals and acute pancreatitis in humans.65,227,172

Sulfonamides

Sulfonamides are antibiotics that antagonize p-aminobenzoic acid or p-aminobenzyl glutamic acid, which are required for the biosynthesis of folic acid. Table 46–1 lists the pharmacologic mechanism of sulfonamides, and Table 46–2 lists their pharmacokinetic properties. Acute Overdose. Acute oral overdoses of sulfonamides are usually not life-threatening and symptoms are generally confined to nausea, although allergy and methemoglobinemia are rarely seen. Treatment is similar to acute oral penicillin overdoses. Adverse Effects After Therapeutic Use. The most common adverse effects associated with chronic therapy with sulfonamides are nausea and cutaneous hypersensitivity reactions. Hypersensitivity reactions are thought to be caused by the formation of hapten sulfamethoxazole metabolites, N-hydroxy-sulfamethoxa-

CHAPTER 46

zole-NHOH and nitroso-sulfamethoxazole-NO. The degree of hapten binding is mitigated in vitro by cysteine and glutathione.154 The incidence of adverse reactions to sulfonamides, including allergy, is increased in the HIV-positive population and is positively correlated to the number of opportunistic infections that the patient has had despite similar CD4 counts among the groups.124 This may be caused by a decrease in the mechanisms available for detoxification of free radical formation as cysteine and glutathione levels are low in these patients.233 It is unknown whether supplementation with a glutathione precursor such N-acetylcysteine will reduce the incidence of these reactions. One study using 800 mg of N-acetylcysteine daily found no difference in the incidence of adverse effects between the groups.3 Methemoglobinemia and hemolysis also rarely occur.60,132 The mechanism for adverse reactions is not entirely clear. However, when sulfamethoxazole is exposed to ultraviolet B (UVB) radiation in vitro, free radicals are formed that can participate in the development of tissue peroxidation and hemolysis.244 This finding may be of particular importance in treating patients with G6PD deficiency caused by a decrease in reducing capabilities.4 The sulfonamides are associated with many chronic adverse effects. Bone marrow suppression is rare, but an increased incidence occurs in patients with folic acid or vitamin B12 deficiency, and in children, pregnant women, alcoholics, dialysis patients, and immunocompromised patients, as well as in those patients those receiving other folate antagonists. Other adverse effects include hypersensitivity pneumonitis, stomatitis, aseptic meningitis, hepatotoxicity, renal toxicity, and central nervous system toxicity.22

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Other chronic effects associated with the tetracyclines include nephrotoxicity, hepatotoxicity, and skin hyperpigmentation in sunexposed areas and hypersensitivity reactions.38,82,105,221 More severe hypersensitivity reactions, drug-induced lupus, and pneumonitis are reported after minocycline use, as are cases of necrotizing vasculitis of the skin and uterine cervix, and lymphadenopathy with eosinophilia.137,197,204 Demeclocycline is reported in a single case to cause nephrogenic diabetes insipidus.39 Outdated older formulations, but not newer formulations, of tetracycline are reported to cause hypouricemia, hypokalemia, and a proximal and distal renal tubular acidosis.44

Vancomycin

Tetracyclines

Vancomycin is obtained from cultures of Nocardia orientalis and is a tricyclic glycopeptide. Vancomycin is biologically active against numerous gram-positive organisms. Table 46–1 lists the pharmacologic mechanism of vancomycin, and Table 46–2 lists its pharmacokinetic properties.

Tetracyclines are derivatives of Streptomyces cultures. Currently available tetracyclines include demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, and tetracycline. Table 46–1 lists the pharmacologic mechanism of tetracyclines, and Table 46–2 lists their pharmacokinetic properties. Acute Overdose. Significant toxicity after acute overdose of tetracyclines is unlikely. Gastrointestinal effects consisting of nausea, vomiting, and epigastric pain have been reported.29 Adverse Effects After Therapeutic Use. Tetracycline should not be used in children during the first 6–8 years of life or in pregnant women after the 12th week of pregnancy because of the risk of development of secondary tooth discoloration in the child or in the offspring.

Acute Overdose. Acute oral overdoses of vancomycin rarely cause significant toxicity and most cases can be treated with supportive care alone. Multiple-dose activated charcoal therapy decreases the half-life of vancomycin and can be considered in patients with large overdoses when the patient is expected to have a long clearance time.121 Adverse Effects After Therapeutic Use. Patients who receive intravenous vancomycin may develop the “red man syndrome,” which is a glycopeptide-induced anaphylactoid reaction.76 Symptoms include chest pain, dyspnea, pruritus, urticaria, flushing, and angioedema.182 Signs and symptoms spontaneously resolve, typically within 15 minutes. Other symptoms attributable to “red man syndrome” may include hypotension, cardiovascular collapse, and seizures.12,157 The incidence, signs, and symptoms of red man syndrome are variable. The incidence of red man syndrome appears to be related to the rate of infusion. The incidence is 14% (11/76) when 1 g is given over 10 minutes versus 3.4% when given over 1 hour.157,162 A trial in healthy humans studied the relationship between intra-

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dermal skin hypersensitivity and the development of red man syndrome. Each of the 11 subjects underwent skin testing followed 1 week later by an intravenous dose of vancomycin 15 mg/kg over 60 minutes. Following intravenous vancomycin, all subjects developed dermal flare responses and erythema, and 10 of 11 subjects developed pruritus within 20–45 minutes. After the infusion was terminated, symptoms resolved within 60 minutes.171 The signs and symptoms of the red man syndrome are related to the rise and fall of histamine concentrations.94,128 Tachyphylaxis occurs in patients given multiple doses.93,232 Animal models demonstrated a direct myocardial depressant and vasodilatory effect of vancomycin.47 More serious reactions result when vancomycin is given via intravenous bolus, further supporting a rate-related anaphylactoid mechanism.19 Patients most often experience red man syndrome after vancomycin is administered intravenously. In rare cases, oral administration of vancomycin can also result in the syndrome.16 Treatment includes increasing the dilution of vancomycin and a slower intravenous administration. Antihistamines may be useful as pretreatment, especially prior to the first dose.176 A placebo-controlled trial in adult patients studied the incidence of these symptoms in patients given 1 g of vancomycin over 1 hour, as well as the effect of diphenhydramine in the prevention of the syndrome.232 There was a 47% incidence of reaction without diphenhydramine and a 0% incidence with diphenhydramine. Chronic use of vancomycin may cause reversible nephrotoxicity, particularly in patients with prolonged excessive steady-state serum levels.8,178 Concomitant administration of aminoglycoside antibiotics may increase the risk of nephrotoxicity.186 Vancomycin also rarely causes thrombocytopenia and neutropenia.43,58

ANTIFUNGALS Numerous antifungals are available. Toxicity related to the use of antifungal agents is variable and is based generally upon their mechanism of action.

Amphotericin B

Exchange transfusion may be useful in neonates and infants and should be considered after large intravenous exposures.25 In adults, extracorporeal elimination is not expected to be useful because of the drug’s low water solubility and high blood-protein binding. Adverse Effects After Therapeutic Use. Infusion of amphotericin B results in fever, rigors, headache, nausea, vomiting, hypotension, tachycardia, and dyspnea.138 Pretreatment with acetaminophen, diphenhydramine, ibuprofen, and hydrocortisone is helpful in alleviating the febrile symptoms along with slower rates of infusion and lower total daily doses.78,226 Doses greater than 1 mg/kg/d and rapid administration of drug in less than 1 hour are not recommended. Infusion concentrations of amphotericin B greater than 0.1 mg/mL can result in localized phlebitis. Slower infusion rates, hot packs, and frequent line flushing with dextrose in water may also help to alleviate symptoms. Eighty percent of patients exposed to amphotericin B will sustain some degree of renal insufficiency (Chap. 23).36 Azotemia is caused by distal renal tubule damage, which causes renal artery vasoconstriction. Studies in animals show depressed renal blood flow and glomerular filtration rate, and increased renal vascular resistance. It is unclear why this occurs, but at this time, renal nerves, angiotensin II, endothelium-derived relaxing factor, and tubuloglomerular feedback are excluded.187,192 The toxic effects associated with amphotericin B may be caused by the vehicle, deoxycholate.243 After large total doses of amphotericin B, residual decreases in glomerular filtration rate may occur even after discontinuation of therapy. This is hypothesized to be the result of nephrocalcinosis. Potassium and magnesium wasting, proteinuria, decreased renal concentrating ability, renal tubular acidosis, and hematuria also occur.14,138 Strategies to reduce renal toxicity after amphotericin B include intravenous saline or magnesium and potassium supplementation.23,67,96 Lipid and colloidal formulations of amphotericin B attenuate the adverse effects associated with amphotericin B.87 Here the amphotericin B is complexed with either a lipid or cholesteryl sulfate. Upon contact with a fungus, lipases are released to free the complexed amphotericin B, resulting in focused cell death.97 Other adverse effects reported after treatment with amphotericin B include normochromic, normocytic anemia; decreased erythropoietin release; respiratory insufficiency with infiltrates; and, rarely, dysrhythmias, tinnitus, thrombocytopenia, peripheral neuropathy, and leukopenia.131,136,138

Triazole and Imidazoles

Amphotericin B is a potent antifungal derived from Streptomyces nodosus. Amphotericin B is generally fungistatic against fungi that contain sterols in their cell membrane. Table 46–1 lists the pharmacologic mechanism of amphotericin B, and Table 46–2 lists its pharmacokinetic properties. Acute Overdose. There are several case reports of amphotericin B overdose in infants and children. Significant clinical findings include hypokalemia, aspartate aminotransferase elevations, and cardiac complications including dysrhythmias and cardiac arrest after being given 5–15 mg/kg of amphotericin B.45,118

CHAPTER 46

TABLE 46–5. Consequential Organ System Manifestations Associated with Antibiotics and Antifungals Drug Antibiotics Bacitracin Clindamycin

Organ System Toxicity

Novobiocin

Immune Gastrointestinal Hematologic

Polymyxin B sulfate

Neurologic Renal Cutaneous Other Cutaneous Hematologic Immune

Hypersensitivity reactions Hypersensitivity reactions Nausea, vomiting, diarrhea Dizziness, headache, vertigo Decreased function, acute tubular necrosis Peripheral paresthesias, confusion, coma, seizures, neuromuscular blockade Proteinuria, nephrosis Increased liver enzymes Nausea, vomiting, diarrhea Granulocytopenia Disulfiram reactions, increased porphyrins Nausea, vomiting, diarrhea Hypersensitivity reactions Peripheral neuropathy, seizures Nausea, vomiting Disulfiram reactions Hypersensitivity reactions Ointment contains polyethylene glycols (renal dysfunction) Nausea, vomiting, diarrhea Jaundice Rash; acute and chronic pulmonary hypersensitivity Peripheral neuropathy Skin rash Nausea, vomiting, diarrhea Pancytopenia, hemolytic anemia Muscle weakness, seizures Azotemia, proteinuria Contact dermatitis Selenium: hair loss (rare) Contact dermatitis Anemia, aplastic anemia Rash (rare)

Gastrointestinal Gastrointestinal

Nausea, vomiting, diarrhea Nausea, vomiting, diarrhea

Gastrointestinal Immune Gastrointestinal Unknown

Nausea, vomiting, diarrhea Rarely rash Nausea, vomiting, diarrhea Unknown

Gastrointestinal and dermal Gastrointestinal

Higher concentrations are caustic Nausea, vomiting, diarrhea

Colistimethate (colistin sulfate)

Immune Immune Gastrointestinal Nervous Renal

Signs, Symptoms, Laboratory

Nervous

Griseofulvin

Renal Hepatic Gastrointestinal Immune Other

Lincomycin

Gastrointestinal Immune Neurologic

Metronidazole

Nitrofurazone

Nitrofurantoin

Gastrointestinal Other Immune Other

Gastrointestinal Hepatic Immune Neurologic

Selenium sulfide Silver sulfadiazine Spectinomycin Antifungals Benzoic acid Carbol-fuchsin solution (phenol/ resorcinol/ fuchsin) Gentian violet Nystatin Pradimicins (investigational) Salicylic acid Undecylenic acid and undeclyenate salt

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Common triazole antifungals include fluconazole and itraconazole. Common imidazoles include clotrimazole, econazole, ketoconazole, and miconazole. Severe toxicity is not expected in the overdose setting. The majority of toxic effects seen after the use of these drugs result from their drug interactions. Fluconazole, itraconazole, ketoconazole, and miconazole competitively inhibit CYP3A4, the enzyme system responsible for the metabolism of many drugs. Clinically significant interactions are reported with many of the drugs listed in Chapter 11. Table 46–5 lists other organ system manifestations associated with antifungal agents and other antibiotics.

SUMMARY Adverse effects attributable to antibiotics are largely related to chronic administration, although rarely, acute toxicity does occur. Acute toxic effects of antibiotics are more common after large intravenous administration, drug interactions, or iatrogenic overdose. Careful vigilance on the part of the healthcare provider will prevent the majority of acute toxic manifestations following antibiotic use.

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161. Oberg KC, Bauman JL: QT prolongation and torsades de pointes due to erythromycin lactobionate. Pharmacotherapy 1995;15:687–692. 162. O’Sullivan TL, Ruffing MJ, Lamp KC, et al: Prospective evaluation of red man syndrome in patients receiving vancomycin. J Infect Dis 1993;168:773–776. 163. Paradelis AG: Aminoglycoside antibiotics and neuromuscular blockade. J Antimicrob Chemother 1979;5:737–738. 164. Paris DG, Parente TF, Bruschetta HR, et al: Torsades de pointes induced by erythromycin and terfenadine. Am J Emerg Med 1994; 12:636–638. 165. Park SY, Parker RH: Review of imipenem. Infect Control 1986; 7:333–337. 166. Patterson LJ, Milne B: Latex anaphylaxis causing heart block: Role of ranitidine. Can J Anesth 1999;46:776–778. 167. Pestotnik SL, Classen DC, Evans RS, et al: Prospective surveillance of imipenem/cilastatin use and associated seizures using a hospital information system. Ann Pharmacother 1993;27:497–501. 168. Phelps SJ, Tsiu W, Barrett FF, et al: Chloramphenicol-induced cardiovascular collapse in an anephric patient. Pediatr Infect Dis J 1987; 6:285–288. 169. Pierfitte C, Gillet P, Royer RJ: More on fluoroquinolone antibiotics and tendon rupture [letter]. N Engl J Med 1995;332(3):193. 170. Pimiento PA, Martinez GM, Mena MA, et al: Aztreonam and ceftazidime: Evidence of in vivo cross allergenicity. Allergy 1998;53: 624–625. 171. Polk RE, Israel D, Wang J, et al: Vancomycin skin tests and prediction of “red man syndrome” in healthy volunteers. Antimicrob Agents Chemother 1993;37:2139–2143. 172. Prazic M, Salaj B, Sunotic R: Familial sensitivity to streptomycin. J Laryngol Otol 1964;78:1037–1043. 173. Ptachainski RJ, Carpenter BJ, Burckart GJ, et al: Effect of erythromycin on cyclosporine levels [letter]. N Engl J Med 1985;313: 1416–1417. 174. Ramilo O, Kinane BT, McCracken GH: Chloramphenicol neurotoxicity. Pediatr Infect Dis J 1988;7:358–359. 175. Regan TJ, Khan MI, Olde IHA, Passannant AJ: Antibiotic effect on myocardial K transport and the production of ventricular tachycardia [abstract]. J Clin Invest 1969;48:66A. 176. Renz CL, Thurn JD, Finn HA, et al: Antihistamine prophylaxis permits rapid vancomycin infusion. Crit Care Med 1999;27:1732–1737. 177. Richardet JP, Mallat A, Zafrani ES, et al: Prolonged cholestasis with ductopenia after administration of amoxicillin/clavulanic acid. Dig Dis Sci 1999;44:1997–2000. 178. Riley HD Jr: Vancomycin and novobiocin. Med Clin North Am 1970;54:1277–1289. 179. Rippelmeyer DJ, Synhavsky A: Ciprofloxacin and allergic interstitial nephritis [letter]. Ann Intern Med 1988;109:170. 180. Rockwood RP, Embardo LS: Theophylline, ciprofloxacin, erythromycin: A potentially harmful regimen [letter]. Ann Pharmacother 1993;27:651–652. 181. Romero-Gomez M, Suarez GE, Fernandez MC: Norfloxacin-induced acute cholestatic hepatitis in a patient with alcoholic liver cirrhosis [letter]. Am J Gastroenterol 1999;94:2324–2325. 182. Rothenberg HJ: Anaphylactoid reaction to vancomycin. JAMA 1959;171:1101–1102. 183. Rubart M, Pressler ML, Pride HP, Zipes DP: Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome. Circulation 1993;88(pt 1):1832–1844. 184. Rudolph AH, Prince EV: Penicillin reactions among patients in venereal disease clinics: A national survey. JAMA 1973;223: 499–501. 185. Sacristan JA, Soto JA, deCos MA: Erythromycin-induced hypoacusis: 11 new cases and literature review. Ann Pharmacother 1993;27: 950–955. 186. Rybak MJ, Boike SC: Additive toxicity in patients receiving vancomycin and aminoglycosides [letter]. Clin Pharm 1983;2:508.

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187. Sabra R, Takahashi K, Branch RA, Badr KF: Mechanisms of amphotericin B-induced reduction of glomerular filtration rate: A micropuncture study. J Pharmacol Exp Ther 1990;253:34–37. 188. Sage DJ: Management of acute anaphylactoid reactions. Int Anesthesiol Clin 1985;23(3):175–86. 189. Samaha FF: QTC interval prolongation and polymorphic ventricular tachycardia in association with levofloxacin [letter]. Am J Med 1999;107:528–529. 190. Saraway SM, Marke J, Steinberg M, et al: Doom anxiety and delirium in lidocaine toxicity. Am J Psychiatry 1987;144:159–163. 191. Saxon A, Swabb EA, Adkinson NF Jr: Investigation into the immunologic cross-reactivity of aztreonam with other beta lactam antibiotics. Am J Med 1985;78(Suppl A):19–26. 192. Sayawa BP, Weihprecht H, Cambell WR, et al: Direct vasoconstriction as a possible cause for amphotericin B-induced nephrotoxicity in rats. J Clin Invest 1991;87:2079–2107. 193. Schacht J: Biochemistry and pharmacology of aminoglycosideinduced hearing loss. Acta Physiol Pharmacol Ther Latinoam 1999; 49:251–256. 194. Schentag JJ, Plaut ME: Patterns of beta-2-microglobulin excretion in patients treated with aminoglycosides. Kidney Int 1980;16:654–661. 195. Schluter G: Ciprofloxacin: Review of potential toxicologic effects. Am J Med 1987;82(Suppl 4A):91–93. 196. Schmuck G, Schurmann A, Schluter G: Determination of the excitatory potencies of fluoroquinolones in the central nervous system by an in vitro model. Antimicrob Agents Chemother 1998;42: 1831–1836. 197. Schrodt BJ, Kulp-Shorten CL, Callen JP: Necrotizing vasculitis of the skin and uterine cervix associated with minocycline therapy for acne vulgaris. South Med J 1999;92:502–504. 198. Schweitzer VG, Olson NR: Ototoxic effect of erythromycin therapy. Arch Otolaryngol 1984;110:258–260. 199. Scott JL, Finegold SM, Belkins GA, et al: A controlled double-blind study of the hematologic toxicity of chloramphenicol. N Engl J Med 1965;272:1137. 200. Seamans KB, Gloor P, Dobell RAR, Wyant JD: Penicillin-induced seizures during cardiopulmonary bypass: A clinical and electroencephalographic study. N Engl J Med 1968;278:861–868. 201. Seldon R, Sasahara AA: Central nervous system toxicity induced by lidocaine. JAMA 1967;202:908–909. 202. Serdaru M, Diquet B, Lhermitte F: Generalized seizures after ampicillin [letter]. Lancet 1982;2:617–618. 203. Sha SH, Schacht J: Are aminoglycoside antibiotics excitotoxic? Neuroreport 1998;9:3893–3895. 204. Shapiro LE, Knowles SR, Shear: Comparative safety of tetracycline, minocycline and doxycycline. Arch Dermatol 1997;133:1224–1230. 205. Shu XO, Gao YT, Linet MS, et al: Chloramphenicol use and childhood leukaemia in Shanghai. Lancet 1987;2:934–937. 206. Silber T, D’Angelio L: Doom, anxiety, and Hoigne’s syndrome [letter]. Am J Psychiatry 1987;144:1365. 207. Silber TJ, D’Angelio LJ: Panic attack following injection of aqueous procaine penicillin G (Hoigne’s syndrome). J Pediatr 1985;107: 314–315. 208. Silvian C, Levillain P, Labat-Labourdette J, Beauchant M: Granulomatous hepatitis due to a combination of amoxicillin and clavulanic acid. Dig Dis Sci 1992;37:150–152. 209. Slaughter RL, Cerra FB, Koup JR: Effect of hemodialysis on total body clearance of chloramphenicol. Am J Hosp Pharm 1980;37(8): 1083–1086. 210. Slayton W, Anstine D, Lakhdir F, et al: Tetany in a child with AIDS receiving intravenous tobramycin. South Med J 1996;89:1108–1110. 211. Slavich IL, Gleffe RF, Haas EJ: Grand mal epileptic seizures during ciprofloxacin therapy. JAMA 1989:261:558–559. 212. Solomkin JS, Fant WK, Rivera JU, Alexander JW: Randomized clinical trial of imipenem/cilastatin versus gentamycin and clindamycin in mixed flora infections. Am J Med 1985;78(Suppl 6A):85–91.

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213. Somer T, Finegold SM: Vasculitis associated with infections, immunization, and antimicrobial drugs. Clin Infect Dis 1995;20: 1010–1036. 214. Song BB, Sha SH, Schacht J: Iron chelators protect from aminoglycoside-induced cochleo- and vestibulo-toxicity. Free Radic Biol Med 1998;25:189–195. 215. Stahlmann R, Lode H: Toxicity of quinolones. Drugs 1999;58(Suppl 2):37–42. 216. Stevens DC, Kleiman MB, Lietman PS, et al: Exchange transfusion in acute chloramphenicol toxicity. J Pediatr 1981;99:651–653. 217. Stupp H, Kupper K, Lagler F, et al: Inner ear concentrations and ototoxicity of different antibiotics in local and systemic application. Audiology 1973;12:350–363. 218. Sunagawa M, Matsumura H, Sumita Y, Nouda H: Structural features resulting in convulsive activity of carbapenem compounds: Effect of C-2 side chain. J Antibiot (Tokyo) 1995;48:408–416. 219. Swanson DJ, Sung RJ, Fine MJ, et al: Erythromycin ototoxicity: Prospective assessment with serum concentrations and audiograms in a study of patients with pneumonia. Am J Med 1992;92:61–68. 220. Takada S, Kato M, Takayama S: Comparison of lesions induced by intra-articular injections of quinolones and compounds damaging cartilage components in rat femoral condyles. J Toxicol Environ Health 1994;42:73–88. 221. Teitelbaum JE, Perez-Atayde AR, Cohen M, et al: Minocyclinerelated autoimmune hepatitis: case series and literature review. Arch Pediatr Adolesc Med 1998;152:1132–1136. 222. Thompson WL, Anderson SE Jr, Lipsky JJ, et al: Overdose of chloramphenicol. JAMA 1975;234:149–150. 223. Timmermans L: Influence of antibiotics on spermatogenesis. J Urol 1974;112:348–349. 224. Tsuji A, Sato H, Kume Y, et al: Inhibitory effects of quinolone antibacterial agents on gamma-aminobutyric acid binding to receptor sites in rat brain membranes. Antimicrob Agents Chemother 1988; 32:190–194. 225. Turner WM: Lidocaine and psychotic reactions. Ann Intern Med 1982;97:149–150. 226. Tynes BS, Utz JP, Bennett JE, et al: Reducing amphotericin B reactions. Am Rev Resp Dis 1963;87:264–268. 227. Unal M, Peyman GA, Liang C, et al: Ocular toxicity of intravitreal clarithromycin. Retina 1999;19:442–446. 228. Utley PM, Lucas JB, Billings TE: Acute psychotic reactions to aqueous procaine penicillin. South Med J 1966;59:1271–1274.

229. Van Arsdel PP Jr: The risk of penicillin reactions. Ann Intern Med 1968;69:1071–1073. 230. Walker PD, Barri Y, Shah SV: Oxidant mechanisms in gentamycin nephrotoxicity. Ren Fail 1999;21:433–442. 231. Wallace KL: Antibiotic-induced convulsions. Med Toxicol 1997;13: 741–762. 232. Wallace MR, Mascola JR, Oldfield EC 3rd: Red man syndrome: Incidence, etiology and prophylaxis. J Infect Dis 1991;164:1180–1185. 233. Walmsley SL, Winn LM, Harrison ML, et al: Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: Toxicological and pathological implications. AIDS 1997;11:1689–1697. 234. Warner WA, Sanders E: Neuromuscular blockade associated with gentamycin therapy. JAMA 1971;215:1153–1154. 235. Weisberger AS, Wessler S, Avioli LV: Mechanisms of action of chloramphenicol. JAMA 1969;209:97–103. 236. Welage LS, Borin MT, Wilton JH, et al: Comparative evaluation of the pharmacokinetics of N-methylthiotetrazole following administration of cefoperazone, cefotetan and cefmetazole. Antimicrob Agents Chemother 1990;34:2369–2374. 237. Westphal JF, Vetter D, Brogard JM: Hepatic side-effects of antibiotics. J Antimicrob Chemother 1994;33:387–401. 238. Wolf R, Brenner DS: An active amide group in the molecule of drugs that induce pemphigus: A casual or causal relationship? Dermatology 1994;189:1–4. 239. Yarbrough JA Moffitt JE, Brown DA, Stafford C: Cimetidine in the treatment of refractory anaphylaxis. Ann Allergy 1989;63:235–238. 240. Ying LS, Johnson CA: Ciprofloxacin-induced interstitial nephritis. Clin Pharm 1989;8:518–521. 241. Yunis AA: Chloramphenicol toxicity: 25 years of research. Am J Med 1989;87:3–44N–3–48N. 242. Yunis AA: Chloramphenicol-induced bone marrow suppression. Semin Hematol 1973;10:255–234. 243. Zager RA, Bredl CR, Schimpf BA: Direct amphotericin B-mediated tubular toxicity: Assessments of selected cytoprotective agents. Kidney Int 1992;42:1588–1594. 244. Zhou W, Moore DE: Photosensitizing activity of the anti-bacterial drugs sulfamethoxazole and trimentoprim. J Photochem Photobiol 1997;39:63–72. 245. Zifko U, Wimberger D, Volc B, Grisold W: Jarisch-Herxheimer reaction in a patient with neurosyphilis. J Neurol Neurosurg Psychiatry 1994;57:865–867.

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47

ANTINEOPLASTIC AGENTS Richard Y. Wang / Paul Calabresi

doses of cisplatin were a result of errors in duration of administration (100 mg/m2 for 3–4 consecutive days instead of for a single day). Lack of healthcare-provider familiarity with the agent and its dosing was a major cause of these events. In another study evaluating drug errors, 49% occurred at the ordering/prescribing stage. This was most commonly caused by physicians who lacked knowledge of the drug and of the intended patient.155 Other areas in which errors occurred were during transcription and nurse administration. As more antineoplastic agents become available and their indications broaden, exposures will increase in number and frequency. In the last 10 years, the annual number of exposures reported to the AAPCC TESS increased 4-fold (Chap. 116 and page 1752). Most antineoplastic agents can be grouped into one of these four categories: alkylating agents, antimetabolites, antimitotics, and antibiotics (Table 47–1). The antimetabolites are grouped by the substrates with which they interfere. They include pyrimidine, purine, and folic acid antagonists. Methotrexate is a folate antagonist, and other agents with similar but lesser toxicity include trimethoprim and pyrimethamine. The antimitotics include the plant alkaloids (eg, vinca, taxanes, and epipodophyllotoxins). These agents exert toxic effects by interrupting microtubule assembly. The antibiotic agents are isolated from bacteria and comprise the anthracyclines bleomycin, mitomycin, and dactinomycin. The alkylating agents are more commonly used than their counterparts and cause covalent binding to nucleic acids, which inhibits DNA activity. These agents include the nitrogen mustards, platinoids, and nitrosoureas. The antimetabolites and the alkylating agents are cell-cycle active, meaning they only affect cells undergoing cell division. Some agents are phase specific; that is, they affect the cell only at a period during cell division. Vincristine is M (mitotic)-phase specific and cytarabine is S (DNA replication)-phase specific. Because the majority of the cases of antineoplastic agent overdoses involve the mustards, cisplatin, methotrexate, vincristine, and mitoxantrone (related to the anthracyclines), this discussion focuses on these agents.

A 70-year-old female was brought to the Emergency Department (ED) from an extended-care facility because of the sudden onset of epistaxis. Vital signs were blood pressure, 120/70 mm Hg; pulse, 100 beats/min; respiratory rate, 18 breaths/min; and temperature, 37°C (98.6°F). The patient stated that for the last 2 days she had dysphagia, progressive weakness, and intermittent shakes. The patient had a past medical history of rheumatoid arthritis and pulmonary emboli. The patient’s medications include methotrexate (MTX) and Coumadin, which were both started in the last month for her underlying medical disorders. An anterior nasal packing was placed to stop the bleeding. Further examination of the oropharynx demonstrated several ulcers. The skin showed ecchymoses. Chest and abdominal findings were unremarkable. A large-bore IV line was established, and blood was drawn for complete blood count (CBC) with platelets, prothrombin time (PT), partial thromboplastin time (PTT), electrolytes, blood urea nitrogen (BUN), and creatinine. Blood was also sent for an MTX level and a type and cross-match. The CBC showed hemoglobin, 8 g/dL; white cell count, 2000/mm3 (81% neutrophils, 13% lymphocytes, 1% monocytes, 5% eosinophils); platelet count, 3000/mm3; prothrombin time, 16.5 seconds; and international normalized ratio (INR), 2.0. PTT and renal function were normal. The extended-care facility was contacted, and it was discovered that the patient was inadvertently administered methotrexate 2.5 mg qd instead of once a week for 1 month. The patient was transfused with packed red blood cells, platelets, and fresh-frozen plasma. Prophylactic broad-spectrum antibiotics were initiated. Leucovorin 10 mg/m2 was started and administered every 4 hours IV. The serum MTX was determined later to be zero, and leucovorin therapy was discontinued. The white blood cell count (WBC) was lowest on day 3 of hospitalization and rose thereafter.

Overdoses of antineoplastic medications are infrequent; however, they are of greater consequence than many other medications because of their narrow therapeutic margin.160,217 From 1987 to 1999, 85% of the annual exposures to these agents that were reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System (AAPCC TESS) were unintentional (Chap. 116 and page 1752) Twenty percent of all reported exposures resulted in moderate or severe symptoms. A review of the 2819 orders for cytotoxic agents at a pharmacy satellite showed that 93 orders (3%) contained at least 1 error in the dosage regimen and 442 (16%) contained at least 1 error in the instructions for drug preparation.87 Three of the errors in dosage regimen were classified as potentially lethal, 13 as serious, 5 as significant, and 72 as minor. Two of the potentially lethal over-

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TABLE 47–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Classification of Antineoplastic Agents and Their Effects

Class

Agent

Adverse Effects

Alkylating

Busulphan

Hyperpigmentation, pulmonary fibrosis, hyperuricemia Hypotension, transaminitis, flulike syndrome Pulmonary fibrosis

Dacarbazine Melphalan Mustards Chlorambucil, Cyclophosphamide, Ifosfamide, Mechlorethamine Nitrosoureas Carmustine, Lomustine, Semustine Platinoids Cisplatin

Carboplatin, Iproplatin

Antimetabolite

Procarbazine Thiotepa Hydroxyurea Methotrexate Purine Analogues Chlordeoxyadenosine Fludarabine Mercaptopurine Pentostatin Thioguanine Pyrimidine Analogues Cytarabine Fluorouracil

Antimitotic

Epipodophyllotoxin Etoposide, Teniposide Paclitaxel Vinca Alkaloids Vinblastine, Vincristine, Vindesine

Antibiotics

Enzyme

Anthracyclines Daunorubicin, Doxorubicin, Epirubicin, Idarubicin Bleomycin Dactinomycin Mithramycin Mitomycin C Mitoxantrone L-Asparaginase

Hemmorrhagic cystitis, encephalopathy, pulmonary fibrosis

Overdose

Seizures, myocardial necrosis

Pulmonary fibrosis, transaminitis, renal insufficiency Renal failure, peripheral neuropathy, hypomagnesemia, hypocalcemia, hyponatremia, ototoxicity Myelosuppression, hypomagnesemia, hypocalcemia, hyponatremia MAOI activity

Seizures, encephalopathy, ototoxicity, retinal toxicity

Mucositis, nausea, diarrhea, transaminitis

Mucositis, myelosuppression, renal failure

Encephalopathy, muscle weakness Hyperuricemia, pancreatitis, cholestasis Transaminitis Hyperuricemia Acute lung injury, neuropathy, cerebellar ataxia Cardiogenic shock, cardiomyopathy, neuropathy, cerebellar ataxia CHF, hypotension GI perforation, peripheral neuropathy, dysrhythmias Peripheral neuropathy

Encephalopathy, seizures, autonomic instability, SIADH, paralytic ileus, myelosuppression

Congestive cardiomyopathy

Dysrhythmias, CHF

Pulmonary fibrosis Transaminitis Skin flushing Hemolytic uremic syndrome Congestive cardiomyopathy Hypersensitivity, pancreatitis

MTX is an important therapy for a variety of cancers, such as nonHodgkin lymphoma, lymphocytic leukemia, breast cancer, and small-cell lung carcinoma. Its immunosuppressive activity allows it to also be used for rheumatoid arthritis, organ transplantation, psoriasis, trophoblastic diseases, and therapeutic abortion.50,131 MTX’s therapeutic and toxic effects are based on its ability to limit DNA and RNA synthesis by inhibiting dihydrofolate reductase (DHFR) and thymidylate synthetase (Fig. 47–1). DHFR reduces folic acid to tetrahydrofolate (FH4), which serves as an

essential cofactor in the synthesis of purine nucleotides. These reduced folates are required by thymidylate synthetase to serve as methyl donors in the formation of thymidylate as well. Thymidylate is then used for DNA synthesis. MTX is a structural analogue of folate and competitively inhibits DHFR by binding to this substrate’s site of action. This stops reduced folate production, which is necessary for nucleotide formation and DNA/RNA synthesis. Administration of the reduced folate (folinic acid or leucovorin) allows for continual purine synthesis despite a blocked DHFR.

CHAPTER 47

Figure 47–1. Mechanism of methotrexate (MTX) toxicity. MTX inhibits DHFR activity, which is necessary for DNA and RNA synthesis. Leucovorin bypasses blockade to allow for continued synthesis.

Leucovorin is used as an antidote or rescue agent to limit the toxic effects of high-dose methotrexate therapy. The bioavailability of methotrexate appears to be limited by a saturable intestinal absorption mechanism. At doses less than 30 mg/m2, the absorption is 90%; at doses greater than 80 mg/m2, the absorption is less than 10–20%.35 The weekly adult dose used for the treatment of psoriasis and rheumatoid arthritis is low (ie, 7.5–15 mg) and can be administered orally. The dose used to induce abortion is higher (50 mg/m2 or 1 mg/kg) and must be administered parenterally to achieve effective drug concentrations. MTX dosing regimens for chemotherapy are variable, but can be generally classified as low dose—30–40 mg/m2 IV every 1–3 weeks; moderate dose—250–500 mg/m2 IV infusion every 2–3 weeks; and high dose—greater than 1000 mg/m2 (or 20 mg/kg) infusion every 2–3 weeks. Conventional doses of up to 100 mg/m2 can be administered without leucovorin rescue. Doses of 1000 mg/m2 are considered potentially lethal. Much higher doses (eg, 2–3 g/m2) can be given when MTX is followed by leucovorin in order to prevent life-threatening toxicity. Mortality from highdose MTX is about 6%, and occurs primarily when patients’ MTX levels are not monitored.84,239,259 Neurotoxicity may occur with high-dose therapy; however, the process reverses upon discontinuation of MTX treatment. The mechanisms remain unclear, but may be the result of direct toxicity to neuronal glial and endothelial cells and decreased neurotransmitter synthesis.2 MTX has a triphasic plasma clearance. The initial plasma distribution half-life is short—0.75 hours. The second half-life is 2–3.4 hours and represents renal clearance of the drug. The third phase has a half-life of about 8–10.4 hours and represents tissue redistribution into the plasma. This phase can be prolonged in the setting of renal failure and is associated with bone marrow and gastrointestinal (GI) toxicity. The kidneys eliminate 50–80% of MTX unchanged. At high doses, drug and insoluble drug metabolites—7-hydroxy methotrexate and 2,4-diamino-10-methyl pteroic acid—accumulate and may precipitate in the renal tubules, causing reversible acute tubular necrosis. MTX is one-tenth as soluble at a pH of 5.5 as it is at a pH of 7.5.35,219 The serum concentration threshold for nephrotoxicity is 2.2 mmol/L at a urine pH of 5.5, and 22 mmol/L at a urine pH of 6.9. Acute renal failure may result

ANTINEOPLASTIC AGENTS

707

from drug precipitation in the renal tubule, and is most common in patients who are inadequately hydrated or not alkalinized.3,90,133 The majority (90%) of MTX is excreted unchanged in the urine, within 48 hours, by both glomerular filtration and active tubular secretion. Folic acid blocks MTX renal reabsorption and can enhance drug elimination during leucovorin rescue.117 A small amount of MTX is metabolized intracellularly to polyglutamate derivatives, which inhibit DHFR and are believed to be responsible for MTX’s persistent cytotoxic effect. Toxicity of MTX is dependent more on the duration of concentration than the dose itself. Thus, greater toxicity is expected from a 7 g IV dose administered over 48 hours than from a 20 g dose administered over 24 hours.98 Patients with a plasma MTX concentration greater than 1.0 µmol/L at 48 hours posttreatment are considered at risk for bone marrow and gastrointestinal mucosal toxicity.239 Risk factors for MTX toxicity are impaired renal function (primary route of drug elimination), third compartment spacing (eg, ascites, pleural effusions), use of nonsteroidal anti-inflammatory drugs (NSAIDs), age, folate deficiency, and concurrent infection.239

Clinical Manifestations In the course of MTX therapy, a variety of disorders may occur, resulting from either increased patient susceptibility to toxicity or an excessive administration. The clinical manifestations of MTX toxicity include stomatitis, esophagitis, renal failure, and myelosuppression. Hepatitis and central neurologic system dysfunction may appear as well. In a group of 23 patients who received 45 courses of high-dose MTX therapy, the commonly observed signs included increased AST/ALT (81%), nausea and vomiting (66%), mucositis (33%), dermatitis (18%), leukopenia (11%), thrombocytopenia (9%), and creatinine elevation (7%).204 Nausea and vomiting, considered rare after low-dose therapy, typically begin 2–4 hours after high-dose therapy and last for about 6–12 hours. Mucositis, characterized by mouth soreness, stomatitis, or diarrhea, usually occurs 1–2 weeks after therapy and can last for 4–7 days. Other gastrointestinal symptoms resulting from MTX therapy include pharyngitis, anorexia, gastrointestinal hemorrhage, and toxic megacolon.15 Hepatotoxicity, as described by increased AST ( 4 mg digoxin in child > 10 mg digoxin in adult ≥ 5.0 mEq/L (acute)

Values greater than or equal to the action level necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical condition of the patient.

Steroid nucleus (cyclopentanoperhydrophenanthrene)

CH3 O

=

O OH

Aglycone, Genin (Basic cardenolide structure)

OH OH

laboratory results returned: serum sodium, 142 mEq/L; chloride, 114 mEq/L; potassium, 3.6 mEq/L; bicarbonate, 24 mEq/L; BUN, 12 mg/dL; creatinine, 1.4 mg/dL; glucose, 98 mg/dL; calcium, 9.8 mg/dL, magnesium, 2.0 mEq/L. Liver enzymes, amylase, and lipase were normal. Hematocrit was 37.8%. A serum digoxin level was pending. Fifteen minutes after the examination was completed, the patient vomited. Although her heart rate decreased to 30 beats/min, her blood pressure remained at 130/80 mm Hg. Atropine 1 mg IV was administered for the bradycardia with no response, and 5 vials of Digibind were administered IV. Within 20 minutes of the infusion of Digibind, her heart rate had increased to 86 beats/min. The initial digoxin level was 3.8 ng/mL.

A 92-year-old woman was brought to the hospital by her grandson. The grandson stated that she had lost her appetite for several days, refused her medications for 2 days, and had begun to vomit on the day of admission. The woman complained of being weak and having no appetite because of her constant nausea. Her grandson reported that 5 days prior to admission, she had initiated a course of clarithromycin for sinusitis, and her past medical history was significant for congestive heart failure and hypertension. Her medications included digoxin, furosemide, and enteric-coated aspirin. On presentation to the Emergency Department (ED) the patient was not in acute distress, laying quietly on the bed, alert and oriented to place and person. Her vital signs were blood pressure, 140/95 mm Hg; pulse, 50 beats/min and regular; respiratory rate, 16 breaths/min; and rectal temperature, 98.8°F (37.1°C). The woman weighed 55 kg. Her neck was supple; she had no jugular venous distension or carotid bruits. Lung examination revealed bibasilar rales. Heart examination revealed a normal S1 and S2 with an S3 gallop, but no murmurs were heard. Abdominal examination revealed increased bowel sounds, with no other abnormal findings. Examination of the patient’s extremities revealed 1+ pitting edema without clubbing, or cyanosis, and all pulses were 2+. Neurologic examination was nonfocal. The patient was attached to a cardiac monitor with continuous pulse oximetry. An IV line was inserted, and blood samples were obtained for complete blood count (CBC); electrolytes, including calcium and magnesium; blood urea nitrogen (BUN); creatinine; glucose; liver enzymes; amylase and lipase; digoxin; and salicylate levels. An initial rhythm strip and 12-lead electrocardiogram (ECG) revealed high-degree heart block with a ventricular rate of 30–50 beats/min (Fig. 48–1), which then converted into atrial flutter with variable block, and a ventricular response rate of 30–40 beats/min (Fig. 48–2). Transcutaneous pacer pads were placed on standby, and 5 vials of Digibind (digoxin-specific Fab) were requested. Stat

HISTORY AND EPIDEMIOLOGY Although there is evidence in the Ebers Papyrus (Papyrus Smith) that the Egyptians used plants containing cardiac glycosides at least 3000 years ago, it was not until William Withering wrote the first organized account about the effects of the foxglove plant in 1785 that its use was more widely accepted into the Western apothecary. The discussion and case reports of the 163 patients for whom Withering prescribed foxglove and his correspondence with other physicians on the subject, comprise the first work related to the medical use of cardiac glycosides. Foxglove was initially used as a diuretic and for the treatment of “dropsy,” and Withering eloquently described its “power over the motion of the heart, to a degree yet unobserved in any other medicine.”95 Subsequent to these reports, cardiac glycosides became the mainstay of treatment for chronic heart failure, and for the control the ventricular response rate in atrial tachydysrhythmias. Because of the widespread use of cardiac glycosides, both acute and

724

CHAPTER 48

Figure 48–1.

CARDIAC GLYCOSIDES

High-degree heart block with a ventricular rate of 30–50 beats/min.

Figure 48–2. The patient in Figure 48–1 subsequently converted into atrial flutter with variable block and a ventricular rate of 30–40 beats/min.

725

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

chronic toxicity has remained an important problem.62 According to the American Association of Poison Control Centers data, between the years 1995 and 1999 there were approximately 18,000 exposures to cardiac glycoside-containing products resulting in over 70 deaths. In 1999 it was noted that 75% of the deaths were a result of “therapeutic errors” (Chap. 116 and page 1752). Poisoning is typically encountered in the very young or the very old. In children most acute overdoses result from dosing errors, usually a decimal point error resulting in 10 times the appropriate dose, or inadvertent ingestions. Older patients more often have acute exposures related to intentional ingestion of the drug. Adults are also at risk for acute toxicity complicating a chronic regimen related to changes in chronic dosing or an alteration in the absorption or elimination kinetics, which results in an increased serum concentration of the drug. This may be caused by drug-drug interactions that change cardiac glycoside clearance in the liver or kidney, or from altered protein binding, or from coingested medications that increase the bioavailability. The most commonly prescribed cardiac glycoside in the United States is digoxin; other, less commonly used preparations are digitoxin, ouabain, lanatoside C, deslanoside, and gitalin. Cardiac glycoside poisoning also results from specific plant or animal ingestions. Documented sources of plant toxicities include oleander, foxglove, lily of the valley, dogbane, Siberian ginseng, and red squill; foods skewered and cooked with cardiac glycoside–containing plants and teas containing seeds of these plants; drinking contaminated water; and contaminated herbal products (Chap. 77).12,36,59,67,73,87 Cardiac glycoside poisoning also results from ingestion, instead of topical application, of a purported aphrodisiac derived from the dried secretion of the Bufo toad containing certain cardioactive bufadienolide-class agents.8,9,11

PHARMACOLOGY Cardiac glycosides all contain an aglycone or “genin” nucleus structure with a steroid core and an unsaturated lactone ring attached at C-17 and several sugars attached to C-3. Cardenolides are plant-derived aglycone structures with a 5-member unsaturated lactone ring. The bufadienolide group of cardioactive steroid molecules are mainly animal derived (with notable exceptions such as scillaren from red squill) and have a 6-member unsaturated lactone ring. Digoxigenin needs sugar residues to become a glycoside. Digoxin, which is the most widely prescribed cardiac glycoside in the United States, may be thought of as the model molecule for cardenolides. Digitoxin aglycone differs from digoxin aglycone by the lack of a hydroxyl group on C-12, and ouabain differs by both the absence of a hydroxyl group on C-12 and the addition of hydroxyl groups on C-1, 5, 10, and 11. These plant-derived aglycone molecules are linked to one or more hydrophilic sugar (digitoxoses) residues at C-3, which confer increased water solubility and enhanced ability to enter cells, to compose a cardiac glycoside. The cardioactive components in toad venom are genins, and lack sugar moieties. The clinical manifestations following the ingestion of cardiac glycoside-containing plants or toad venom are clinically indistinguishable from those following the ingestion of digoxin. Those patients with cardiac glycoside poisoning from plant or animal ingestion may differ from pharmaceutic digoxin ingestions by a low or nonexistent digoxin level (depending on the digoxin assay),

despite the persistence of toxicity and the need for large doses of digoxin-specific antibody fragments (Chaps. 77 and 78.)

Mechanisms of Action and Pathophysiology Electrophysiologic Effects on Inotropy. The cardiac glycosides increase the force of contraction of the heart (positive inotropic effect) because of an increase of cytosolic Ca2+ during systole. Both Na+ and Ca2+ ions enter and exit cardiac muscle cells during each cycle of depolarization, contraction, and repolarization. Sodium entry heralds the start of the action potential (phase 0) and carries the inward, depolarizing positive charge. Calcium enters the cardiac myocyte through L-type calcium channels during the plateau phase of depolarization, which subsequently triggers the release of more calcium into the cytosol from the sarcoplasmic reticulum. During repolarization and relaxation (diastole), calcium is pumped back into the sarcoplasmic reticulum by a local Ca2+-ATPase and is removed from the cytoplasm by an Na+-Ca2+ antiporter and a sarcolemmal Ca2+-ATPase58 (Fig. 48–3). All cardiac glycosides inhibit active transport of Na+ and K+ across cell membranes by binding to a specific site on the extracytoplasmic face of the
subunit of the membrane Na+-K+-ATPase preventing its normal function. This Na+-Ca2+ exchanger derives its power not from ATP but rather from the Na+ gradient generated by the Na+- K+ transport mechanism.18 The amount of intracellular Na+ determines how much Ca2+ is extruded from the cell. The cardiac glycosides bind to sarcolemmal Na+-K+-ATPase, and inhibit cellular Na+ pump activity, which decreases Na+ extrusion and increases Na+ in the cytosol, thereby decreasing the transmembrane Na+ gradient preventing extrusion of intracellular Ca2+ during repolarization. Small changes in intracellular Na+ concentration yield large increases in cardiac muscle shortening. Other proposed mechanisms under investigation for cardiac glycosides increasing cytosolic Ca2+ include an interaction with the L-type calcium channels, and interactions with the Ca2+-triggered calcium release from myocardial sarcoplasmic reticulum.41 Effects on Cardiac Conduction. At therapeutic levels, cardiac glycosides increase inotropy, increase automaticity, and shorten the repolarization intervals of the atria and ventricles (Table 48–1). There is a concurrent decrease in the rate of conduction through the SA and AV nodes with direct depression of this tissue and an indirect effect through an increase in vagally mediated parasympathetic tone. These changes in repolarization are reflected on the ECG by a decrease in ventricular response rate to suprajunctional rhythms, QT segment shortening, and ST segment and T-wave forces opposite in direction to the major QRS forces. That last effect results in the characteristic scooping of the ST segments (referred to as “digitalis effect”). Excessive increases in intracellular Ca2+ caused by excessive cardiac glycoside levels result in transient late depolarizations (delayed afterdepolarizations), which may initiate contractions.17,42 Effects of Cardiac Glycosides on the Autonomic Nervous System. Digitalis affects the parasympathetic system by increasing the release of acetylcholine from vagal fibers,55,86 possibly through augmentation of intracellular calcium. Cardiac glycosides affect the sympathetic system by increasing efferent sympathetic discharge,63,82 which, in turn, may exacerbate myocardial intracellular hypercalcemia.

CHAPTER 48

Ca ++

Na +

Ca ++

Na +

2K+

3Na +

Repolarization

Depolarization

---------

+++++++

+30

+30

Na +

727

CARDIAC GLYCOSIDES

Ca ++

mV

Ca ++

3Na +

mV -90

-90

t

t +

Ca ++

=

=

Ca ++

Ca ++

Calsequestrin

Calsequestrin

Ca ++ Myocardial cell

Myocardial cell A

B

Ca ++

Na +

2K+

X

Depolarization +++++++

+ Ca ++ 3Na

Na +

3Na +

Ca ++

Na +

X

Depolarization

-

+++++++

Ca ++

+ Ca ++ 3Na

Na +

3Na +

-

Ca ++

+

+

Ca ++

Ca ++

Ca ++

=

Ca ++

=

Ca ++

2K+

Calsequestrin

Calsequestrin Excess Ca++

Myocardial cell

Myocardial cell +30

C

mV -80 -90

↔

= Na +/K + ATPase = Na +/Ca ++ Antiporter = L-type calcium channel = Calcium release channel

t

D

Figure 48–3. A. Normal Depolarization. Depolarization occurs following the opening of fast Na+ channels; the rise in intracellular potential opens voltagedependent Ca2+ channels; the influx of Ca2+ induces the massive release of Ca2+ from the sarcoplasmic reticulum, producing contraction. B. Normal Repolarization. Repolarization begins with active expulsion of Na+ ions in exchange for K+ using an ATPase. This electrogenic (3 for 2) pump creates an Na+ gradient that is used to expel Ca2+ via an antiporter. The sarcoplasmic reticulum resequesters its Ca2+ load via a separate ATPase. C. Pharmacologic Cardiac Glycoside. Digitalis inhibition of the Na+/K+ ATPase raises the intracellular Na+ content, preventing the antiporter from expelling Ca2+ in exchange for Na+. The net result is an elevated intracellular Ca2+, resulting in enhanced inotropy. D. Toxic Cardiac Glycoside. Excessive elevation of the intracellular Ca2+ elevates the resting potential, producing myocardial sensitization, and predisposes to dysrhythmias. The addition of exogenous Ca2+ may overwhelm the capacity of the sarcoplasmic reticulum to sequester this ion, resulting in systolic arrest.

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

PART D

TABLE 48–1. Electrophysiologic Effects of Cardiac Glycoside on the Myocardium Atria and Ventricles

AV Node

Excitability

↑

—

Automaticity

↑

—

Conduction velocity Refractoriness

↓

↓

↓

↑

ECG Extrasystoles, tachydysrhythmias Extrasystoles, tachydysrhythmias ↑ PR interval, AV block ↑ PR interval, AV block, decreased QTc interval

Clinical Manifestations

PHARMACOKINETICS Whether an ingestion of cardiac glycosides will result in a toxic effect depends upon the preparation, mode of administration, amount absorbed, volume of distribution, route of administration, and drug-drug interactions, together with the pathophysiologic characteristics of the host (Table 48–2). Correlation between clinical effects and toxic serum levels are based on steady-state levels; measurement of a level before 6 hours after an ingestion gives misleadingly high levels, which reflect a biphasic distribution. After therapeutic dosing, the intravascular distribution and elimination of digoxin are best described by a two-compartment system with the first (the
phase) a 30-minute half-life and exponential decline because of rapid distribution from the blood volume to peripheral tissues. This phase is followed by an elimination phase (the  phase) with a half-life of 36–48 hours for total body clearance, which is achieved primarily by the kidneys (70% in a person

TABLE 48–2.

Pharmacology of Selected Cardiac Glycosides

Onset of Action

Digoxin

Digitoxin

Oral IV

1.5–6 h 5–30 min

3–6 h 30 min–2 h

4–6 h 1.5–3 h 40–90% (mean 75%) 25% 6–7 L/kg (adults) 16 L/kg (infants) 10 L/kg (neonates) 4–5 L/kg (adults with renal failure) 1.6 days Renal (60–80%), with limited hepatic metabolism 7%

6–12 h 4–8 h >95%

Maximal effect Oral IV Intestinal absorption Plasma protein binding Volume of distribution

Elimination half-life Route of elimination

Enterohepatic circulation

with normal renal function).13 After a massive digoxin ingestion the half-life may be shortened to as little as 13–15 hours. With therapeutic administration of cardiac glycosides, factors such as age, hypothyroidism, hepatic and renal disease associated with decreased creatinine clearance, hypokalemia, hypernatremia, alkalosis, hypercalcemia, hypomagnesemia, hypoxemia, myocardial disease, and cor pulmonale can all result in toxicity unless dosage and frequency regimens of the drug are appropriately adjusted. Drug interactions between digoxin and quinidine, verapamil, diltiazem, amiodarone, and spironolactone are common.15,31,49,68 In approximately 10–15% of the population, a significant amount of digoxin is inactivated in the gut by enteric bacterium, primarily Eubacterium lentum, and the reversal of this inactivation by erythromycin or tetracycline may result in increased bioavailability.53 Indeed, the use of certain antibiotics may produce as much as a 2-fold increase in serum cardiac glycoside concentration, potentially leading to toxicity.68

97% 0.6 L/kg (adults)

6–7 days Hepatic metabolism (80%)

26%

“The Foxglove when given in very large and quicklyrepeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow; increased secretion of urine, with frequent motion to part with it, and sometimes inability to retain it; slow pulse, even as low as 35 in a minute, cold sweats, convulsions, syncope, death.”95 In general, adults and children with cardiac glycoside poisoning present in a similar manner depending upon whether the exposure is acute or chronic. Both groups may present with either acute or chronic poisoning and while clinical manifestations differ, the types of poisoning are treated in similar manners. The following descriptions apply to both clinical situations. Noncardiac Toxicity Acute Toxicity. An asymptomatic period of several minutes to several hours may follow a single orally administered toxic dose of cardiac glycoside. The first symptom is typically nausea, vomiting, or abdominal pain. Central nervous system effects of acute toxicity may include lethargy, confusion, and weakness that are not caused by hemodynamic changes.12 Chronic Toxicity. Chronic toxicity is often difficult to diagnose secondary to its insidious development and protean manifestations. Symptoms may include those that occur with acute poisonings; however, they are often less obvious. Gastrointestinal symptoms include, anorexia, nausea, vomiting, abdominal pain, and weight loss. Neuropsychiatric disorders include delirium, confusion, disorientation, drowsiness, headache, hallucinations, or, rarely, convulsions.12,25,26 Visual disturbances include transient amblyopia, photophobia, blurring, scotomata, photopsia, decreased visual activity, and aberrations of color vision (chromatopsia), such as yellow halos (xanthopsia) around lights.50 Electrolyte Abnormalities. Elevated serum potassium levels frequently occur in patients with acute cardiac glycoside poisoning.42,45 Hyperkalemia in acute cardiac glycoside poisoning has important prognostic implications, as the serum potassium concentration is a better predictor of lethality than either the initial ECG changes or the serum cardiac glycoside concentration.4,5 In a

CHAPTER 48

study of 91 acutely digitalis-poisoned (digitoxin) patients conducted before digoxin-specific Fab was available, approximately 50% of the patients with serum potassium levels of 5.0–5.5 mEq/L died. Although a serum potassium level lower than 5.0 mEq was associated with no deaths, all of the 10 patients with serum potassium levels above 5.5 mEq died.4 This hyperkalemia causes further depolarization of myocardial conduction tissue, in particular increasing AV nodal block, thereby exacerbating cardiac glycoside–induced bradydysrhythmias and conduction delays.42 However, correction of hyperkalemia does not increase patient survival,4 as it is a marker of, and not the cause of, the morbidity and mortality associated with cardiac glycoside poisoning. Elevation of the serum potassium concentration after toxic as well as therapeutic administration of cardiac glycoside is a result of (a) the release of potassium from many tissues, including the liver; (b) cardiac glycoside inhibition of potassium uptake by skeletal muscle; and (c) cardiac glycoside inhibition of the cardiac Na+-K+ATPase pump. The interrelationships between intracellular and extracellular potassium and cardiac glycoside therapy are complex and not clearly understood. Hypokalemia resulting from a variety of mechanisms, such as the use of loop diuretics, poor dietary intake, diarrhea, and the administration of potassium binding resins, enhances the effects of cardiac glycosides on the myocardium and is associated with dysrhythmias at lower cardiac glycoside levels. Hypokalemia itself inhibits Na+-K+-ATPase activity and contributes to the pump inhibition induced by cardiac glycosides, enhances myocardial automaticity, and therefore increases myocardial susceptibility to cardiac glycoside–related dysrhythmias. This may be partly a result of decreased competitive inhibition between the cardiac glycoside and potassium at the Na+-K+-ATPase exchanger.71 Severe hypokalemia (5.0 mEq/L in setting of acute digoxin poisoning Chronic digoxin poisoning with dysrhythmias, significant gastrointestinal symptoms, or acute onset of significantly altered mental status, or renal insufficiency Serum digoxin concentration ≥15 ng/mL at any time, or ≥10 ng/mL 6 h postingestion Ingestion of 10 mg in adult Ingestion of 4 mg in a child To aid in treatment of suspected cardiac glycoside poisoning without a confirmatory level Poisoning by nondigoxin cardiac glycoside Digoxin Fab Dosing: (Round up vial calculation) No. of vials =

Digoxin serum concentration (ng / mL) × Pt Wt (kg) 100

No. of vials =

Amount ingested (mg) 0.5 (mg / vial)

Empiric therapy for acute poisoning:

CARDIAC GLYCOSIDES

731

Fifty-one patients were treated with cardiac pacing and/or digoxinspecific Fab, and the overall mortality rate was 13%. Prevention of life-threatening dysrhythmias failed in 8% of patients treated with immunotherapy and in 23% of patients treated with pacemakers. The main reason for failure of digoxin-specific Fab was pacing-induced dysrhythmias and delayed or insufficient administration of digoxin-specific Fab. Iatrogenic complications of pacing occurred in 36% of patients. Thus, overdrive suppression with a temporary transvenous pacemaker should not be used to abolish ventricular tachydysrhythmias in the presence of cardiac glycoside poisoning.5,85 The authors concluded that the pacemaker has limited utility in cardiac glycoside toxicity and encouraged early use of digoxin-specific Fab as first-line therapy.85 Transthoracic electrical cardioversion for atrial tachydysrhythmias in the setting of digoxin toxicity is both clinically and experimentally associated with the development of potentially lethal ventricular dysrhythmias. The dysrhythmias induced were similar to digoxin toxic rhythms, and seemed to be related to the degree of cardiac glycoside poisoning, and the amount of administered current.74 In cardiac glycoside–toxic patients with unstable rhythms such as ventricular tachycardia or ventricular fibrillation, cardioversion and defibrillation, respectively, are indicated.

10–20 vials (adult or pediatric) Empiric therapy for chronic poisoning: 3–6 vials (adult) 1–2 vials (pediatric)

been evaluated in this setting. Maintenance oral doses of phenytoin 300–400 mg/d in an adult and 6–10 mg/kg/d in a child should be continued until digoxin toxicity is resolved. Lidocaine is given as a 1.0–1.5 mg/kg IV bolus followed by continuous infusion at 1–4 mg/min in an adult, or given as a 1.0–1.5 mg/kg IV bolus followed by 30–50 µg/kg/min in a child, as required to control the rhythm disturbance. Fifteen minutes after the initial bolus, an additional 1 mg/kg IV bolus should be administered in an adult and child (Chap. 52). In general, class IA antidysrhythmic agents are contraindicated in the setting of cardiac glycoside poisoning because they may induce or worsen AV nodal block and decrease His-Purkinje conduction. IA antidysrhythmic agents may also induce ventricular dysrhythmias (prodysrhythmogenic effects). In patients with severe supraventricular bradydysrhythmias or high degrees of AV block, atropine 0.5 mg should be administered intravenously to an adult, or 0.02 mg/kg with a minimum of 0.1 mg to a child. Atropine should be titrated to block the vagotonic effects of the cardiac glycoside. The dose may be repeated at 5-minute intervals if necessary. Therapeutic success is unpredictable because the depressant actions of digitalis are mediated only in part through the vagus nerve. The use of isoproterenol should be avoided in digitalis-induced conduction disturbances, as there may be an increased incidence of ventricular ectopic activity in the presence of toxic levels of digitalis.

Pacemakers and Cardioversion External or transvenous pacemakers have limited indication since the availability of digoxin-specific Fab. In one retrospective study over a 6-year period, 92 digitalis-poisoned patients were studied.85

Electrolyte Therapy Potassium. Hypokalemia and hyperkalemia can exacerbate digitalis cardiotoxicity. When hypokalemia is noted in conjunction with tachydysrhythmias or bradydysrhythmias, potassium replacement should be given, with close monitoring of serum potassium, because iatrogenic hyperkalemia is detrimental and avoidable. In the presence of acute cardiac glycoside toxicity when potassium exceeds 5.0 mEq/L, digoxin-specific antibodies are probably indicated. Most investigators agree that when marked hyperkalemia develops in conjunction with ECG evidence of potassium toxicity and if digoxin-specific Fab is not available immediately, an attempt should be made to lower the serum potassium with IV insulin, dextrose, sodium bicarbonate, and oral administration of ion-exchange resins such as sodium polystyrene sulfonate. Caution should be used in the subsequent administration of Fab because the reinstitution of the exchange of Na+ for K+ causes hypokalemia which may be profound. In most hyperkalemic patients calcium chloride is beneficial, but in the presence of digitalis poisoning calcium may be disastrous, as intracellular hypercalcemia is already present. A number of experimental studies cite the additive or synergistic actions of calcium and cardiac glycosides on the heart, resulting in increasing dysrhythmias,24,61,79 cardiac dysfunction43 (eg, hypercontractility, hypocontractility), and cardiac arrest.52,79,90 Furthermore, 3 case reports7,46 of deaths in cardiac glycoside–poisoned patients following calcium administration support the withholding of bolus calcium administration in the setting of hyperkalemia caused by this specific etiology. The purported mechanism is augmented intracellular cytoplasmic calcium resulting from an increased transmembrane concentration gradient further inhibiting calcium extrusion through the Na+-Ca++ exchange and/or increased intracytoplasmic stores.41 This additional cytoplasmic calcium may result in altered contraction of myofibril organelles,43 altered ion exchange affecting intracellular electronegativity (resting potential and Phase 4) allowing afterdepolarizations to reach firing threshold,33,41,61 altered function of the sarcoplasmic reticulum,43,71 or increased calcium interfering with myocardial mitochondrial

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

function.43 Although some investigators suspect that the rate of administration of the calcium may be a factor in the subsequent cardiac toxicity,61,52 calcium administration should be avoided as there are better, safer alternative treatments available for cardiac glycoside-induced hyperkalemia (digoxin-specific Fab, insulin, sodium bicarbonate). Intractable ventricular fibrillation, ventricular tachycardia, or even a systolic arrest (the so-called “stone heart”) could ensue if additional calcium is administered, although the literature is unclear whether this effect is additive or synergistic.7,24,46,61,79 Magnesium. Hypomagnesemia may also occur in cardiac glycoside–poisoned patients secondary to the contributory factors mentioned with hypokalemia (eg, diuretic use, congestive heart failure). Concomitant hypomagnesemia may result in refractory hypokalemia despite potassium replacement. The theoretical benefits of magnesium therapy include transient inward calcium current blockade, antagonism of calcium at intracellular binding sites, decreased cardiac glycoside–related ventricular irritability, and blockade of potassium egress from cardiac glycoside–poisoned cells.3,19,38,66,75,83,93 Hypomagnesemia increases myocardial digoxin uptake and decreases cellular Na+-K+-ATPase activity. Patients with hypomagnesemia, hypokalemia, or both may become cardiotoxic even with therapeutic digitalis levels.93 The successful use of intravenous magnesium sulfate in the treatment of ventricular tachydysrhythmias caused by digoxin toxicity, even in the presence of elevated serum magnesium levels, is reported.44 The mechanism of efficacy of magnesium may be its ability to suppress early afterdepolarizations and its indirect antagonism of digoxin at the sarcolemma Na+-K+-ATPase pump. However, this treatment is only temporizing until digoxin-specific Fab is available for definitive therapy, and is not advocated as first-line therapy. The precise dosing of magnesium sulfate in digitalis-poisoned patients is not established.3,19,38,44,66,75,93 A common regimen uses 2 g of magnesium sulfate IV over 20 minutes in an adult, or 25–50 mg/kg/dose to a maximum of 2 g in a child. Following stabilization, a patient with severe hypomagnesemia may require a magnesium infusion of 1–2 g/h in an adult or 25–50 mg/kg/h to a maximum of 2 g in a child with serial monitoring of serum magnesium levels, telemetry, respiratory rate (observing for bradypnea), deep-tendon reflexes (observing for hyporeflexia), and monitoring of blood pressure. Magnesium is contraindicated in the setting of bradycardia or atrioventricular block. Extracorporal Removal. Forced diuresis,47 hemoperfusion,57,91 and hemodialysis 91 are ineffective in enhancing the elimination of digoxin because of its large volume of distribution (4–10 L/kg), which makes it relatively inaccessible to these techniques. Because of its high affinity for tissue proteins, approximately 10–50 times less digoxin is found in the serum than is found at the tissue level, and of that amount approximately 20–40% is proteinbound.39

SUMMARY Cardiac glycosides have a narrow therapeutic index. Signs and symptoms of cardiac glycoside toxicity range from subtle to profound. Both cardiac and noncardiac effects follow cardiac glycoside poisoning. A systematic approach toward treating patients

utilizing basic supportive and decontamination management techniques, supplemented by the early administration of immunotherapy, can significantly reduce morbidity and mortality in these high-risk patients.

ACKNOWLEDGMENTS Mary Ann Howland, PharmD, and Robert H. Kirstein, MD, contributed to this chapter in a previous edition.

REFERENCES 1. Banner W, Bach P, Burk B, et al: Influence of assay methods on serum concentrations of digoxin during Fab fragment treatments. J Toxicol Clin Toxicol 1992;30:259–267. 2. Bayer MJ: Recognition and management of digitalis intoxication: Implications for emergency medicine. Am J Emerg Med 1991;9(Suppl 1): 29–32. 3. Beller GA, Hood WB, Smith TW, et al: Correlation of serum magnesium level and cardiac digitalis intoxication. Am J Cardiol 1974;33: 225–229. 4. Bismuth C, Gaultier M, Conso F, Efthymiou ML: Hyperkalemia in acute digitalis poisoning: Prognostic significance and therapeutic implications. Clin Toxicol 1973;6:153–162. 5. Bismuth C, Motte G, Conso F, Chauvin M: Acute digitoxin intoxication treated by intracardiac pacemaker: Experience in sixty-eight patients. Clin Toxicol 1977;10:443–456. 6. Blaustein MP: Physiologic effects of endogenous ouabain: Control of intracellular Ca2+ stores and cell responsiveness. Am J Physiol 1993; 264:C1367–C1387. 7. Bower JO, Mengle HAK: The additive effect of calcium and digitalis. JAMA 1936;106:1151–1153. 8. Brubacher JR, Hoffman RS, Bania T, et al: Deaths associated with a purported aphrodisiac. New York City, February 1993–May 1995. MMWR Morb Mortal Wkly Rep 1995;44:853–855. 9. Brubacher JR, Ravikumar PR, Bania T, et al: Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest 1996; 110:1282–1288. 10. Carver JL, Valdes R: Anomalous serum digoxin concentrations in uremia. Ann Intern Med 1983;98:483–484. 11. Chern MS, Ray CY, Wu DL: Biological intoxication due to digitalislike substance after ingestion of cooked toad soup. Am J Cardiol 1991;67:443–444. 12. Cooke D: The use of central nervous system manifestations in the early detection of digitalis toxicity. Heart Lung 1993;22:477–481. 13. Critchley JA, Critchley LA: Digoxin toxicity in chronic renal failure: Treatment by multiple-dose activated charcoal intestinal dialysis. Hum Exp Toxicol 1997;16:733–735. 14. Cummins RO, Haulman J, Quan L: Near-fatal yew berry intoxication treated with external cardiac pacing and digoxin-specific Fab antibody fragments. Ann Emerg Med 1990;19:38–43. 15. Doering W: Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications. N Engl J Med 1979;301: 400–404. 16. Doolittle MH, Lincoln K, Graves SW: Unexplained increase in serum digoxin: A case report. Clin Chem 1994;40:487–492. 17. Eisner DA, Lederer WJ, Vaughan-Jones RD: The quantitative relationship between twitch tension and intracellular sodium activity in sheep cardiac Purkinje fibres. J Physiol 1984;355:251–266. 18. Eisner DA, Smith TW: The Na-K pump and its effect in cardiac muscle. In: Fozzard HA, ed: The Heart and Cardiovascular System, 2nd ed. New York, Raven Press, 1991, pp. 863–902. 19. French JH, Thomas RG, Siskind AP, et al: Magnesium therapy in massive digoxin intoxication. Ann Emerg Med 1984;13:562–566.

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20. Friedman HS, Abramowitz I, Nguyen T, et al: Urinary digoxin-like immunoreactive substance in pregnancy. Am J Med 1987;83: 261–264. 21. George S, Brathwaite RA, Hughes EA: Digoxin measurements following plasma ultrafiltration in two patients with digoxin toxicity treated with specific Fab fragments. Ann Clin Biochem 1994;31: 380–381. 22. Giampietro O, Clerico A, Gregori G, et al: Increased urinary excretion of digoxin-like immunoreactive substance by insulin-dependent diabetic patients: A linkage with hypertension? Clin Chem 1988;34: 2418–2422. 23. Gibb T, Adams PC, Parnham AJ, Jennings K: Plasma digoxin: Assay anomalies in Fab-treated patients. Br J Clin Pharmacol 1983;16: 445–447. 24. Gold H, Edwards DJ: The effects of ouabain on heart in the presence of hypercalcemia. Am Heart J 1927;3:45–50. 25. Gorelick DA, Kussin SZ, Kahn I: Paranoid delusions and auditory hallucinations associated with digoxin intoxication. J Nerv Ment Dis 1978;166:817–819. 26. Graves SW, Adler G, Stuenkel C, et al: Increases in plasma digitalisinduced hypoglycemia. Neuroendocrinology 1989; 49:586–591. 27. Graves SW, Brown BA, Valdes R: Digoxin-like substances measured in patients with renal impairment. Ann Intern Med 1983;99: 604–608. 28. Graves SW, Valdes R, Brown BA, et al: Endogenous immunoreactive digoxin-like substance in human pregnancies. J Clin Endocrinol Metab 1984;58:748–751. 29. Graves SW: Endogenous digitalis-like factors. Crit Rev Clin Lab Sci 1986;23:177–200. 30. Haddy FJ: Endogenous digitalis-like factor or factors [letter]. N Engl J Med 1987;316:621–622. 31. Hager WD, Fenster P, Mayersohn M, et al: Digoxin-quinidine interaction: Pharmacokinetic evaluation. N Engl J Med 1979;300: 1238–1241. 32. Hastreiter AR, John EG, van der Horst RL: Digitalis, digitalis antibodies, digitalis-like immunoreactive substances, and sodium homeostasis: A review. Clin Perinatol 1988;15:491–522. 33. Hauptman PJ, Kelly RA: Digitalis. Circulation 1999;99:1265–1270. 34. Henderson RP, Solomon CP: Use of cholestyramine in the treatment of digoxin intoxication. Arch Intern Med 1988;148:745–746. 35. Hilton PJ, White G, Lord A, et al: An inhibitor of the sodium pump obtained from human placenta. Lancet 1996;348:303–305. 36. Hollman A: Plants and cardiac glycosides. Br Heart J 1985;54: 258–261. 37. Isensee L, Solomon RJ, Weinberg MS, et al: Digoxin levels in dialysis patients. Hosp Physician 1988;24:50–52. 38. Karkal SS, Ordog G, Wasserberg J: Digitalis intoxication: Dealing rapidly and effectively with a complex cardiac toxidrome. Emerg Med Rep 1991;12:29–44. 39. Katzung BG, Parmley WM: Cardiac glycosides & other drugs used in congestive heart failure. In: Katzung BG, ed: Basic & Clinical Pharmacology, 7th ed. Stamford, CT, Appleton & Lange, 1998, pp. 197–215. 40. Kelly RA, Smith TW: Endogenous cardiac glycosides. Adv Pharmacol 1994;25:263–288. 41. Kelly RA, Smith TW: Pharmacological treatment of heart failure. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, eds: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996, pp. 809–838. 42. Kelly RA, Smith TW: Recognition and management of digitalis toxicity. Am J Cardiol 1992;69:108–109. 43. Khatter JC, Agbanyo M, Navaratnam S, Nero B, et al: Digitalis cardiotoxicity: Cellular calcium overload as a possible mechanism. Basic Res Cardiol 1989;84:553–563. 44. Kinlay S, Buckley N: Magnesium sulfate in the treatment of ventricular arrhythmias due to digoxin toxicity. J Toxicol Clin Toxicol 1995; 33:55–59.

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45. Klausen T, Kjeldsen K, Norgaard A: Effects of denervation on sodium, potassium and [3H] ouabain binding in muscles of normal and potassium depleted rats. J Physiol 1983;345:123–124. 46. Kne T, Brokaw M, Wax P: Fatality from calcium chloride in a chronic digoxin toxic patient. J Toxicol Clin Toxicol 1997;5:505. 47. Koren G, Klein J: Enhancement of digoxin clearance by mannitol diuresis: In vivo studies and their clinical implications. Vet Hum Toxicol 1988;30:25–27. 48. Lalonde RL, Deshpande R, Hamilton PP, et al: Acceleration of digoxin clearance by activated charcoal. Clin Pharmacol Ther 1985; 37:367–371. 49. Leahy EB Jr, Reiffel JA, Drusin RE, et al: Interaction between quinidine and digoxin. JAMA 1978;240:533–534. 50. Lee TC: Van Gogh’s vision. JAMA 1981;245:727–729. 51. Levy G: Gastrointestinal clearance of drugs with activated charcoal. N Engl J Med 1982;307:676–678. 52. Lieberman AL: Studies on calcium VI. Some interrelationships of the cardiac activities of calcium gluconate and scillaren-B. J Pharmacol Exp Ther 1933;47:183–192. 53. Lindenbaum J, Rund DG, Butler VP: Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy. N Engl J Med 1981;305: 789–794. 54. Lown B, Byatt NF, Levine HD: Paroxysmal atrial tachycardia with block. Circulation 1960;21:129–143. 55. Madan BR, Khanna NK, Soni RK: Effect of some arrhythmogenic agents upon the acetylcholine content of the rabbit atria. J Pharm Pharmacol 1970;22:621–622. 56. Mahdyoon H, Battilana G, Rosman H, et al: The evolving pattern of digoxin intoxication: Observations at a large urban hospital from 1980 to 1988. Am Heart J 1990;120:1189–1194. 57. Marbury T, Mahoney J, Juncos L, et al: Advanced digoxin toxicity in renal failure: Treatment with charcoal hemoperfusion. South Med J 1979;72:279–282. 58. McGary SJ, Williams AJ: Digoxin activates sarcoplasmic reticulum Ca2+ release channels: A possible role in cardiac inotropy. Br J Pharmacol 1993;108:1043–1050. 59. McRae S: Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. Can Med Assoc J 1996;155:292–295. 60. Nanji AA, Greenway DC: Falsely raised plasma digoxin concentrations in liver disease. Br Med J 1985;290:432–433. 61. Nola GT, Pope S, Harrison DC: Assessment of the synergistic relationship between serum calcium and digitalis. Am Heart J 1970;79: 499–507. 62. Ordog GJ, Benaron S, Bhasin V, et al: Serum digoxin levels and mortality in 5,100 patients. Ann Emerg Med 1987;16:32–39. 63. Pace DG, Gillis RA: Neuroexcitatory effects of digoxin in the cat. J Pharmacol Exp Ther 1976;199:583–600. 64. Pond S, Jacos M, Marks J, et al: Treatment of digitoxin overdose with oral activated charcoal. Lancet 1981;2:1177–1178. 65. Rabetory GM, Price CA, Findlay JWA, et al: Treatment of digoxin intoxication in a renal failure patient with digoxin-specific antibody fragments and plasmapheresis. Am J Nephrol 1990;10:518–521. 66. Reisdorff EJ, Clark MR, Walter BL: Acute digitalis poisoning: The role of intravenous magnesium sulfate. J Emerg Med 1986;4: 463–469. 67. Rich SA, Libera JM, Locke RJ: Treatment of foxglove extract poisoning with digoxin-specific Fab fragments. Ann Emerg Med 1993;22: 1904–1907. 68. Rodin SM, Johnson BF: Pharmacokinetic interactions with digoxin. Clin Pharmacokinetic 1988;15:227–244. 69. Rose AM, Valdes R: Understanding the sodium pump and its relevance to disease. Clin Chem 1994;40:1674–1685. 70. Rosen MR, Wit AL, Hoffman BF: Cardiac antiarrhythmic and toxic effects of digitalis. Am Heart J 1975;89:391–399. 71. Rosen MR: Cellular electrophysiology of digitalis toxicity. J Am Coll Cardiol 1985;2:22A–34A. 72. Rumack BH, Wolfe RR, Gilfinch H: Diphenylhydantoin treatment of massive digoxin overdose. Br Heart J 1974;36:405–408.

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73. Safadi R, Levy T, Amitai Y, et al: Beneficial effect of digoxin-specific Fab antibody fragments in oleander intoxication. Arch Intern Med 1995;155:2121–2125. 74. Sarubbi B, Ducceschi V, D’Antonello A, et al: Atrial fibrillation: What are the effects of drug therapy on the effectiveness and complications of electrical cardioversion? Can J Cardiol 1998;14: 1267–1273. 75. Seller RH: The role of magnesium in digitalis toxicity. Am Heart J 1971;82:551–556. 76. Selzer A: Role of serum digoxin assay in patient management. J Am Coll Cardiol 1985;5:106A–110A. 77. Shilo LM, Adawi A, Solomon G, Shenkman L: Endogenous digoxinlike immunoreactivity in congestive heart failure. Br Med J 1987; 295:415–416. 78. Silber B, Sheiner LB, Powers JL, et al: Spironolactone-associated digoxin radioimmunoassay interference. Clin Chem 1979;25:48–54. 79. Smith PK, Winkler AW, Hoff HE: Calcium and digitalis synergism: The toxicity of calcium salts injected intravenously into digitalized animals. Arch Intern Med 1939;64:322–328. 80. Smith TW, Haber E, Yeatman L, et al: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294:797–800. 81. Smith TW: Digitalis. N Engl J Med 1988;318:358–365. 82. Somberg JC, Bounous H, Levitt B: The antiarrhythmic effects of quinidine and propranolol in the ouabain-intoxicated spinally transected cat. Eur J Pharmacol 1979;54:161–166. 83. Spechter MJ, Schweizer E, Goldman RH: Studies on magnesium’s mechanism of action in digitalis-induced arrhythmias. Circulation 1975;52:1001–1005. 84. Sullivan JB: Immunotherapy in the poisoned patient. Med Toxicol 1986;1:47–60. 85. Taboulet P, Baud FJ, Bismuth C, et al: Acute digitalis intoxication: Is pacing still appropriate? J Toxicol Clin Toxicol 1993;31:261–273.

86. Torsti P: Acetylcholine content and cholinesterase activities in the rabbit heart in experimental heart failure and the effect of g-strophanthin treatment on them. Ann Med Exp Biol Fenn 1959;37(Suppl 4): 4–9. 87. Tuncok Y, Kozan O, Cavdar C, et al: Urginea maritima (squill) toxicity. J Toxicol Clin Toxicol 1995;33:83–86. 88. Valdes R, Graves SW, Brown BA, et al: Endogenous substances in newborn infants causing false-positive digoxin measurements. J Pediatr 1983;102:947–950. 89. Valdes R, Hagberg JM, Vaughn TE, et al: Endogenous digoxin-like immunoreactivity in blood is increased during prolonged strenuous exercise. Life Sci 1988;42:103–110. 90. Wagner J, Salzer WW: Calcium-dependent toxic effects of digoxin in isolated myocardial preparations. Arch Int Pharmacodyn 1976;223: 4–14. 91. Warren SE, Fanestil DD: Digoxin overdose: Limitations of hemoperfusion-hemodialysis treatment. JAMA 1979;242:2100–2101. 92. Watson WA: Factors influencing the clinical efficacy of activated charcoal. Drug Intell Clin Pharm 1987;21:160–166. 93. Whang R, Aikawa J: Magnesium deficiency and refractoriness to potassium repletion. J Chron Dis 1977;30:65–68. 94. Wildicks EFM, Vermeulen M, van Brummelen P, et al: Digoxin-like immunoreactive substance in patients with aneurysmal subarachnoid hemorrhage. Br Med J 1987;294:729–732. 95. Withering W: An account of the foxglove and some of its medical uses: With practical remarks on dropsy and other diseases. Med Classics 1937;2:295–443. 96. Woolf AD, Wenger T, Smith TW, et al: The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med 1992;326:1739–1744.

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ANTIDOTES IN DEPTH

Digoxin-Specific Antibody Fragments (Fab) Mary Ann Howland Digoxin-specific antibody fragments (Fab) are indicated for the management of patients with toxicity related to digoxin, digitoxin, and all natural cardiac glycosides, including oleander, squill, and toad venom. Digoxin-specific antibody fragments have an excellent record of efficacy and safety, and should be administered early in established and suspected digoxin and digoxinlike cardiac steroid poisoning.

HISTORY The production of antibody fragments to treat patients poisoned with digoxin was initiated subsequent to the development of digoxin antibodies for measuring serum digoxin concentrations by radioimmunoassay (RIA).10 The RIA technique permitted the correlation between serum digoxin concentrations and clinical digoxin toxicity. One of the earliest prospective studies of patients receiving therapeutic digoxin demonstrated that toxic patients had statistically significantly higher mean serum digoxin concentrations (2.3 ± 1.6 ng/mL) than nontoxic patients (1.0 ± 0.5 ng/mL), although considerable overlap was present (29% of the toxic group had levels less than 1.7 ng/mL and 15% of the nontoxic group had levels greater than 1.7 ng/mL).3 Subsequent studies reaffirmed the benefits of appropriate monitoring of serum digoxin concentrations.16,17,46 Butler and Chen suggested that purified digoxin antibodies with a high affinity and specificity should be developed to treat digoxin toxicity in humans.10 The digoxin molecule alone, with a molecular weight of 780 daltons, would be too small to be immunogenic. But digoxin could function as a hapten when joined to an immunogenic protein carrier such as serum albumin. These investigators immunized sheep with this conjugate to generate antibodies. The immunized sheep subsequently produced a mixture of antibodies that included antialbumin antibodies and antidigoxin antibodies. The antibodies were separated and highly purified to retain the digoxin antibodies while removing the antibodies to the albumin and all other extraneous proteins. The antibodies developed have a high affinity for digoxin and sufficient cross-reactivity with digitoxin to be clinically useful for the treatment of poisoning from either agent. Moreover, the specificity is so significant that endogenous steroids, which resemble digoxin structurally, are not affected by antibody administration. In vitro studies followed by in vivo studies in animals demonstrated biologic activity of these antibodies.12,15,57,58 Investigations proceeded and contributed significantly to understanding of the pharmacodynamics and pharmacokinetics of the antibodies.11,39,65 Intact IgG antidigoxin antibodies reversed digoxin toxicity in dogs. Unfortunately, the urinary excretion of digoxin was delayed, and free digoxin was released later after antibody degradation occurred. Furthermore, concern for hypersensitivity reactions also existed. To make these antibodies safe and effective in humans,

the whole IgG antidigoxin antibodies were cleaved with papain, yielding 2 antigen-binding Fab with a molecular weight of 50,000 daltons each and 1 Fc.11 Because the Fc does not bind antigen, but it does increase the potential for hypersensitivity reactions, it was eliminated. The advantages of the digoxin-specific Fab when compared to the whole IgG antibodies include larger volume of distribution, more rapid onset of action, smaller risk of adverse immunologic effects, and more rapid elimination.11,39,41 Ultimately, the commercial product (Digibind) is a relatively pure Fab product that is very safe and extremely effective. Other commercial products are now available abroad and may be available in the United States shortly.

MECHANISM OF ACTION OF DIGOXIN-SPECIFIC ANTIBODIES Immediately following IV administration, Fab digoxin-specific antibodies bind intravascular free digoxin. They then diffuse into the interstitial space, binding free digoxin there. This accounts for the 3-fold larger apparent volume of distribution (Vd) at steady state.68 A concentration gradient is then established, which facilitates movement of the free intracellular digoxin and digoxin that is dissociated from its binding sites (the external surface of Na+-K+ATPase enzyme) in the heart, into the interstitial or intravascular spaces. The binding affinity of Digibind for digoxin is about 109–1011, which is greater than the affinity of digoxin for the Na+K+-ATPase pump receptor. Intravascular concentrations of inactive, antibody-bound digoxin rise substantially. The elimination kinetics of the Fab-bound digoxin are dependent on the patient’s renal function and capacity for renal and nonrenal elimination.

EFFICACY OF DIGOXIN-SPECIFIC ANTIBODIES One hundred twenty-five patients with a median age of 65 years (all ≥16 years) and 25 patients with a median age of 3 years were treated.1 Forty-nine percent of cases involved a single unintentional or suicidal overdose, and the remainder involved patients on chronic digitalis therapy. Of the 150 patients treated, 148 were evaluated for cardiovascular manifestations of toxicity: 79 patients (55%) had high-grade AV block, 68 (46%) had refractory ventricular tachycardia, 49 (33%) had ventricular fibrillation, and 56 (37%) had hyperkalemia. Ninety percent of patients had a response to digoxin-specific Fab within minutes to several hours of Digibind administration. Complete resolution of all signs and symptoms of digoxin toxicity occurred in 80% of cases. A partial response was observed in 10% of patients, and of the 15 patients who did not respond, 14 were moribund or actually found not to be digoxin toxic. The spectacular success of digoxin-specific Fab for patients with digoxin toxicity is demonstrated by the fact that of the 56 patients who had cardiac arrest caused by digoxin, 54% survived hospitalization, as compared with 100% mortality before the advent of these fragments.1,5 Newborns, infants, and children

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have all been successfully treated with Digibind.4,32,59 Pediatric patients with cardiac abnormalities who develop chronic digoxin toxicity require small doses of Fab because the total body burden of digoxin is small, whereas children with acute overdoses require Fab doses based on the amount of digoxin ingested, in a manner similar to adults.

PHARMACOKINETICS AND PHARMACODYNAMICS In 1976, Smith and associates described the first clinical use of digoxin-specific antibody fragments in a human.56 Within 1 hour of administration, free (unbound and active) digoxin dropped to an undetectable level. It did not rise until 9 hours later, and the free digoxin reached a peak of only 2 ng/mL at 16 hours and remained at approximately 1.5 ng/mL for the next 40 hours.64 Total (free plus bound) digoxin, which was 17.6 ng/mL before digoxin-specific antibody fragments were given, rose to 226 ng/mL 1 hour after the start of the infusion, remained there for 11 hours, and then fell over the next 44 hours, with a half-life of 20 hours.64 Fab concentrations peaked at the end of the infusion and then apparently exhibited a biphasic or triphasic decline, probably reflecting distribution into different compartments as well as excretion and catabolism. An analysis of renal elimination based on an incomplete collection suggested that digoxin was excreted only in the bound form during the first 6 hours, but by 30 hours after Fab administration all digoxin was free digoxin. However, the amount of free digoxin is dependent on the dose of Fab as compared to the total body load of digoxin. The pharmacokinetics of Fab were evaluated in two different studies of 33 adult patients (total) who had attempted suicide.52,56 The distribution half-life was 1.1–1.5 hours. Data from 11 patients in the first study were used to calculate a median total body digoxin-specific Fab clearance of 24.5 mL/min, of which 13.6 mL/min was renal clearance. The second study demonstrated a total body clearance of 18 mL/min, which was directly related to creatinine clearance and age.52 The apparent distribution volume for the Fab in the first study varied from 25.4 to 54 L, depending on when the calculation was made, and averaged 20 L in the second study.52,56 In the first 11 patients, the dose was 400–480 mg (10–12 vials), infused over 0.5–5 hours. In the last 6 patients, 160 mg (4 vials) was given as a loading dose over 15 minutes, followed by an additional 160 mg given over 7 hours. If the Fab is given so rapidly that elimination occurs before redistribution of digoxin from the binding sites, the total amount of Fab actually bound to digoxin is less than the predicted or the optimal amount, and digoxin levels may once again increase. In the first 11 patients, the ratio of bound to unbound digoxin-specific Fab was about 50%, free digoxin concentrations appeared earlier, and maximum levels were higher than in the subsequent 6 patients. In those 6 patients who received a loading dose followed by a maintenance infusion, the amount of bound Fab was 70%, indicating a more effective access of Fab to digoxin. Free digoxin levels reappeared at 12–24 hours and maximum levels averaged only 2.2 ng/mL (0–4.4 ng/mL).56 A pharmacokinetic study in a rat model using a monoclonal Fab that cross-reacted well with digoxin and active digoxin metabolites evaluated the effects of dose and timing on efficacy.53 Administration of Fab was more effective prior to complete distri-

bution of digoxin. Postdistribution, increasing the dose of Fab improved efficacy as measured by comparing the area-under-thetime-versus-concentration-curve (AUC) of digoxin to that of the Fab-digoxin complex.53 These findings53,56 suggest some important points. It is more logical to give a loading dose of Fab followed by a maintenance infusion to optimize the binding of digoxin to Fab. The loading dose immediately captures digoxin already in the vascular space and digoxin that can be rapidly redistributed to the vascular space. The maintenance dose provides enough Fab to bind any digoxin that redistributes from the tissues into the serum. It appears that in acute intentional overdose, 4–6 vials given as a loading dose, followed by 0.5 mg/min for 8 hours, and then followed by 0.1 mg/min for about 6 hours should be safe, effective, and efficient.56 More patients should be studied and the protocol validated before this approach can be generally adopted or recommended. The other important issue raised by these authors is that the apparent volume of distribution (Vd) of Fab suggests that the molecule does enter the cells in spite of a molecular weight of 50,000 daltons.56 Additional pharmacokinetic studies indicate that in renal failure, the half-life of Fab is prolonged 10-fold with no change in the apparent Vd.68 Fab serum concentrations remain detectable for 2–3 weeks. Total digoxin serum concentrations generally follow Fab. There is no evidence for dissociation of digoxin-Fab over time.74 However, there is a rebound in free digoxin levels that appears later, up to 130 hours following administration, in patients with renal dysfunction, as compared to 12–24 hours in patients with normal renal function.14,18,21,34,43,44,60,62,69,70,74 This rebound is presumed secondary to changes associated with digoxin redistribution to vascular space in the absence of any Fab. The rebound is delayed in patients with renal dysfunction presumably secondary to prolonged distribution and elimination phases.

SAFETY OF DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS Digoxin-specific antibody fragments are effective, as well as very safe. In the multicenter study of 150 patients, the only acute clinical manifestations were hypokalemia in 6 patients (4%), worsening of congestive heart failure in 4 patients (3%), and transient apnea in a several-hours-old neonate.1 There were no other reactions reported in any of the patients in this series, although vigilance should continue with regard to concern for allergic reactions and serum sickness. In a postmarketing surveillance study of Digibind that included 451 patients, however, 2 patients with a prior history of allergy to antibiotics reportedly developed rashes.49 One of these patients developed a total body rash, facial swelling, and a flush during the infusion. The other experienced a pruritic rash. Two other adverse reactions (thrombocytopenia and shaking chills) were probably unrelated to the use of Digibind.49 One patient received Digibind on 3 separate occasions over the course of 1 year for multiple suicide attempts with no adverse effects.7

INDICATIONS FOR DIGOXIN-SPECIFIC FAB To define the indications for digoxin-specific Fab, the signs and symptoms of digoxin toxicity must be recognized.19,63 In general, the manifestations of digoxin toxicity are exaggerations of the

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pharmacologic effects or alterations of these effects caused by ingestion of a single large dose (suicidal or unintentional) or accumulation from chronic dosing, the presence or absence of cardiac pathology, or the patient’s age.19,63 Pediatric patients with normal cardiac function generally tolerate higher µg/kg dosages of digoxin than do adults. Potassium concentrations in these children tend to remain in the therapeutic range except in extreme circumstances. Serum potassium concentrations result from a balance between the degree and extent of inhibition of the Na+-K+-ATPase pump and the patient’s renal function.19,63 Both adults and children with diseased hearts become digoxin toxic at lower levels of toxic exposure than their respective healthy counterparts. In the chronically exposed patient, the magnitude of Na+-K+-ATPase enzyme inhibition in the heart and throughout the body is less extensive prior to the development of symptoms. Many patients who chronically receive digoxin also receive diuretics, which may contribute to smaller rises in serum potassium levels in these patients. Adult patients who ingest a large, single dose of digoxin or digitoxin have extensive Na+-K+-ATPase inhibition, and, consequently, have significant elevations in potassium. When hyperkalemia occurred, before the advent of digoxin-specific Fab, rises in potassium above 5.0 or 5.5 mEq/L indicated a 50 or 100% probability of death, respectively.5 Digoxin-specific antibody fragments are indicated for potentially life-threatening digoxin or digitoxin toxicity.48 Patients with progressive bradydysrhythmias, including severe sinus bradycardia or second- or third-degree heart block unresponsive to atropine, and those patients with severe ventricular dysrhythmias, including ventricular tachycardia or ventricular fibrillation, should be treated with digoxin-specific antibody fragments. A ventricular tachycardia with a fascicular block is likely to be a digoxin-toxic rhythm.40 Any patient with a potassium concentration exceeding 5 mEq/L should also be treated. Acute ingestions greater than 4 mg in a healthy child, or 10 mg in a healthy adult, probably require antibody treatment. Serum digoxin concentrations do not correlate with myocardial concentrations and are not stable until tissue distribution occurs within about 4–6 hours. This time delay is required for digoxin to distribute from the serum to the heart. Serum concentrations of ≥15 ng/mL in an acute ingestion will probably require digoxin-specific antibody fragments and are an indication for treatment. Because the elderly appear at greatest risk of lethality, the threshold for treating those older than 60 should be lowered.6 Before the advent of digoxin-specific antibody fragments mortality in patients older than 60 years of age was 58%, as compared to 8% in those younger than 40 years of age, and to 34% in those between the ages of 40 and 50 years of age. 6 A rapid progression of clinical signs and symptoms, such as cardiac and gastrointestinal effects and a rising potassium level in the presence of an acute overdose, suggests a potentially life-threatening ingestion and the need for digoxin antibodies. In a patient with an unknown ingestion who is clinically ill with characteristics suggestive of intoxication by digoxin, a calcium channel blocking agent, or a -adrenergic antagonist, digoxin antibodies should be administered early in management, and always prior to calcium use. If digoxin is involved, its effects can be reversed, obviating the need to administer calcium and avoiding the danger of giving calcium to a digoxin-toxic patient. Digoxin toxicity causes intracellular myocardial hypercalcemia, and the administration of exogenous calcium may further exacerbate conduction abnormalities.

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When it is difficult to distinguish clinically between digoxin intoxication and intrinsic cardiac disease, the administration of digoxin antibodies can help establish the diagnosis.

TIME OF ONSET OF RESPONSE TO DIGOXIN-SPECIFIC FAB In the multicenter study of 150 patients, the mean time to initial response from the completion of the digoxin antibody infusion (accomplished over 15 minutes to 2 hours) was 19 minutes (range, 0–60 minutes), and the time to complete response was 88 minutes (range, 30–360 minutes).15 Time to response was not affected by age, concurrent cardiac disease, or presence of chronic or acute ingestion.1

DOSING OF DIGOXIN-SPECIFIC FAB The dose of antibodies depends on the total body load (TBL) of digoxin. Estimates of TBL can be made in three ways: (a) estimate the quantity of digoxin acutely ingested and assume 80% bioavailability (X mg ingested × 0.8 = TBL); (b) obtain a serum digoxin concentration, and using a pharmacokinetic formula, incorporate the apparent Vd of digoxin and the patient’s body weight (in kg); or (c) use an empiric dose based on the average requirements for an acute or chronic overdose in an adult or child. Sample calculations for each of these methods are shown in Tables 48–4 to 48–6. Each vial of Digibind contains 38 mg of purified digoxin-specific antibody fragments, which will bind approximately 0.5 mg of digoxin or digitoxin. If the quantity of ingestion cannot be reliably estimated, it may be safest to use the largest calculated estimate. Alternatively, the clinician should be prepared to increase dosing should resolution be incomplete. Inaccurate estimations can occur if the history is faulty; if serum digoxin concentration is determined during the acute phase of distribution (overestimating requirements); and because the volume of distribution of 5 L/kg is merely a population estimate that varies considerably in individuals and in certain disease states, such as the decreases that occur in patients with renal disease and hypothyroidism.75

Administration According to the manufacturer, Digibind should be administered IV over 30 minutes via a 0.22-micron membrane filter.48 The 38-

TABLE 48–4. Sample Calculation Based on History of Acute Digoxin Ingestion Adult Weight: 70 kg Ingestion: Fifty 0.25-mg digoxin tablets Calculation: 0.25 mg  50 = 12.5 mg ingested dose 12.5 mg  0.80 (80% bioavailability) = 10.0 mg (absorbed dose) 10.0 mg 0.5 mg = 20 vials Child Weight: 10 kg Ingestion: Fifty 0.25-mg digoxin tablets Calculation: Same as for adult. Child will require 20 vials

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TABLE 48–5. Sample Calculations Based on the Serum Digoxin Concentration Adult Weight: 70 kg Serum digoxin concentration = 10 ng/mL Volume of distribution = 5 L/kg Calculationa: No. of vials =

mg of digoxin or digitoxin. A new product called DigiTab is currently undergoing FDA review.

MEASUREMENT OF DIGOXIN SERUM CONCENTRATION AFTER FAB ADMINISTRATION

Total body load (mg)

Digoxin-specific antibody fragments are available as Digbind (Digoxin Immune Fab—Ovine). Vials contain 38 mg of purified lyophilized digoxin-specific Fab fragments and each vial binds 0.5

Many laboratories are not equipped to determine free serum digoxin concentrations. Therefore, after digoxin-specific antibody fragments are administered, serum digoxin concentrations are no longer clinically useful, because they represent free plus bound digoxin.2,24,29,37,66 The type of test employed can either result in falsely high or falsely low serum concentrations, depending on which phase (solid or supernatant) is sampled.28 If the correct dose of Fab is administered, the free serum digoxin concentrations should be near zero. Free digoxin concentrations begin to reappear 5–24 hours or longer after Fab administration, depending on the antibody dose, infusion technique, and the patient’s renal function. Newer commercial methods employing ultrafiltration or immunoassays make free digoxin measurements easier to perform and, therefore, more clinically useful, but they remain associated with errors in the underestimation or overestimation of the free digoxin level.23,30,45,51,67,71 Free digoxin concentrations are particularly useful in patients with severe renal dysfunction. Independent of the availability of these data, the patient’s cardiac status must be carefully monitored for signs of recurrent toxicity. Other pitfalls in the measurement and utility of serum digoxin concentrations include endogenous and exogenous factors. Endogenous digoxinlike immunoreactive substances (DLIS) have been described in infants, in women in the third trimester of pregnancy, and in patients with renal and hepatic failure.22,25,26,31,33,42,72,73 When endogenous DLIS are free or weakly bound, as in these circumstances, they are measurable by the typical RIA and can account for factitiously high reported serum digoxin concentrations in the absence of digoxin treatment. The role of endogenous DLIS in the body has not been fully elucidated, but it does have an effect on both the sodium potassium ATPase pump and the digoxin glycoside receptor site.26 Endogenous DLIS are implicated as a causative factor in hypertension and renal disease. Exogenous factors relate primarily to measurement techniques and interpretation.35 Digoxin is metabolized to compounds with varying levels of cardioactivity.38 Some metabolites cross-react and are measured by RIA, while others are not. The in vivo production of these metabolites varies in patients, and may depend on intestinal metabolism by gut flora as well as renal and liver clearance.

TABLE 48–6. Empiric Dosing Recommendations

EXTRACORPOREAL REMOVAL

0.5 mg / vial =

Digoxin serum concentration × V × Pt Wt (kg) d 1000 × 0.5 mg / vial

No. of vials =

10 ng / mL × 5 L / kg × 70 kg 1000 × 0.5 mg / vial

(Round up)

No. of vials = 7 Child Weight: 10 kg Serum digoxin concentration: 10 ng/mL Volume of distribution: 5 L/kg Calculationa: No. of vials =

10 ng / mL × 5 L / kg × 10 kg 1000 × 0.5 mg / vial

(Round up)

No. of vials = 1 Quick Estimation (for Adults and Children) No. of vials =

Digoxin serum concentration (ng / mL) × Pt Wt (kg) 100

a

1000 is a conversion factor to change ng/mL to mg/L.

mg vial must be reconstituted with 4 mL of sterile water for IV injection, furnishing an isoosmotic solution. This preparation can be further diluted with sterile isotonic saline (for small infants, addition of 34 mL to the 4 mL (for 38 mL total achieves 1 mg/mL). After it is reconstituted, it should be used immediately, or if refrigerated, it should be used within 4 hours.48 In the critically ill, Digibind maybe given by IV bolus.

Availability

Acute Ingestion Adult: 10–20 vials Childa: 10–20 vials Chronic Toxicity Adult: 3–6 vials Childb: 1–2 vials a

Monitor for volume overload in children. Package insert contains table for infants and children, with corresponding serum concentrations.

b

Hemodialysis and activated charcoal hemoperfusion have no role in the management of digoxin poisoning. Even in the absence of Fab, these procedures are not indicated because both the molecular weight and volume of distribution of digoxin are too large to make either approach useful. Digoxin-specific antibody fragments are effective even in anephric patients, although toxic symptoms may recur 7–14 days later, possibly indicating the need for another dose of Fab. Hemoperfusion through columns with antidigoxin antibodies bound to agarose polyacrolein microsphere beads has

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CHAPTER 48

been accomplished, but the availability of Fab in the United States has supplanted this modality.41,55 The principles that make activated charcoal hemoperfusion less than ideal (Vd of digoxin, extracorporeal access, anticoagulation) also apply to the antidigoxin antibody columns. Continuous arteriovenous hemofiltration in an experimental model has failed to remove the digoxin-Fab complex.50

ROLE OF DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS IN POISONING WITH OTHER CARDIAC GLYCOSIDES Digoxin-specific antibody fragments were designed to have highaffinity binding for digoxin and digitoxin. There are structural similarities, however, between all cardiac glycosides. In fact, RIAdetermined digoxin levels have been reported in patients following intoxication with nondigoxin cardiac glycosides,27,47,61 suggesting that cross-reactivity exists between digoxin-specific antibodies and other cardiac glycosides. Thus, Digibind may have some efficacy in all natural cardiac glycoside poisonings including oleander, squill, and toad venom.8,9,13,20,54 The successful reversal by Digibind of cardiotoxicity resulting from ingestion of Nerium oleander was reported.61 This patient responded to 5 vials (200 mg) of Fab, but larger doses may be required in other cardiac glycoside poisonings because of the lower-affinity binding of Digibind for these toxins. Treatment decisions should be based on empirical grounds, with initial therapy consisting of 10–20 vials. Subsequent doses can be based on clinical response.

REFERENCES 1. Antman EM, Wenger TL, Butler VP, et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin specific Fab antibody fragments: Final report of multicenter study. Circulation 1990; 81:1744–1752. 2. Argyle JC: Effect of digoxin antibodies on TDX digoxin assay. Clin Chem 1986;32:1616–1617. 3. Beller GA, Smith TW, Abelmann WH, et al: Digitalis intoxication: A prospective clinical study with serum level correlations. N Engl J Med 1971;284:989–997. 4. Berkovitch M, Akilesh MR, Gerace R, et al: Acute digoxin overdose in a newborn with renal failure: Use of digoxin immune Fab and peritoneal dialysis. Ther Drug Monit 1994;16:531–533. 5. Bismuth C, Gaultier M, Conso F, et al: Hyperkalemia in acute digitalis poisoning: Prognostic significance and therapeutic implications. Clin Toxicol 1973;6:153–162. 6. Borron S, Bismuth C, Muszynski J: Advances in the management of digoxin toxicity in the older patient. Drugs Aging 1997;10:18–33. 7. Bosse GM, Pope TM: Recurrent digoxin overdose and treatment with digoxin-specific Fab antibody fragments. J Emerg Med 1994;12: 179–185. 8. Brubacher J, Lachmanen D, Ravikumar PR, Hoffman RS: Efficacy of digoxin specific Fab fragments (Digibind) in the treatment of toad venom poisoning. Toxicon 1999;37:931–942. 9. Brubacher J, Ravikumar P, Bania T, et al: Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest 1996;110: 1282–1288. 10. Butler VP, Chen J: Digoxin specific antibodies. Proc Natl Acad Sci U S A 1967;57:71–78. 11. Butler VP, Schmidt DH, Smith TW, et al: Effects of sheep digoxin: Specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs. J Clin Invest 1977;59:345–359.

CARDIAC GLYCOSIDES

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12. Butler VP, Smith TW, Schmidt DH, et al: Immunological reversal of the effects of digoxin. Fed Proc 1977;36:2235–2241. 13. Cheung K, Urech R, Taylor L, et al: Plant cardiac glycosides and digoxin Fab antibody. J Pediatr Child Health 1991;27:312–313. 14. Colucci R, Choses M, Kluger J, et al: The pharmacokinetics of digoxin immune Fab, total digoxin and free digoxin in patients with renal impairment [abstract]. Pharmacotherapy 1989;9:175. 15. Curd J, Smith TW, Jaton J, et al: The isolation of digoxin specific antibody and its use in reversing the effects of digoxin. Proc Natl Acad Sci U S A 1971;68:2401–2406. 16. D’Angio RG, Stevenson JG, Lively BT, et al: Therapeutic drug monitoring: Improved performance through educational intervention. Ther Drug Monit 1990;12:173–181. 17. Duhme DW, Greenblatt DJ, Kock-Weser J: Reduction of digoxin toxicity associated with measurement of serum levels: A report from the Boston Collaborative Drug Surveillance Program. Ann Intern Med 1974;80:516–519. 18. Durham G, Califf RM: Digoxin toxicity in renal insufficiency treated with digoxin immune Fab. Prim Cardiol 1988;1:31–34. 19. Eagle KA, Haber E, DeSanctis RW, et al, eds: The Practice of Cardiology, 2nd ed. Boston, Little, Brown, 1989. 20. Eddleston M, Rajapakse S, Rajakanthan, et al: Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: A randomized controlled trial. Lancet 2000;355:967–972. 21. Erdmann E, Mair W, Knedel M, et al: Digitalis intoxication and treatment with digoxin antibody fragments in renal failure. Klin Wochenschr 1989;67:16–19. 22. Frisolone J, Sylvia LM, Gelwan J, et al: False-positive serum digoxin concentrations determined by three digoxin assays on patients with liver disease. Clin Pharm 1988;7:444–449. 23. George S, Braithwaite RA, Hughes EA: Digoxin measurements following plasma ultrafiltration in two patients with digoxin toxicity treated with specific Fab fragments. Ann Clin Biochem 1994;31: 380–381. 24. Gibb I, Adams PC, Parnham AJ, et al: Plasma digoxin: Assay anomalies in Fab treated patients. Br J Clin Pharmacol 1983;16:445–447. 25. Graves SW, Brown B, Valdes R: An endogenous digoxin like substance in patients with renal impairment. Ann Intern Med 1983;99: 604–608. 26. Hastreiter AR, John EG, Nander Hoist RL: Digitalis, digitalis antibodies, digitalis-like immunoreactive substances, and sodium homeostasis: A review. Clin Perinatol 1988;15:491–522. 27. Haynes BE, Bessen HA, Wightman WD, et al: Oleander tea: Herbal draught of death. Ann Emerg Med 1985;14:350–353. 28. Honda SAA, Rios CN, Murakami L, et al: Problems in determining levels of free digoxin in patients treated with digoxin immune Fab. J Clin Lab Anal 1995;9:407–412. 29. Hursting MJ, Raisys VA, Opheim KE, et al: Determination of free digoxin concentrations in serum for monitoring Fab treatment of digoxin overdose. Clin Chem 1987;33:1652–1655. 30. Jortani S, Pinar A, Johnson N, Valdes R: Validity of unbound digoxin measurements by immunoassays in presence of antidote (Digibind). Clin Chim Acta 1999;283:159–169. 31. Karboski JA, Godley PJ, Frohna PA, et al: Marked digoxin like immunoreactive factor interference with an enzyme immunoassay. Drug Intell Clin Pharm 1988;2:703–705. 32. Kaufman J, Leikin J, Kendzierski D, Polin K: Use of digoxin Fab immune fragments in a seven-day-old infant. Pediatr Emerg Care 1990;6:118–121. 33. Kelly RA, O’Hara DS, Canessa MG, et al: Characterization of digitalis like factors in human plasma. J Biol Chem 1905;260: 11396–11405. 34. Koren G, Deatie D, Soldin S: Agonal elevation in serum digoxin concentrations in infants and children long after cessation of therapy. Crit Care Med 1988;16:793–795. 35. Koren G, Parker R: Interpretation of excessive serum concentrations of digoxin in children. Am J Cardiol 1985;55:1210–1214.

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36. Lechat P, Mudgett-Hunter M, Margolies M, et al: Reversal of lethal digoxin toxicity in guinea pigs using monoclonal antibodies and Fab fragments. J Pharmacol Exp Ther 1984;229:210–215. 37. Lemon M, Andrews DJ, Binks AM, et al: Concentrations of free serum digoxin after treatment with antibody fragments. Br Med J 1987;295:1520–1521. 38. Lindenbaum J, Rund D, Butler VP, et al: Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy. N Engl J Med 1981; 305:789–794. 39. Lloyd BL, Smith TW: Contrasting rates of reversal of digoxin toxicity by digoxin: Specific IgG and Fab fragments. Circulation 1978;58: 280–283. 40. Marchlinski FE, Hook BG, Callans DJ: Which cardiac disturbances should be treated with digoxin immune Fab (ovine) antibody? Am J Emerg Med 1991;9:24–34. 41. Marcus L, Margel S, Savin H, et al: Therapy of digoxin intoxication in dogs by specific hemoperfusion through agarose polyacrolein microsphere beads: Antidigoxin antibodies. Am Heart J 1985;110: 30–39. 42. Naomi S, Graves S, Lazarus M, et al: Variation in apparent serum digitalis-like factor levels with different digoxin antibodies: The “immunochemical fingerprint.” Am J Hypertens 1991;4:795–800. 43. Nollet H, Verhaaren H, Stroobandt R, et al: Delayed elimination of digoxin antidotum determined by RIA. J Clin Pharmacol 1989;29: 41–45. 44. Nuwayhid N, Johnson G: Digoxin elimination in a functionally anephric patient after digoxin specific Fab fragment therapy. Ther Drug Monit 1989;11:680–685. 45. Ocal I, Green T: Serum digoxin in the presence of Digibind: Determination of digoxin by the Abbott AxSYM and Baxter Stratus II immunoassays by direct analysis without pretreatment of serum samples. Clin Chem 1998;44:1947–1950. 46. Ordog GJ, Benaron S, Bhasin V: Serum digoxin levels and mortality in 5100 patients. Ann Emerg Med 1987;16:32–39. 47. Osterloh J, Herold S, Pond S: Oleander interference in the digoxin radioimmunoassay in a fatal ingestion. JAMA 1982;247:1596–1597. 48. Physicians Desk Reference, 55th ed. Oradell, NJ, Medical Economics, 2001, pp. 1372–1373. 49. Postmarketing Surveillance Study of Digibind: Interim Report to Contributors. Research Triangle Park, NC, Burroughs Wellcome, July 1986–July 1987. 50. Quaife EJ, Banner W, Vernon D, et al: Failure of CAVH to remove digoxin Fab complex in piglets. J Toxicol Clin Toxicol 1990;28: 61–68. 51. Rainey P: Digibind and free digoxin. Clin Chem 1999;5:719–721. 52. Renard C, Grene-Lerouge N, Beau N, et al: Pharmacokinetics of digoxin-specific Fab: Effects of decreased renal function and age. Br J Clin Pharmacol 1997;44:135–138. 53. Renard C, Weinling E, Pau B, Schermann JM: Time and dose-dependent digoxin redistribution by digoxin-specific antigen binding fragments in a rat model. Toxicology 1999;137:117–127. 54. Safadi R, Levy I, Amitai Y, Caraco Y: Beneficial effect of digoxinspecific Fab antibody fragments in oleander intoxication. Arch Intern Med 1995:155:2121–2125. 55. Savin H, Marcus L, Margel S, et al: Treatment of adverse digitalis effect by hemoperfusion through columns with antidigoxin antibodies bound to agarose polyacrolein microsphere beads. Am Heart J 1987; 113:1078–1084.

56. Schaumann W, Kaufmann B, Neubert P, et al: Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication. Eur J Clin Pharmacol 1986;30:527–533. 57. Schmidt DH, Butler VP: Immunological protection against digoxin toxicity. J Clin Invest 1971;50:866–871. 58. Schmidt DH, Butler VP: Reversal of digoxin toxicity with specific antibodies. J Clin Invest 1971;50:1738–1744. 59. Schmitt K, Tulzer G, Hackel F, et al: Massive digitoxin intoxication treated with digoxin-specific antibodies in a child. Pediatr Cardiol 1994;15:48–49. 60. Sherron PA, Gelband H: Reversal of digoxin toxicity with Fab fragments in a pediatric patient with acute renal failure. Paper presented at Management of Digitalis Toxicity: The Role of Digibind, San Francisco, July 26–28, 1985. Burroughs Wellcome, sponsor. 61. Shumaik GM, Wu AU, Ping AC: Oleander poisoning: Treatment with digoxin-specific Fab antibody fragments. Ann Emerg Med 1988;17: 732–735. 62. Sinclair AJ, Hewick DS, Johnston PC, et al: Kinetics of digoxin and anti-digoxin antibody fragments during treatment of digoxin toxicity. Br J Clin Pharmacol 1989;28:352–356. 63. Smith TW: New advances in the assessment and treatment of digitalis toxicity. J Clin Pharmacol 1985;25:522–528. 64. Smith TW, Haber E, Yeatman L, et al: Reversal of advanced digoxin intoxication with Fab fragments of digoxin specific antibodies. N Engl J Med 1976;294:797–800. 65. Smith TW, Lloyd BL, Spicer N, et al: Immunogenicity and kinetics of distribution and elimination of sheep digoxin specific IgG and Fab fragments in the rabbit and baboon. Clin Exp Immunol 1979;36: 384–396. 66. Soldin S: Digoxin: Issues and controversies. Clin Chem 1986;32: 5–12. 67. Ujhelyi MR, Colucci RD, Cummings DM, et al: Monitoring serum digoxin concentrations during digoxin immune Fab therapy. Ann Pharmacother 1991;25:1047–1049. 68. Ujhelyi MR, Robert S: Pharmacokinetic aspects of digoxin-specific Fab therapy in the management of digitalis toxicity. Clin Pharmacokinet 1995;28:483–493. 69. Ujhelyi MR, Robert S, Cummings DM, et al: Disposition of digoxin immune Fab in patients with kidney failure. Clin Pharmacol Ther 1993;54:388–394. 70. Ujhelyi MR, Robert S, Cummings DM, et al: Influence of digoxin immune Fab therapy and renal dysfunction on the disposition of total and free digoxin. Ann Intern Med 1993;119:273–277. 71. Valdes R, Jortani S: Monitoring of unbound digoxin in patients treated with antidigoxin antigen-binding fragments: A model for the future? Clin Chem 1998;44:1883–1885. 72. Vasdev S, Johnson E, Longerich L, et al: Plasma endogenous digitalis-like factors in healthy individuals and in dialysis dependent and kidney transplant patients. Clin Nephrol 1987;27:169–174. 73. Vinge E, Ekman R: Partial characterization of endogenous digoxinlike substance in human urine. Ther Drug Monit 1988;10:8–15. 74. Wenger TL: Experience with digoxin immune Fab (ovine) in patients with renal impairment. Am J Emerg Med 1991;9:21–23. 75. Winter ME: Digoxin. In: Koda-Kimble MA, Young LY, eds: Basic Clinical Pharmacokinetics, 3rd ed. Vancouver, WA, Applied Therapeutics, 1994, pp. 198–235.

CHAPTER

49


-ADRENERGIC ANTAGONISTS Jeffrey R. Brubacher

was placed and dopamine was started. There was no response to a dopamine infusion at 20 µg/kg/min. Further history was obtained from the patient’s son. The patient was previously healthy except for a history of depression and hypertension. The patient stopped taking antidepressants several months ago. He was currently taking only an antihypertensive medication, and no one else in the family took any pills. The family stated that the patient was more depressed in the last 2 weeks with apathy, decreased appetite, and inability to sleep. On the day of admission, however, he seemed better. He ate breakfast, took a shower, and went for a walk before he returned home to take a nap before lunch. The patient was well prior to taking his nap but 2 hours later, when the family could not arouse him for lunch, they called the ambulance. A family member was requested to return home and bring all medication bottles to the emergency department. A call was placed to the patient’s family physician. Given the possibility of an overdose, blood was analyzed for acetaminophen. The history of depression, seizures, hypotension, and widened QRS interval suggested a tricyclic antidepressant overdose and the patient was given 100 mEq of hypertonic sodium bicarbonate. There was no change in the patient’s vital signs following this and a repeat electrocardiogram was essentially unchanged except that the QRS interval had decreased to 130 msec from 140 msec. A bicarbonate infusion was started. Because of the possibility of a calcium-channel-blocking medication, the patient was given 1 g of calcium chloride intravenously. Following this, his blood pressure increased to 75 mm Hg and the pulse remained at 40 beats/min. The family physician returned the call and stated that propranolol had just been prescribed for hypertension 2 weeks earlier. One of the patient’s daughters returned with all the medication bottles that she could find. Several bottles of vitamins and over-the-counter

A 64-year-old man was brought to the emergency department by ambulance after being found comatose by his family. The emergency medical personnel found him hypoventilating with respirations of 10 breaths/min, a pulse of 45 beats/min, and a blood pressure of 80 mm Hg by palpation. They intubated him and gave him 2 mg naloxone, 1 mg atropine, and a 500-mL bolus of 0.9% NaCl. During transport, the patient had a generalized seizure that responded to 5 mg of intravenous diazepam. On arrival in the emergency department the patient was intubated, ventilated, and comatose with the following vital signs: blood pressure, 85 mm Hg by palpation; pulse, 50 beats/min; and temperature 36°C (96.8°F). On 100% oxygen the patient’s oxygen saturation by pulse oximetry was 99% and his fingerstick blood glucose was 80 mg/dL. Physical examination showed that the pupils were 6 mm and reactive and the skin was cool. There were scattered basilar crackles. Heart sounds were normal with no murmurs. Bowel sounds were decreased. The patient was given 100 mg thiamine IV, 50 mL 50% dextrose IV, and 2 mg naloxone IV with no response. One of the medical staff was sent to interview the family. Blood was obtained for laboratory analysis and sent for a complete blood count, electrolytes, glucose, renal function, and creatine phosphokinase. Arterial blood was sent for blood gas analysis. A 12-lead electrocardiogram showed sinus bradycardia with a PR interval of 280 msec and a QRS duration of 140 msec. During the next several minutes the patient’s vital signs deteriorated. His blood pressure decreased to 75 mm Hg and his pulse decreased to 40 beats/min. He was given an additional 2 mg of atropine and another 500 mL of 0.9% NaCl with little change in blood pressure or heart rate. External cardiac pacing was instituted with an increase in the pulse to 70 beats/min. The blood pressure fell to 60 mm Hg with pacing and this intervention was discontinued. A central venous line

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analgesics were almost full; however, the propranolol bottle was empty; an estimated 5 g of propranolol was missing. With this additional information, the patient was given intravenous glucagon. After a total of 5 mg of glucagon given over a 10minute period, the patient improved. His blood pressure increased to 105/60 mm Hg and his pulse increased to 55 beats/min. A glucagon infusion at 5 mg/h was started and the patient was admitted to the intensive care unit. Laboratory analysis was negative for acetaminophen. The electrolytes, glucose, renal function, complete blood count, and arterial blood gases were all within normal limits except for a mild anion gap metabolic acidosis, which resolved on repeat analysis performed after the patient’s vital signs normalized. By the next day, the patient had regained consciousness and was able to maintain his blood pressure after the glucagon infusion was stopped. He was extubated and stated that he had taken an overdose of propranolol in a suicide attempt. The patient was assessed by a psychiatrist who suggested that his depression was exacerbated by the propranolol. Propranolol was discontinued and his antidepressants were restarted. The patient was started on a calcium channel blocker for hypertension and briefly admitted to the psychiatric service. On followup examination 1 month later, the patient was doing well with no complaints. He no longer felt depressed, and his blood pressure was well controlled.


-Adrenergic antagonists have been available for clinical use for four decades. They are commonly used in the treatment of cardiovascular disease: hypertension, coronary artery disease, and tachydysrhythmias. Additional indications for
-adrenergic antagonists include congestive heart failure, migraine headaches, tremor, panic attacks, and hyperthyroidism. Ophthalmic preparations containing
-adrenergic antagonists are also used in the treatment of glaucoma.51 When taken in overdose,
-adrenergic antagonists cause hypotension and bradycardia. The clinical course is often benign, although patients with any compromise in cardiac status and those who have taken a cardioactive coingestant are at risk for cardiovascular collapse and death.

HISTORY In 1948, Raymond Alquist postulated that the cardiovascular actions of epinephrine, hypertension and tachycardia, were best explained by the existence of two distinct sets of receptors that he generically named  and
receptors.5 Contemporary “antiepinephrine” drugs such as phenoxybenzamine reversed the hypertension but not the tachycardia associated with epinephrine. According to Alquist’s theory, these drugs acted at the  receptors, whereas the
receptors mediated catecholamine-induced tachycardia. The British pharmacist Sir James Black was influenced by Alquist’s work and recognized the potential clinical benefit of a
-adrenergic antagonist. In 1958, Black synthesized the first
-adrenergic antagonist, pronethalol. This drug was briefly marketed as Alderlin, named after Alderly Park, the research headquarters of ICI Pharmaceuticals. Pronethalol was discontinued because it produced thymic tumors in mice. Propranolol was soon developed and marketed as Inderal (an anagram of Alderlin) in the United Kingdom in 1964,16,131 and in the United States in 1973. Prior to the introduction of
-adrenergic antagonists, the management of angina was limited to agents such as nitrates that increased myocardial oxygen delivery by vasodilation of the

coronary arteries. Propranolol gave clinicians the ability to decrease myocardial oxygen requirements. This new approach decreased morbidity and mortality in angina sufferers.69 New drugs soon followed, and by 1979, there were 10
-adrenergic antagonists available in the United States.31 Unfortunately, it soon became apparent that these agents were dangerous when taken in overdose, and by 1979, cases of severe toxicity and death from
-adrenergic overdose were reported.31

EPIDEMIOLOGY Intentional
-adrenergic antagonist overdose, although relatively uncommon, continues to account for a number of deaths annually. From 1985 to 1995, there were 52,156
-adrenergic antagonist exposures reported to the toxic exposure surveillance system of the American Association of Poison Control Centers (Chap. 116 and p. 1752). These exposures accounted for 164 deaths with
-adrenergic antagonists implicated as the primary cause of death in 38 cases. The other fatalities could not be clearly ascribed to
-adrenergic antagonists because of coingestants with cardioactive drugs such as calcium channel blockers or because of other factors. Children younger than 6 years of age accounted for 19,388 exposures but no fatalities. The youngest fatality reported in this age group was 7 years old. More than half of the patients who died developed cardiac arrest only after arriving at a healthcare facility.84 In England and Wales,
-adrenergic antagonist toxicity accounted for just over 20 deaths annually during the period from 1975 to 1984. Several authors report that, as compared to the other
-adrenergic antagonists, propranolol accounts for a disproportionate number of cases of self-poisoning22,112 and deaths.68,84 This may be explained by the fact that propranolol is frequently prescribed for patients with diagnoses such as anxiety, stress, and migraine who may be more prone to suicide attempts.112 Propranolol is also more toxic because of its lipophilic and membrane-stabilizing properties.44,112

PHARMACOLOGY Myocyte Calcium Flow and Contractility Myocyte contraction occurs when actin and myosin filaments interact and slide past each other. At rest, the troponin-tropomyosin complex blocks this interaction. Excitation triggers a series of events that increase cytoplasmic calcium concentrations. Calcium binds to troponin C causing movement of the troponintropomyosin complex. This permits actin-myosin linkage and results in sliding of myosin and actin chains relative to each other and ultimately in muscle contraction.2,9,120 Low intracellular calcium concentrations are maintained by pumps that actively remove calcium from the cytoplasm.108,111 Voltage-sensitive slow calcium channels open in response to depolarization and allow calcium to flow into the myocyte. This triggers the opening of calcium release channels in the sarcoplasmic reticulum, a phenomenon known as calcium-induced calcium release.39,152 More calcium causes stronger actin-myosin interaction and greater contractility. Actin-myosin interaction is also modulated by troponin phosphorylation, ischemia, intracellular pH, and myofilament stretch9,120 (Fig. 49–1A).

CHAPTER 49

Relaxation occurs when calcium is released from troponin and removed from the cytoplasm. Most calcium is pumped back into the sarcoplasmic reticulum by the sarcoplasmic calcium pump. This pump is modulated by
-adrenergic stimulation as discussed below. Calcium is also removed by an active cytoplasmic membrane calcium pump and by the calcium-sodium transporter, which exchanges 1 molecule of calcium for 3 molecules of sodium (Fig. 49–1B).9,13


-Adrenergic Receptors
-Adrenergic receptors are divided into
1,
2, and
3 subtypes.
1-Adrenergic receptors are coupled to Gs proteins, which activate adenylate cyclase when the receptor is stimulated. This increases


-ADRENERGIC ANTAGONISTS

743

intracellular production of cyclic adenosine monophosphate (cAMP), which binds to and activates protein kinase A and other cAMP-dependent protein kinases.75 Protein kinase A, in turn, phosphorylates important myocyte proteins including phospholamban, the voltage-sensitive calcium channels, and troponin.42,138 Calcium channel phosphorylation increases contractility by increasing the influx of calcium during each cell depolarization.113,129 Phosphorylation of phospholamban increases the activity of the sarcoplasmic calcium ATPase and thus enhances contractility by increasing sarcoplasmic calcium stores.24,138 This also results in a more rapid removal of cytoplasmic calcium during diastole, and aids in myocyte relaxation. Troponin phosphorylation facilitates calcium unbinding and decreases contractility, but improves cardiac performance by enhancing myocyte relaxation2,9,77,138 (Fig. 49–2).

Figure 49–1. A. Fluctuations in calcium levels couple myocyte depolarization with contraction and myocyte repolarization with relaxation. ➀ Depolarization causes voltage-sensitive calcium channels to open and calcium to flow down its concentration gradient into the myocyte. ➁ This calcium current triggers the opening of calcium release channels (ryanodine receptor) in the sarcoplasmic reticulum (SR) and calcium pours out. The amount of calcium released from the SR is proportional to the initial inward calcium current and to the amount of calcium stored in the SR. ➂ At rest, actin-myosin interaction is prevented by troponin. When calcium binds to troponin, this inhibition is removed, actin and myosin slide relative to each other, and the cell contracts. B. Following contraction, calcium is actively removed from the myocyte to allow relaxation. ➀ Most calcium is actively pumped into the SR where it is bound to calsequestrin. Calcium stored in the SR is thus available for release during subsequent depolarizations. The sarcoplasmic calcium ATPase is inhibited by phospholamban (Fig. 49–2). ➁ The calcium sodium antiporter couples the flow of 3 molecules of sodium in one direction to that of a single molecule of calcium in the opposite direction. This transporter is passively driven by electrochemical gradients which usually favor the inward flow of sodium coupled to the extrusion of calcium. Extrusion of calcium is therefore inhibited by high intracellular sodium or extracellular calcium concentrations and by cell depolarization. Under these conditions, the pump may “run in reverse.” ➂ Some calcium is actively pumped from the cell by calcium ATPase. ➃ As myocyte calcium concentrations fall, calcium is released from troponin and the myocyte relaxes.

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY hearts,34,35 where it appears to be a mediator of negative inotropy.34

Effects of
-Adrenergic Receptor Activation

Figure 49–2. β-Adrenergic agonists are positive inotropes by virtue of their ability to activate protein kinase A (PKA). ➀ β-Adrenergic receptors are coupled to Gs proteins, which activate adenyl cyclase when catecholamines bind to the receptor. This causes increased formation of cAMP from ATP. ➁ Increased cAMP levels activate PKA, which mediates the ultimate effects of βadrenergic receptor stimulation by phosphorylating key intracellular proteins. ➂ Phosphorylation of phospholamban disinhibits the sarcoplasmic reticulum (SR) calcium ATPase, resulting in increased SR calcium stores available for release during subsequent depolarizations. ➃ Phosphorylation of voltage-sensitive calcium channels increases calcium influx through these channels during systole. ➄ Troponin phosphorylation improves cardiac performance by facilitating unbinding of calcium during diastole.

In addition to activating adenyl cyclase through GS proteins, cardiac
2-adrenergic receptors also appear to be coupled to inhibitory GI proteins. The net effect of
2-adrenergic stimulation is to improve cardiac contractility and relaxation independent of increases in cytoplasmic cAMP. One explanation for this is that
2-adrenergic receptor–induced increases in cAMP (via GS protein stimulation) are localized to the cell membrane, where they result in phosphorylation and improved function of slow calcium channels. The GI protein-linked receptor inhibits adenyl cyclase elsewhere in the cytoplasm and prevents the global increase in cAMP that occurs with
1-adrenergic activation.
2-Adrenergic receptor stimulation may also improve contractility by increasing cytoplasmic pH independent of G protein activation.132,154 The pharmacology of the
3-adrenergic receptor differs substantially from that of the other
receptors. Whereas isoproterenol is an agonist at all three
-adrenergic receptors, classic
-adrenergic antagonists actually act as agonists at the β3 receptor.135 The role of the
3-adrenergic receptor in man is incompletely understood. This receptor is found on human adipocytes where it plays a role in thermogenesis and lipolysis,27 and is also found in human


-Adrenergic stimulation modulates the function of the heart, vasculature, lungs, and numerous other organs, and causes complex metabolic effects. The most prevalent subtype in the heart is the
1-adrenergic receptor. The relative density of cardiac
2-adrenergic receptors increases in persons with heart failure.132
1-Adrenergic stimulation of the heart results in increased contractility, increased conduction velocity, and increased automaticity. Peripheral vascular resistance is largely controlled by arteriolar muscle tone. -Adrenergic stimulation causes arteriolar constriction in contrast to
2-adrenergic receptors, which mediate arteriolar dilation. In the lungs,
2-adrenergic receptor stimulation results in bronchodilation and decreased respiratory secretions.
-Adrenergic agonists have important endocrine and metabolic effects. Renin secretion is increased by
1-adrenergic stimulation. Insulin secretion is increased by
2-adrenergic receptor stimulation, but is decreased by 2-adrenergic receptor stimulation so that the net effect of epinephrine is to decrease insulin levels.
2-Adrenergic receptor stimulation causes increased glucose secondary to increased hepatic gluconeogenesis, and skeletal muscle and hepatic glycogenolysis. Skeletal muscle potassium uptake is increased by
2 stimulation, resulting in hypokalemia. Gut motility is decreased by both
1- and
2-adrenergic stimulation.
-Adrenergic agonists act at fat cells to cause lipolysis and thermogenesis.51

Action of
-Adrenergic Antagonists
-Adrenergic antagonists competitively antagonize the effects of catecholamines at the
-adrenergic receptor. This causes decreased chronotropy and contractility, which is manifested clinically as lowered heart rate and blood pressure. These effects are more important in times of exertion, stress, or illness, when sympathetic tone is increased. The antihypertensive effect of
-adrenergic antagonists is counteracted by a reflex increase in peripheral vascular resistance. This effect is augmented by the
2-adrenergic antagonism of nonselective
-adrenergic antagonists. With longterm use of
-adrenergic antagonists there is a fall in peripheral vascular resistance. The mechanism for this effect is poorly understood.51 Several adverse effects are related to
2-adrenergic antagonism.
-Adrenergic antagonists cause bradycardia and hypotension which may be severe in patients with cardiac conduction defects and in those who take calcium channel blockers or other medications that impair cardiac conduction. Although
-adrenergic antagonists slow the progression of congestive heart failure and have become a standard of care for mild heart failure,1 they acutely exacerbate symptoms in some patients with congestive heart failure. Rarely,
-Adrenergic antagonists will worsen peripheral vascular disease. Patients with reactive airways disease may suffer severe bronchospasm after using
-adrenergic antagonists because of loss of
2-mediated bronchodilation. Catecholamines inhibit mast cell degranulation through a
2-adrenergic mechanism, and interference with this may predispose to life-threatening anaphylactic reactions in atopic individuals.55 Patients taking
-adrenergic antagonists who develop allergic reactions should be monitored more closely than other pa-

CHAPTER 49

tients are monitored and allergy testing should be avoided in these patients. Although
2-adrenergic stimulation augments insulin release,
-adrenergic antagonists rarely lower insulin levels.
2-Adrenergic antagonists interfere with glycogenolysis and gluconeogenesis, resulting in impaired ability to recover from hypoglycemia. Furthermore,
-adrenergic antagonism may mask the sympathetic discharge that serves to warn of hypoglycemia. This combination of effects frequently proves dangerous for diabetic patients at risk for hypoglycemic episodes. The
1-adrenergic-selective agents may be safer in patients with reactive airways or diabetes mellitus. Because
2-adrenergic antagonism interferes with peripheral vasodilation, the
1-adrenergic-selective agents may also be more effective antihypertensive agents. It is important to realize that
1-adrenergic selectivity is incomplete, and that adverse reactions secondary to
2-adrenergic antagonism may occur with the
1-adrenergic-selective agents. This is especially likely to be the case when higher doses are used.11,51,78,126 Intrinsic sympathomimetic activity (ISA) describes the properties of
-adrenergic antagonists that are actually partial agonists at the
-adrenergic receptors. This property is unrelated to
1-adrenergic selectivity. Like other
-adrenergic antagonists, these agents are antihypertensives and prevent exercise-induced tachycardia. These agents may avoid the severe decrease in resting heart rate that occurs with
-adrenergic antagonism in susceptible patients, but their clinical benefit is not demonstrated in controlled trials.28 Table 49–1 lists the important agents with ISA. Three of the
-adrenergic antagonists are also vasodilators. Carvedilol and labetalol are -adrenergic antagonists, and nebivolol causes vasodilation by increasing nitric oxide release.89

TABLE 49–1.


-ADRENERGIC ANTAGONISTS

Vasodilation may prove beneficial in patients with congestive heart failure and may make these agents more effective antihypertensives. Because labetalol is 5- to 10-fold more potent as a
-adrenergic antagonist than as an  antagonist, it remains contraindicated in situations such as pheochromocytoma or cocaine toxicity, where
-adrenergic antagonism could result in an “unopposed ” adrenergic effect.37,51 Sotalol is unique in that it prolongs action potential duration and increases the refractory period by blocking delayed rectifier potassium channels.52 These actions make sotalol an effective class III antidysrhythmic agent; unfortunately, these actions also predispose patients to the development of polymorphic ventricular tachycardia (torsades de pointes) (see “Clinical Manifestations”).

PHARMACOKINETICS
-Adrenergic antagonists differ in their lipophilicity, oral bioavailability, first-pass metabolism, protein binding,
1-adrenergic selectivity, and intrinsic sympathomimetic activity (Table 49–1). Lipid solubility is a measure of the ability of a drug to partition into fat. Highly lipid-soluble agents cross lipid membranes rapidly and concentrate in adipose tissue. These properties allow rapid entry into the central nervous system (CNS), and typically result in large volumes of distribution. Lipid solubility enhances intestinal absorption by allowing rapid transit across lipid membranes but because compounds must enter an aqueous phase in the intestines before being absorbed, excessive lipid solubility may actually impede absorption. Highly lipid-soluble and highly pro-

Pharmacologic Properties of the
-Adrenergic Antagonists Adrenergic Blocking Activity

Partial Agonist Activity (ISA)

MembraneStabilizing Activity

Lipid Solubility

Protein Binding

Oral Bioavailability

Half-Life (hours)

Acebutolol


1

Yes

Yes

Low

25%

40%

2–4

Atenolol Betaxolol


1
1

No No

No Yes

Low Low

sensory Primary axonal polyneuropathy, typically motor > sensory Evidence of anterior horn cell disease

Yes

Common

Flaccid Quadriplegia and respiratory failure. Associated with prolonged use NDNMBs. Risk factors: active metabolites of vecuronium, pancuronium, or rapacuronium, and other drugs that potentiate weakness. Delayed drug clearance in MOF.

Normal

Abnormal muscle response to repetitive nerve stimulation

Normal

Yes/No

Common

Normal

Yes/No

Common

Catabolic state and immobility typically >7 days. Diffuse muscle wasting, reduced muscle mass. Diffuse symmetric quadriparesis, respiratory failure, and weak neck flexors and facial muscles. Critically ill patient associated with sepsis/MOF,organ transplantation, renal failure, severe asthma, respiratory failure, aminoglycosides, and glucocorticoids.

Normal or uniformly atrophic type 2 myofibers without patchy necrosis Diffuse focal myonecrosis and vacuolization, myofibrolysis, myofibrillar disorganization. Preferential loss of thick filaments especially in type 2 fibers.

Yes

Rare

Flaccid quadriplegia and myoglobinuria, preserved sensation. Associated with sepsis, severe asthma, glucocorticoids, and NDNMBs (especially vecuronium). Renal failure commonly caused by rhabdomyolysis.

Very high, >10,000 IU

Myopathic EMG changes and normal NCV Myopathic changes including low amplitude or absent compound muscle action potentials, defibrillation potentials and positive sharp waves by needle EMG, normal NCV; normal sensory nerve action potentials. Intact NMJ function.86 Myopathic EMG changes; normal NCV

816

Creatine Phosphokinase (CPK)

Myopathy Disuse myopathy83 (cachectic myopathy) Critical illness myopathy (CIM),86 includes thick filament myopathy (TFM, aka steroid or asthma myopathy)74,77 and acute myopathy of intensive care (AMIC) 7,34,84,99

Acute necrotizing myopathy of intensive care (ANMIC)126,160

Mildmoderate increase in 50%, typically 1 g. However, in a 10kg toddler, as few as two 50-mg imipramine tablets may cause significant toxicity (10 mg/kg).

CYCLIC ANTIDEPRESSANTS

A

851

+30

Na+

Ca++

mV -90 t

PATHOPHYSIOLOGY The CAs’ effects on various neurotransmitters and the myocardial cells explain the pathophysiology of cardiac and central nervous system toxicity. Conduction delays, dysrhythmias, and hypotension characterize the cardiotoxicity caused by cyclic antidepressants. This toxicity results from drug effects on the myocardial action potential, direct effects on the vascular tone, and effects mediated by the autonomic nervous system. The CAs block the rapid inward movement of sodium ions into the fast sodium channel, slowing phase 0 depolarization of the action potential in the distal His-Purkinje system, as well as the ventricular myocardium50,163,166 (Figs. 57–2 and 21–6). Impaired depolarization within the conduction system slows the propagation of ventricular depolarization, which is manifested as prolongation of the QRS interval on the electrocardiogram. The right bundle branch has a relatively longer refractory period, and the subsequent intraventricular conduction delay and increased heart rate because of the anticholinergic effects disproportionately affect the right bundle.108 This toxicity results in the rightward shift of the terminal QRS axis and right bundle-branch block that are seen in CA toxicity. QT interval prolongation can occur in the setting of both therapeutic and toxic doses of CAs. This repolarization prolongation is a result of the CAs’ effect on slowing repolarization and phase 4 (spontaneous) depolarization.129 QT prolongation can predispose to the development of torsades de pointes. However, this dysrhythmia is probably more common in patients taking therapeutic doses of CAs than following overdose. Because torsades de pointes is more likely to occur in the setting of bradycardia, it is an unlikely finding in patients with acute CA toxicity. Cyclic antidepressant–associated hypotension is multifactorial in its etiology. It is caused by direct myocardial depression secondary to the CA blockade of sodium entry into myocardial cells.79 The inhibition of sodium entry into myocardial cells by the TCA blockade disrupts the subsequent coupling of calcium entry into the cells, thereby impairing myocardial contractility. Downregulation of adrenergic receptors with subsequent blunted physiologic responses to catecholamines is also suggested as another mechanism based on evidence of TCA-poisoned patients with actually normal to high serum catecholamine levels.101 Peripheral vasodilation from TCAs’ -adrenergic blockade also contributes to the hypotension. The lack of efficacy of high doses of exogenous catecholamines suggests the mechanism of hypotension is not predominantly the depletion of norepinephrine.101 The most common dysrhythmia observed with CA toxicity is sinus tachycardia, which is primarily the result of peripheral cholinergic blockade. Norepinephrine reuptake inhibition also contributes to the tachycardia. Wide-complex tachycardia is the characteristic potentially life-threatening dysrhythmia observed in patients with severe CA toxicity and is probably multifactorial in etiology. By prolonging antegrade conduction, nonuniform conduction slowing may result, leading to reentry ventricular dysrhythmias.163 Ventricular tachycardia may also occur in the setting of hypoxia and tissue ischemia, metabolic acidosis, and the use of
1-adrenergic therapy. It is likely that most causes of wide-com-

+ + ++Depolarization ++ ++ +++++ +

Na+

B

+30

Na+ Ca

Ca++

→

Ca++

mV -90 t

+ + ++Depolarization + ++ +++ +

Na+

C

Na+ Na+ Na+ Na+ Na+ Na+

+30

Ca++

←

Ca++

mV -90 t

+ + ++Depolarization ++ ++ +++++ +

Na+

Ca++

Figure 57–2. The effects of cyclic antidepressants (CA) on the fast sodium channel. A. Sodium depolarizes the cell, which both propagates conduction allowing complete cardiac depolarization and opens voltage-dependent Ca2+ channels producing contraction. B. TCAs and other sodium channel blockers alter the conformation of the sodium channel, slowing the rate of rise of the action potential, which produces both negative dromotropic and inotropic effects. C. Raising the sodium ion gradient across the affected sodium channel speeds the rate of rise of the action potential, counteracting the drug-induced effects. See Figure 57–3 for the effects noted on the ECG.

plex tachycardia are actually sinus tachycardia with rate-dependent aberrancy. In such cases, the preceding P wave may not be apparent because of prolonged AV conduction, or widened QRS interval, or both. Electrophysiologic studies in a canine model demonstrate that QRS prolongation is rate dependent; that is, the faster the heart rate, the greater the conduction delay. In these studies, dogs could not accelerate their heart rate because they had a crushed sinus node and never developed “ventricular tachycardia.”3 Furthermore, induction of bradycardia through experimental

852

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

pharmacologic agents prevented wide-complex tachycardia.4 Earlier studies, however, demonstrated narrowing of the QRS interval with administration of propanolol.134 This physiologic characteristic—use-dependent kinetics—is characteristic of the sodium channel blockade of Type IA antidysrhythmics (Chap. 52). Attempts to find a causal relationship between TCA administration and myocardial disease through controlled trials have failed.51,161 However, some recent data suggest that chronic tricyclic antidepressant drug treatment causes myocardial injury. Clinical studies using monoclonal antimyosin antibodies, a known marker for myocardial damage, demonstrate increased uptake of these antibodies in adults on long-term amitriptyline treatment.94 The agitation, delirium, and depressed sensorium characteristic of CNS toxicity are primarily caused by the central anticholinergic effects of the drug. The pathophysiology of CA-induced seizures has not been fully delineated and may be a result of a combination of increased levels of monoamines (particularly norepinephrine), antidopaminergic properties, anticholinergic properties, inhibition of neuronal sodium channels, and interactions with GABA receptors. Animal studies demonstrate that the interaction of CAs with the GABA-receptor chloride ionophore complex in the brain may be responsible for the convulsant effects of these drugs. Specifically, in drug-naïve rats, some CAs inhibited GABA-mediated chloride conductance, which was correlated with the frequency of seizures they induced.90 A recent study in rats reported that amitriptyline actually augments chloride conductance in tissue.91 This opposite action, may suggest yet another complex mechanism for seizures or may actually confer a protective anticonvulsant effect on patients who are chronically taking the drug prior to their overdose. The exact binding site of these drugs has not been elucidated, although some evidence suggests at least indirect activity at the picrotoxin binding site on the GABA chloride complex.150

CLINICAL MANIFESTATIONS OF TOXICITY Cyclic antidepressant toxicity is characterized primarily by cardiovascular and central nervous system effects (Table 57–2). This toxic profile is qualitatively the same for all of the tricyclic antidepressants, but slightly different for some of the selected CAs, as noted below. The progression of clinical toxicity may be rapid and frequently unpredictable. It is common for a patient to present to the ED awake and alert and to then develop life-threatening cardiovascular and CNS toxicity within a couple of hours.

Acute Toxicity Most clinical toxicity reported is derived from acute ingestions, especially in people who are chronically on the medication (acute on chronic ingestion). Clinical toxicity between these two cohorts of people does not appear to be different, although most studies do not distinguish between these two categories. It may be postulated that acute ingestions of smaller amounts of drug may result in toxicity more rapidly in people chronically taking these drugs because their organs may be more “vulnerable” to the drugs’ effects. Acute Cardiovascular Toxicity. Cardiovascular toxicity is responsible for the morbidity and mortality attributed to CAs. The characteristic features are conduction delays, dysrhythmias, and

TABLE 57–2. Clinical Manifestations of Toxicity Caused by Cyclic Antidepressants Cardiovascular Toxicity Conduction Delays

Dysrhythmias

PR, QRS, QT interval prolongation T40-msec axis rightward rotation (120°–270°) Atrioventricular block Sinus tachycardia Supraventricular tachycardia Wide-complex tachycardia Sinus tachycardia with rate-dependent aberrancy Ventricular tachycardia Torsades de pointes Bradycardia Ventricular fibrillation Asystole

Hypotension Central Nervous System Toxicity Altered mental status Delirium Psychosis Lethargy Coma Myoclonus Seizures Anticholinergic Toxicity Altered mental status Hyperthermia Urinary retention Paralytic ileus

hypotension. These toxic effects result from the drugs’ effects on the myocardial cell’s action potential, direct effects on the vascular tone, and effects mediated by the autonomic nervous system as described in detail below. Conduction delays include prolongation of the QRS interval and rightward shift of the terminal 40-msec QRS axis (T40-ms). PR, QRS, and QT interval prolongation can occur both in the setting of therapeutic and toxic doses of TCAs.93 Second- and third-degree atrioventricular blocks are rare. Sinus tachycardia (rate 120–160 beats/min in an adult) is the most common dysrhythmia associated with CA toxicity and usually does not cause hemodynamic compromise. Ventricular tachycardia is the most common lethal ventricular dysrhythmia although it may be difficult to distinguish this abnormal rhythm from supraventricular tachycardia with aberrant conduction or even markedly prolonged sinus tachycardia without visible P waves. Ventricular tachycardia occurs most often in patients with prolonged QRS interval and/or hypotension, and may be precipitated by seizures with accompanying acidosis.88,156 Hypoxia, acidosis, hyperthermia, and
-adrenergic agonists may predispose the patient to ventricular tachycardia, which is associated with a high mortality. However, true fatal dysrhythmias are probably rare, as ventricular tachycardia and fibrillation occur in only about 4% of all cases.53 Ventricular fibrillation, severe bradycardia and slow ventricular rhythms, and asystole are usually terminal dysrhythmias, although with prolonged administration of appropriate therapy they may be reversible. Prolonged cardiac massage may be necessary in cases of asystole due to CAs. Successful recovery has occurred in both children and adults receiving cardiopulmonary resuscitation despite periods of asystole exceeding 90 min-

CHAPTER 57

utes.110,147,158 Torsades de pointes is not common with acute TCA overdoses; it is more often found in people on therapeutic doses of CAs. Refractory hypotension is probably the most common cause of death from CA overdose.27,67,153 The etiology of CA-induced hypotension is multifactorial, as described previously. Hypoxia, acidosis, volume depletion, seizures, or the concomitant ingestion of other cardiodepressant or vasodilating drugs can exacerbate it. Acute Central Nervous System Toxicity. Seizures and altered mental status are the primary manifestations of central nervous system toxicity. Delirium, disorientation, agitation, and/or psychotic behavior with hallucinations may be present. These alterations in consciousness are then usually followed by lethargy, rapidly progressing to obtundation and coma. The duration of coma is variable and does not necessarily correlate or occur concomitantly with electrocardiogram abnormalities. Coingestion of CNS depressants and/or concomitant hypotension may prolong the coma. Cyclic antidepressant–induced seizures are usually generalized and brief and most often occur within 1 to 2 hours of presentation.38,130 The incidence of seizures is estimated at 4% of patients presenting with overdose and 13% in fatal cases.170 Uncontrolled seizures may result in metabolic acidosis, hyperthermia, rhabdomyolysis, and myoglobinuria with acute renal failure. Abrupt deterioration in hemodynamic status (hypotension, ventricular dysrhythmias) may develop during or within minutes after a seizure.38,88,156 This rapid cardiovascular deterioration may be the result of a combination of seizure-induced acidosis and preexisting cardiovascular toxicity. The risk of seizures with CA overdoses may be increased in those patients on long-term therapy or who have other risk factors such as history of seizures, head trauma, or concomitant drug withdrawal.146 Myoclonus and extrapyramidal symptoms may also occur in CA-poisoned patients. Anticholinergic and Other Clinical Toxicity. Other anticholinergic toxicities include hyperthermia, urinary retention, paralytic ileus, dry flushed skin, and respiratory depression. Reported pulmonary complications include acute lung injury, aspiration pneumonitis, and the adult respiratory distress syndrome. Although pulmonary edema may not be correlated with hypotension, this clinical effect is most likely a result of coma, hypotension, pulmonary infection, and excessive fluid administration rather than the primary toxic effects of CAs.141,142 Bowel ischemia, pseudoobstruction, and pancreatitis are associated with CA overdose.99,128,164 Death directly caused by CA toxicity usually occurs in the first several hours after presentation for those patients who reach a healthcare facility. Late deaths ( >1–2 days after presentation) are usually secondary to other factors such as aspiration pneumonitis, adult respiratory distress syndrome from refractory hypotension, and/or infection.27

Chronic Toxicity Chronic CA toxicity does occur, and is usually manifested by exaggeration of adverse effects, such as sedation and sinus tachycardia, or defined by supratherapeutic drug concentrations in the blood in the absence of an acute overdose.49 Unlike chronic theophylline and aspirin poisoning, this category of toxicity does not appear to cause the same acute life-threatening toxicity, although

CYCLIC ANTIDEPRESSANTS

853

there is little literature describing the clinical course of this cohort and it may even go unrecognized. Several reports of sudden death in children taking therapeutic doses of TCAs have been published in the last 10 years.121,126,127,160 The mechanism is unclear. QT prolongation with resultant torsades de pointes, advanced atrioventricular conduction delays, blood pressure fluctuations, and ventricular tachycardia are postulated mechanisms, although whether any of these effects contributed to the reported deaths is unknown. Prospective studies in children on therapeutic doses of TCAs by using 12-lead electrocardiograms, 24-hour ECG recordings, and Doppler echocardiography have failed to find any significant cardiac abnormalities as compared to children not on TCAs.13,41 However, authors recommend that TCAs should not be initiated or continued on any child with a resting QT interval greater than 450 msec or bundle-branch block.41

Unique Toxicity from “Atypical” Cyclic Antidepressants The CAs amoxapine and maprotiline have slightly different clinical toxic profiles.165 Although the incidence of serious cardiovascular toxicity is lower with amoxapine overdoses, the incidence of seizures is significantly greater than for the traditional TCAs.68,78,89 Moreover, seizures may be more frequent or status epilepticus may develop that is refractory to standard anticonvulsant therapy.100 Similarly, the incidence of seizures, cardiac dysrhythmias, and duration of coma is greater with maprotiline toxicity as compared to the older TCAs.33,77

DIAGNOSTIC TESTING Diagnostic testing for CA poisoning primarily relies on indirect bedside tests (ECG) and on other nonspecific laboratory analyses. Unlike acetaminophen evaluation, quantification of CA concentration provides little help for the acute management, but provides adjunctive information in supporting the diagnosis.

Electrocardiogram The ECG is an easy and convenient bedside tool that can provide important diagnostic information in assessing patients, and in predicting clinical toxicity after a CA overdose. Cyclic antidepressant toxicity results in distinctive and diagnostic electrocardiographic changes that may allow early diagnosis and targeted therapy when the clinical history and physical examination may be unreliable. Furthermore, decisions about treatment and patient disposition must frequently be made in the emergency department without the benefit of other clinical parameters. The maximal limb lead QRS interval duration is an easily measured ECG parameter that is a sensitive indicator of toxicity. One investigation reported that 33% of patients with a limb lead QRS interval of 100 msec or longer developed seizures and that 14% developed ventricular dysrhythmias.17 There was a 50% incidence of ventricular dysrhythmias among patients with a QRS duration of 160 msec or longer. No ventricular dysrhythmias occurred in patients with a QRS duration of 100 msec is associated with an increased incidence of serious toxicity including coma, need for intubation, hypotension, seizures, and dysrhythmias, making this ECG parameter a useful indicator of toxicity.30,86

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A T40-ms axis between 120 and 270 degrees is also associated with TCA toxicity, and in one study, it was found to be a more sensitive indicator of general toxicity than the QRS interval alone.30,108,168 A terminal QRS vector of 130–270 degrees discriminated between 11 patients with positive toxicology screens for TCAs and 14 patients with negative toxicology screens.108 With further analyses, this report concluded that the positive and negative predictive values of this ECG parameter for TCA ingestions were 66% and 100%, respectively, in a population of 299 general overdose patients. A retrospective study reported that a TCA-poisoned patient was 8.6 times more likely to have a T40-ms axis of more than 120 degrees than was a non-TCA-poisoned patient.168 Again, this parameter was a more sensitive indicator of TCA toxicity than the QRS interval. In both of these studies, patients with TCA ingestions/toxicity had altered mental status but not necessarily seizures and/or dysrhythmias specifically. However, the T40-ms axis is not easily measured in the absence of specialized computer-assisted analysis, limiting its practical utility. An abnormal rightward axis can be estimated by observing a negative deflection (terminal S wave) in lead I, and a positive deflection (terminal R wave) in lead aVR (Fig. 57–1B). Easily quantifiable measurements in lead aVR on a routine ECG can also predict toxicity (Fig. 57–3). When prospectively studied, 79 patients with acute TCA overdoses demonstrated that the amplitude of the terminal R wave and R wave/S wave ratio in lead aVR (RaVR, R/S aVR) were significantly greater in those patients who developed seizures and ventricular dysrhythmias.86 The sensitivity of RaVR ≥ 3 mm and R/S aVR ≥ 0.7 in predicting seizures and dysrhythmias was comparable to the sensitivity of a QRS ≥ 100 msec. In this study, an RaVR of 3 mm or more was the only ECG variable that significantly predicted these complications. Thus, specific ECG measurements such as the QRS interval duration and height of the R wave in lead aVR can be useful parameters in assessing and predicting CA toxicity, although neither is 100% sensitive in predicting cardiac and neurologic complications. Documenting the absence of these abnormalities on sequential ECGs, however, provides further evidence that cardiac toxicity is not developing. Serial ECGs should be obtained (at least three ECGs within the first 6 hours) to monitor for worsening of these parameters, which might signal the need for further interventions. Based on published data demonstrating ongoing changes of the QRS and T40-ms axis despite therapeutic interventions,87 ECG parameters alone are not ideal and should be used in conjunction with the patient’s clinical presentation, history, and course during the first several hours in decision making with regard to disposition and interventions.

Laboratory Quantitative determination of CA plasma concentration has limited utility in the immediate evaluation and management of patients with acute overdoses. The CAs’ pharmacologic properties—namely, large volumes of distributions, prolonged absorption phase, long distribution half-lives, pH-dependent protein binding, wide intrapatient variability of terminal elimination halflives, and development of tolerance among people chronically on these medications—limit the value of plasma concentrations in predicting acute toxicity. Plasma concentrations usually do not correlate with acute clinical toxicity for these reasons. In one study, serum drug levels failed to predict the risk of seizures or ventricular dysrhythmias accurately.17 Drug levels measured

A

B Figure 57–3. A. Normal QRS interval in lead aVR. B. Abnormal QRS interval in a patient with severe TCA poisoning. RaVR is measured as the maximal height in millimeters of the terminal upward deflection in the QRS complex. The S wave is measured in millimeters as the depth of the initial downward deflection.

shortly after an overdose may be higher or lower than the final equilibrated level. Because of the high tissue:serum concentrations, the serum concentration does not accurately reflect the total body burden of the drug. However, CA levels exceeding 1000 ng/mL are usually observed in patients with significant clinical toxicity (coma, seizures, and dysrhythmias), although life-threatening toxicity has also been observed in patients with levels less than 1000

CHAPTER 57

ng/mL.14,17,53,81,120,148 This serious toxicity at lower levels is probably a result of a number of factors, including the presence of coingestants, the circumstances of the ingestion (acute or acute on chronic), the timing of the level in relation to the ingestion, and the pharmacologic features as described above. Several studies demonstrate that both single and serial plasma levels are not predictive of clinical outcome or associated with clinical toxicity such as seizures and dysrhythmias and their resolution. Furthermore, quantitative levels are usually not readily obtainable in most hospital laboratories. Thus, evaluation and management should be guided by a combination of clinical signs and symptoms and the electrocardiogram. Analyzing CA levels may be helpful in diagnosing chronic CA toxicity. Therapeutic CA concentrations (including active metabolites) are generally in the range of 50–300 ng/mL. Any level outside this range, when measured at the appropriate time in association with onset or increase in adverse effects (tachycardia, dizziness, prolonged QT on ECG), is an indication to decrease or stop the medication. Finally, quantitative levels may also be helpful in determining the cause of death in suspected overdose patients. Forensic studies have found lethal CA levels ranging from

TABLE 57–3.

CYCLIC ANTIDEPRESSANTS

1100 to 21,800 ng/mL. The measurement of liver drug concentrations or parent-to-metabolite drug ratios is preferable in the postmortem setting because CA levels may increase up to 5-fold5,6 (Chap. 119). Qualitative determination of the presence or absence of CAs may help to confirm a diagnosis in certain circumstances. It may also be helpful in making decisions regarding disposition and/or transfer in young children with unintentional ingestions who are asymptomatic. Cyclic antidepressants can be detected qualitatively in the urine by thin-layer chromatography or by high-performance liquid chromatography (HPLC). Bedside immunoassays are commercially available but have not been adequately studied.136

MANAGEMENT Any person with a suspected or known ingestion of a CA requires immediate evaluation and treatment. Aggressive supportive care and hypertonic sodium bicarbonate are the mainstays of therapy (Table 57–3). The patient should be attached to a cardiac monitor and intravenous access should be secured. Early intubation is ad-

Treatment of Cyclic Antidepressant Toxicity

Toxic Effect

Treatment

Conduction Delays QRS > 100 msec RaVR ≥ 3 mm T40-ms axis > 130°

• NaHCO3 —1 mEq/kg IV boluses to reverse the abnormality or to a target serum pH of no greater than 7.55 • Consider continuous NaHCO3 infusion at 1.5 times maintenance IV fluid rate (150 mEq NaHCO3 in 1 L of D5W) • Controlled ventilation (if clinically indicated for hypoventilation)

Dysrhythmias Sinus tachycardia Wide-complex tachycardia/ ventricular tachycardia

Torsades de pointes

Hypotension

• No treatment • NaHCO3 —1 mEq/kg IV boluses to reverse the dysrhythmia or to a target serum pH of no greater than 7.55, and then consider continuous bicarbonate infusion • Controlled ventilation (if clinically indicated) • Correct hypoxia, acidosis, hypotension • Consider lidocaine—1 mg/kg slow IV bolus, followed by infusion of 20–50 µg/kg/min • Consider magnesium sulfate 25–50 mg/kg (maximum 2.0 g) IV over 20 minutes • Magnesium sulfate • Overdrive pacing • • • • • •

Seizures

• • • • • •

855

Isotonic saline (0.9% NaCl) boluses (up to 30 mL/kg) Trendelenburg position Correct hypoxia, acidosis NaHCO3 —1 mEq/kg IV boluses to a target serum pH of 7.50–7.55, and then consider continuous bicarbonate infusion Norepinephrine Consider extracorporeal mechanical circulation (ECMO, cardiopulmonary bypass) Benzodiazepines Secure airway with intubation if necessary Correct hypoxia, acidosis Barbiturates if benzodiazepines fail Continuous infusion of midazolam or propafol if barbiturates fail Consider neuromuscular paralysis/general anesthesia if all other measures fail

Adapted with permission from Liebelt EL: Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: The pivotal role for alkalinization and sodium loading. Pediatr Emerg Care 1998;14:293–298.

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vised for patients with CNS depression and/or significant ECG changes (ie, wide-complex tachycardia) because of the potential for rapid clinical deterioration. A 12-lead electrocardiogram should be obtained on all patients. Laboratory tests including glucose and electrolytes should be sent on all patients with altered mental status, as well as an arterial blood gas to assess the degree of acidemia and to guide alkalinization therapy. Aggressive interventions for maintenance of blood pressure and peripheral perfusion must be performed early to avoid irreversible damage. The options for gastrointestinal decontamination should then be considered.

Gastrointestinal Decontamination Ipecac-induced emesis is contraindicated, given the potential for precipitous neurologic and hemodynamic deterioration. Because of the potential lethality of large quantities of CAs, orogastric lavage should be considered in the symptomatic patient with an intentional overdose. Although the benefits of orogastric lavage for CA toxicity have not been substantiated by controlled trials, the potential benefits of removing significant quantities of a highly toxic drug must be weighed against the risks of the procedure.18 Because the anticholinergic actions of some CAs may decrease gastric emptying, attempts at gastric lavage up to 12 hours after ingestion may yield unabsorbed drug. Patients with altered mental status or seizures should only undergo orogastric lavage after endotracheal intubation to protect the airway. The benefit of performing orogastric lavage in young children with unintentional ingestions of CAs may not be similar as in adults with intentional ingestions. These scenarios usually do not result in ingestion of large quantities of pills and the procedure may be associated with more risks and impracticalities (size of holes in pediatric tubes). Activated charcoal should be administered in all cases. An additional dose of charcoal several hours later is reasonable after a large ingestion or in a seriously poisoned patient where unabsorbed drug may still be in the GI tract, there may be desorption of CAs from activated charcoal, or if the patient may be a poor metabolizer. It is important to monitor for the development of a paralytic ileus to prevent abdominal complications from additional doses of activated charcoal.

Wide-Complex Dysrhythmias, Conduction Delays, and/or Hypotension (Portions of this section are adapted with permission from Liebelt EL: Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: The pivotal role for alkalinization and sodium loading. Pediatr Emerg Care 1998;14: 293–298.) The mainstay therapy for treating wide-complex dysrhythmias, as well as for reversing conduction delays and hypotension, is the combination of serum alkalinization and sodium loading. This is probably best accomplished with hypertonic sodium bicarbonate (1 M solution, 1 mEq/mL, usually supplied as 8.4% solution giving 50 mEq per 50-mL ampule). In the late 1950s, alkalinization therapy with sodium lactate was proposed as a treatment for quinidine toxicity, which shares many of the CAs’ cardiotoxic effects because of its similar mechanism of action.11 French investigators recommended using sodium bicarbonate for treatment of tricyclicinduced dysrhythmias in the 1960s.15,123 Uncontrolled clinical studies demonstrated that treatment with sodium lactate or sodium bicarbonate was effective in treating the cardiovascular effects as-

sociated with CA toxcity.23 Subsequent controlled in vitro and in vivo studies in various animal models demonstrate that hypertonic NaHCO3 is effective in reducing QRS prolongation, increasing blood pressure, and reversing or suppressing ventricular dysrhythmias caused by CA toxicity.103,104,112,132–134 These studies also showed either equivalent or fewer beneficial effects of hyperventilation, sodium chloride, and other nonsodium buffer solutions as compared to NaHCO3, suggesting multiple reasons for its effectiveness. Several mechanisms are proposed for the beneficial effects of hypertonic sodium bicarbonate. First, elevating the blood pH through alkalinization increases the serum protein binding of CAs, thereby reducing the concentration of the unbound and pharmacologically active drug.83 This mechanism probably contributes the least to the beneficial effects of sodium bicarbonate because only a very small fraction of the total CA dose is present in the serum, owing to its high lipid solubility and very large volume of distribution. Furthermore, animal studies examining the exogenous administration of binding proteins (AAG) to ameliorate TCA toxicity failed to demonstrate any significant differences in cardiotoxicity.115 Second, increases in pH accelerate the recovery of sodium channels blocked by CAs by neutralizing the protonation of the drug-receptor complex, thereby facilitating the egress of the neutral form of the drug from the receptor site in the sodium channel.133,134 Third, lowering of serum potassium levels in the presence of increased bicarbonate concentrations results in membrane hypopolarization, which, in turn, diminishes the blockade of sodium channels, which are voltage-dependent.132 Because underlying acidosis may exacerbate CA cardiotoxicity, an additional beneficial effect of NaHCO3 lies in correction of acidosis. However, NaHCO3 is also effective when the blood pH is normal, suggesting another predominant mechanism for its effects.112,132 Increasing the extracellular concentration of sodium, or sodium loading, may overcome the blockade of the sodium channels through gradient effects (Fig. 57–2). This mechanism explains why in some animal studies NaHCO3 was more effective in decreasing cardiotoxicity than were other sodium-free buffer solutions. Hypertonic sodium chloride loading reverses cardiotoxicity in several animal studies.61,97,112 Hypertonic sodium chloride solution (15 mEq Na/kg) is highly efficacious in reversing QRS prolongation and hypotension, although an adequate direct comparison with NaHCO3 is not available.96 Unfortunately, no controlled human studies are attempting to dissect which mechanism of all those proposed is most important, although it is most likely a combination of all the mechanisms. Furthermore, no controlled studies demonstrate that sodium bicarbonate is effective; however, numerous reports and extensive clinical experience support its efficacy in treating serious CA cardiotoxicity.22,23,62,63 The optimal dosing and mode of administration of hypertonic NaHCO3, as well as indications for initiating and terminating this treatment, are also unsupported by controlled clinical studies. Instead, this information is extrapolated from animal studies, clinical experience, and an understanding of the pathophysiologic mechanisms of CA toxicity. A bolus or rapid infusion over several minutes of NaHCO3 (1 mEq/mL) at a dose of 1–2 mEq/kg should be administered initially.23,96,112 Higher doses have been used successfully to treat patients, but experience is limited. Continuous ECG monitoring should be in place to follow the progression of the ECG abnormalities. Additional boluses may be administered until the QRS interval narrows, the amplitude of RaVR decreases, the wide-complex tachycardia narrows, and the hypotension im-

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proves. Blood pH should be monitored after several bicarbonate boluses, aiming for a target pH of 7.50–7.55. Because there may be redistribution of the CA from the tissues into the blood over several hours for the reasons discussed previously, it may be reasonable to begin a continuous sodium bicarbonate infusion to maintain the pH in this range. Differences in outcomes between repetitive boluses alone and boluses with further bicarbonate infusions are not well studied. Although diluting NaHCO3 in dextrose water or saline renders it less hypertonic, reducing the sodium gradient effect, the beneficial effects of pH elevation may still be warranted. The use of hypertonic saline solutions (3% NaCl) or combined NaHCO3 and normal saline solutions (0.9%) for rapid infusion theoretically should be efficacious, although these modalities have not been adequately studied in humans. Hyperventilation, although a more rapid and easily titratable method of serum alkalinization, is not as effective as a single modality in reversing cardiotoxicity.72,96 Simultaneous hyperventilation and sodium bicarbonate administration may result in profound alkalemia and should be done only with extreme caution and careful monitoring of the pH.169 Hyperventilation without bicarbonate administration may be indicated in patients with pulmonary edema or congestive heart failure where the administration of large quantities of sodium may be contraindicated. Alkalinization and sodium loading with hypertonic NaHCO3 along with controlled ventilation (if clinically indicated) should be administered in all overdose patients presenting with major cardiovascular toxicity. Indications include any conduction delays (QRS ≥100 msec, R aVR ≥3 mm, and/or an unexplained or new right bundle-branch block), wide-complex tachycardia, and hypotension. Although the defined ECG parameters for conduction delays may be conservative indicators to start treatment, it is imperative to initiate treatment until CA toxicity can be excluded because of the risk for rapid and precipitous deterioration. The value of NaHCO3 therapy for isolated sinus tachycardia, narrow-complex supraventricular tachycardia, and its prophylactic use without other signs of cardiotoxicity has not been studied. It is unclear whether the failure of the QRS complex to narrow with sodium bicarbonate treatment excludes CA toxicity. Treatment should not be empirically started because of the risks of hyperosmolarity. Blood pH and resolution of ECG abnormalities have been suggested therapeutic endpoints for sodium bicarbonate therapy. Carefully monitoring and maintaining blood pH of 7.5–7.55 is a reasonable recommendation based on available evidence, avoiding profound alkalemia and its associated consequences. Some authors advocate for continuing alkalinization at least 12–24 hours after the ECG has normalized because of the drug’s redistribution from the tissue. However, the time observed for resolution or normalization of conduction abnormalities is extremely variable, ranging from several hours to several days despite continuous bicarbonate infusion.87 In some patients, clinical improvement occurred both before and during these ECG changes. Alkalinization is typically stopped or tapered when the patient has improved clinically and shown improvement of abnormal ECG findings. Additional therapeutic interventions for dysrhythmias and hypotension may be indicated if sodium bicarbonate and volume expansion with 0.9% NaCl are not effective.

Antidysrhythmic Therapy Sodium bicarbonate therapy should be the first-line treatment for CA-induced ventricular dysrhythmias, although further therapeu-

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tic interventions may be necessary for those dysrhythmias refractory to this therapy.104,134 By overcoming the sodium blockade, sodium bicarbonate can reverse the conduction slowing responsible for reentrant ventricular dysrhythmias. Lidocaine is the antidysrhythmic agent most commonly advocated for the treatment of CA-induced dysrhythmias, although there are no controlled clinical studies demonstrating its efficacy.22,23,113 Because lidocaine has membrane-stabilizing properties similar to CAs, which may impair conductivity and decrease cardiac contractility, some investigators argue against its use in CA poisoning.1 These theoretical concerns, however, are not well supported in the literature. The use of Class IA (quinidine, procainamide, disopyramide, and moricizine) and Class IC (flecainide, propafenone) antidysrhythmics is contraindicated because they have similar pharmacologic actions and thus may worsen the sodium channel inhibition caused by CAs and exacerbate cardiotoxicity. Class III antidysrhythmics (amiodarone, bretylium, and sotalol) prolong the QT interval and although unstudied, may be contraindicated as well. Because of its antidysrhythmic properties, magnesium sulfate may be beneficial in the treatment of ventricular dysrhythmias. Animal studies of the effects of magnesium on CA-induced dysrhythmias have yielded conflicting results.73,74 However, successful use of magnesium sulfate in the treatment of refractory ventricular fibrillation after TCA overdose has been reported.76 The routine use of magnesium, however, needs further evaluation. Based on electrophysiologic studies in animal models, the wide-complex tachycardia/ventricular tachycardia caused by CAs is rate-dependent.3,133 Slowing the heart rate in the presence of CAs may allow more diastolic time for drug unbinding from sodium channels and might result in an improvement in ventricular conduction, which could then abolish the reentry mechanism for dysrhythmias. This mechanism was the rationale for the past use of physostigmine and propranolol. Thus, it is hypothesized that decreasing the sinus rate may itself be effective in abolishing ventricular dysrhythmias by eliminating rate-dependent conduction slowing. Propranolol terminated ventricular tachycardia in an animal model, but, unfortunately, also caused significant hypotension.134 In one case series, patients developed severe hypotension or had a cardiac arrest shortly after receiving a
-adrenergic antagonist.45 Other animal studies suggest that preventing or abolishing tachycardia by sinus node destruction, or by using bradycardic agents that impede sinus node automaticity without affecting myocardial repolarization or contractility, may successfully prevent CA-induced ventricular dysrhythmias.3,4 The combined negative inotropic effects of
-adrenergic antagonists and CAs along with the significant cardiac and CNS effects reported with physostigmine use do not support their routine use in the management of CA-induced tachydysrhythmias at this time. Phenytoin’s use as an antidysrhythmic agent in CA toxicity has been extensively studied. Several animal and human studies advocate phenytoin’s success in preventing or reversing some conduction abnormalities.55,95 These studies show that phenytoin enhances atrioventricular and intraventricular conduction, as well as decreases ventricular automaticity. By increasing conduction velocity and membrane responsiveness, phenytoin could abolish reentrant dysrhythmias, making it a reasonable choice for CA-induced dysrhythmias. However, these studies are not well controlled for other confounding factors such as blood pH and sodium bicarbonate administration, they had very small numbers, and, in some, the cardiotoxicity was not severe. Other studies suggest phenytoin may have a proarrhythmogenic effect in the presence of

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CAs, thus inducing or worsening ventricular dysrhythmias.28 Based on available evidence, phenytoin is not recommended for wide-complex tachydysrhythmias associated with CAs.

Hypotension Hypotension is the most common cause of death secondary to CA toxicity and is the most difficult complication to treat. Standard initial treatment for hypotension should include volume expansion with isotonic saline, placement of the patient in the Trendelenburg position, and alkalinization/sodium loading with hypertonic sodium bicarbonate (if conduction abnormalities are present also). Hypotension unresponsive to these therapeutic interventions necessitates the use of inotropic and/or vasopressor drug support and possibly extracorporeal cardiovascular support. The choice of specific direct-acting or indirect-acting drug(s) to treat CA-associated hypotension is controversial because available data are limited and contradictory and because there is a theoretical concern that these drugs may precipitate potentially fatal dysrhythmias. Norepinephrine, epinephrine, dopamine, and dobutamine are proposed to be effective drugs for hypotension, but no controlled human studies are available. Furthermore, the pharmacologic properties of CAs complicate the choice of a specific agent. Specifically, CA blockade of neurotransmitter reuptake theoretically could result in a depletion of intracellular catecholamines. This blockade of norepinephrine and dopamine reuptake could then blunt the effect of dopamine, which is partially dependent on the release of endogenous norepinephrine for its inotropic activity.25 Also, CAs blunt the dopamine-induced release of norepinephrine directly by preventing its neuronal uptake. These properties along with their -adrenergic blockade and down-regulation of receptors suggest that a direct-acting vasopressor such as norepinephrine is more efficacious than an indirectacting catecholamine such as dopamine. On the other hand, norepinephrine at high doses may be dysrhythmogenic and might exacerbate cardiovascular toxicity. Pure
-adrenergic agonists, such as isoproterenol and dobutamine, and even combination and
-adrenergic agonists such as dopamine, could theoretically result in unopposed
-adrenergic activity and may worsen the hypotension. Animal data comparing various agents are conflicting and their direct applicability to clinical human poisoning is limited. In one study, norepinephrine (0.05–1.0 µg/kg/min) was more effective than dopamine (10–40 µg/kg/min) in an amitriptyline-induced hypotensive feline model; other investigators, however, found that dopamine was more effective in a similar model.42,66 Another study showed that norepinephrine at doses of 0.25–1.0 µg/kg/min and high doses of dopamine at 15–30 µg/kg/min were equally effective in reversing amitriptyline-induced hemodynamic alterations in cardiac output, mean arterial pressure, and systemic vascular resistance.162 A recent study reported that both norepinephrine and epinephrine increased the survival rate in TCApoisoned rats.75 In addition, epinephrine was superior to norepinephrine when used both with and without sodium bicarbonate, and the most effective treatment regimen in their study was epinephrine plus sodium bicarbonate—neither drug precipitated dysrhythmias. The authors propose that epinephrine is more efficacious because it augments myocardial perfusion more than norepinephrine and it improves the recovery of CA sodium channel blockade by hyperpolarization of the membrane potential through its stimulation of increased potassium intracellular trans-

port. These studies are limited because the effect of receptor down-regulation or catecholamine depletion cannot be assessed in the models of acute CA poisoning, which is different than many patients receiving chronic CA therapy prior to an acute ingestion. Furthermore, in all but one of these studies, animals were not treated with sodium bicarbonate, which is unlike clinical practice. Limited clinical data have suggested that norepinephrine is more efficacious than dopamine.157 In a retrospective study of 26 adult hypotensive patients, patients’ response rates to norepinephrine (5–53 µg/min) were significantly better than response rates to dopamine (5–10 µg/kg/min).159 Patients who failed to respond to dopamine at vasopressor doses (10–50 µg/kg/min) responded to norepinephrine (5–74 µg/min). However, the retrospective nature of this study and the subsequent lack of standard management therapies, indications for instituting vasoactive agents, and heterogeneity of the population limit its generalizability. In a case report of CA toxicity, glucagon is also reported to cause sustained increases in blood pressure.139 Based on the available data, pharmacologic effects, theoretical concerns, and experience, norepinephrine (0.1–0.2 µg/kg/min) is a sound choice for initial hypotension unresponsive to volume expansion and hypertonic sodium bicarbonate therapy. Central venous pressure and/or pulmonary artery catheterization may be necessary to guide the choice of additional vasopressor or inotropic agents, depending on the measured cardiac output and systemic vascular resistance, especially in the presence of other cardiodepressant drugs. If pharmacologic measures fail to correct hypotension, extracorporeal life support measures should be considered. Extracorporeal membrane oxygenation (ECMO), extracorporeal circulation (ECC), and cardiopulmonary bypass are successful adjuncts for refractory hypotension and life support when maximum therapeutic interventions fail.54,80,167 These modalities can provide critical perfusion to the heart and brain and maintain metabolic function while giving time for the body to metabolize and clear toxic concentrations of the drug by maintaining hepatorenal blood flow. Extracorporeal measures may then allow the impaired myocardium to recover. Further controlled studies are needed to evaluate these modalities and develop specific criteria for their use.

Central Nervous System Toxicity Adequate airway protection with intubation should be initiated in any comatose patient or patient with a significantly depressed mental status because of acute CA toxicity. The use of flumazenil in the patient with a known or suspected CA ingestion is contraindicated. Several case reports of patients with CA overdoses have reported seizures following the administration of flumazenil.56,84,98 Flumazenil antagonizes benzodiazepines at their receptor on the chloride ionophore of the GABA-receptor complex to reverse their pharmacologic effects. This action along with CAs’ inhibition of GABA-mediated chloride influx may explain the increased risk of seizures in these people. Physostigmine is a short-acting cholinesterase inhibitor, that was used in the past to reverse the CNS toxicity of cyclic antidepressants.26,106 However, physostigmine may increase the risk of cardiac toxicity and can cause bradycardia and asystole, as well as precipitate seizures in CA-poisoned patients, and thus is not recommended.117 Seizures caused by cyclic antidepressants are usually brief and may stop before treatment can be initiated. Recurrent seizures, prolonged seizures (>2 minutes), and status epilepticus need

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prompt treatment to prevent worsening acidosis, hypoxia, and the development of hyperthermia and rhabdomyolysis. Ensuring adequate ventilation and hydration may further minimize acidosis and prevent renal failure.68 Benzodiazepines are effective as first-line therapy for seizures.10 If this therapy fails, barbiturates should be administered. Failure to respond to barbiturates should lead to consideration of neuromuscular paralysis and general anesthesia with continuous EEG monitoring. Propofol controlled refractory seizures due to amoxapine toxicity.100 Propofol also acts at the GABA-chloride ionophore complex. The role of phenytoin as an anticonvulsant for CA-induced seizures is less clear. Some data demonstrate beneficial effects while other data question its efficacy. Phenytoin has been reported to reduce the incidence of amoxapine-induced seizures in dogs, but ineffective for imipramine-induced seizures in a rat study.10,12 Furthermore, there are some animal studies demonstrating that phenytoin may potentiate ventricular dysrhythmias.28 Based on this evidence, phenytoin is not recommended for seizures. The role of alkalinization and sodium loading in the treatment of CAinduced seizures has not been established, but is unlikely to be effective.

Elimination Enhancement No specific treatment modalities have demonstrated efficacy in enhancing the elimination of CAs with subsequent improved clinical outcome. Some investigators propose multiple doses of activated charcoal to enhance CA elimination because of their small enterohepatic and enterogastric circulation.92 Human volunteer studies and case series of patients with CA overdoses suggest that the half-life of CAs may be decreased by multiple-dose activated charcoal (MDAC).32,70,109,155 MDAC reduced the apparent half-life of amitriptyline to 4–40 hours in overdose patients, as compared to previously published values of 30 to more than 60 hours in overdose.155 Changes in the severity or duration of clinical toxicity, however, were not reported. Other investigators showed in human volunteers that MDAC reduced the half-life of therapeutic doses of amitriptyline about 20% as compared with no activated charcoal administration.70 However, the methodologic flaws and equivocal findings of these studies along with the lack of any positive outcome data for this intervention from additional studies do not provide overwhelming evidence to support its use in this setting.31,52 The pharmacokinetic properties of CAs discussed previously (large volumes of distribution, high plasma-protein binding) weighed against the small increases in clearance, and potential complications of MDAC, such as impaction, intestinal infarction, and perforation, do not warrant its routine use.31 However, MDAC conceivably might shorten the duration of clinical toxicity in those patients who are “poor metabolizers.” One additional dose of charcoal should be considered in patients with evidence of CNS and cardiovascular toxicity. Measures to enhance urinary CA excretion have a minimal effect on total clearance.70 Hemodialysis is ineffective in enhancing the elimination of CAs because of their large volumes of distribution, high lipid solubility, and extensive protein binding.58 Hemoperfusion overcomes some of the limitations of hemodialysis, but should not be that effective because of the CAs’ large volumes of distributions.114 However, improvement in cardiotoxicity has been anecdotally reported during hemoperfusion in several uncontrolled case reports, although it may have been coincidental.37 Currently,

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there is little substantial evidence to support the use of hemoperfusion in the management of CA overdose.

Investigational Therapies Tricyclic antidepressant antibodies are showing great promise in providing additional emergent antidotal therapy. The development and investigation of antibodies to TCAs have been underway for more than 10 years.65,71 An affinity-purified ovine polyclonal Fab fragment has sufficient affinity to remove TCAs (but not amoxapine or maprotiline) from serum and tissue receptors.118,124,125,144 Because TCAs are lipophilic and have a large volume of distribution, toxic doses in humans are close to 100-fold larger as compared to digoxin, causing initial concern that immunotherapy for these drugs was perhaps not a rational modality of treatment. The amount of Fab fragments required for equimolar drug neutralization is enormous, which probably significantly impacts the cost, and possibly safety, of the drug. However, animal investigations clearly demonstrated that TCA immune Fab treatment was beneficial in reversing cardiovascular toxicity even when the dose was only about 10—30% of the equimolar dose of TCA.24,36 Partial neutralization provided rapid improvement of QRS interval prolongation, hypotension, and heart rate in several independent animal models. Initial clinical trials show favorable results with TCA-immune Fab treatment in improving both cardiovascular and central nervous system toxicity.57 (Personal communication, Suzanne Ward PharmD, Protherics, Inc., Nashville, TN.) A Phase III clinical trial comparing TCA antibodies with standard treatment is currently being developed and is expected to be implemented in the future. This exciting new antidotal therapy will potentially impact on the mortality that is a result of TCA poisoning. Experimental studies demonstrate that induction of ventricular tachydysrhythmias during tricyclic antidepressant toxicity is heart-rate-dependent.3 A specific bradycardic agent, UL-FS 49, effectively impedes the marked sinus tachycardia and frequencydependent ventricular conduction delay associated with amitriptyline toxicity in a canine model.4 Pretreatment with this drug effectively prevented the onset of sustained ventricular tachydysrhythmias; thus, pretreated animals tolerated much higher serum concentrations of amitriptyline without adverse effect. In addition, unlike other
-adrenergic antagonists that have negative inotropic affects, UL-FS 40 did not appear to influence hemodynamics adversely, thereby potentially decreasing the risk of significant hypotension associated with its use. This investigational drug warrants further clinical studies in patients presenting with marked sinus tachycardia and conduction delays to determine its effectiveness in preventing wide-complex dysrhythmias and/or ventricular tachydysrhythmias.

Hospital Admission Criteria All patients who present with a known or suspected CA ingestion should receive continuous cardiac monitoring and serial electrocardiograms for a minimum of 6 hours. Fears of delayed complications and inability to predict toxicity led clinicians in the past to adopt all-inclusive admission guidelines for the suspected CA ingestion. The once-standard practice of admitting all patients with CA ingestion for medical monitoring because of the risk of late complications or sudden death is not supported by the current literature. Most patients develop major clinical toxicity within several hours of presentation.27 Several retrospective studies support a

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disposition algorithm which takes into account presenting clinical signs and symptoms.8,27,44,158 If the patient is asymptomatic at presentation, undergoes gastrointestinal decontamination, has normal ECGs, or has sinus tachycardia (with normal QRS) which resolves, and remains asymptomatic in the healthcare facility for a minimum of 6 hours without any treatment interventions, the patient may be medically cleared for psychiatric evaluation (if appropriate) or discharged home, unless there are other medical issues. A prospective study used the Antidepressant Overdose Risk Assessment (ADORA) criteria to identify patients who were at high risk for developing serious toxicity and thus proposed the following criteria for hospitalization.43 In this study, the presence of a QRS interval >100 msec, cardiac dysrhythmias, altered mental status, seizures, respiratory depression, or hypotension on presentation to the ED (or within 6 hours of ingestion if the time was known) was 100% sensitive in identifying patients with significant toxicity and subsequent complications. Furthermore, none of the low-risk patients (defined as absence of all these criteria) developed any further toxicity or complications, supporting the decision for medical clearance and/or discharge.Table 57–4 presents proposed guidelines for hospitalization after a cyclic antidepressant ingestion, that are based on current epidemiologic and clinical evidence. These guidelines must be used in conjunction with knowledge of the patient’s medical history and of the presence of coingestants that may present with similar signs and symptoms in making a decision for hospitalization or prolonged observation. This guidelines and other studies also demonstrate that most serious or fatal CA ingestions will declare themselves within several hours after ingestion/presentation with these major signs of toxicity mandating admission. Criteria specifically for ICU admission (other than patients requiring ventilatory and/or blood pressure support) versus an inpatient bed with continuous cardiac monitoring are less clear and probably more institution dependent152 (Chap. 104). The disposition of patients with persistent isolated sinus tachycardia or prolonged QTc with no concomitant altered mental status or blood pressure changes is not clearly defined. Previous studies demonstrate that these two parameters alone are not predictive of subsequent clinical toxicity or complications.43,44,53 In addition, the sinus tachycardia may persist for up to 1 week following ingestion.107,140 However, another study of pure TCA-overdose patients reported that a heart rate >120 beats/min and a QTc interval >480 msec were associated with an increased likelihood of major toxicity.30 These patients might be good candidates for observation units with continuous ECG monitoring and serial ECGs for 24 hours.

TABLE 57–4. Guidelines for Hospitalization after Cyclic Antidepressant Ingestion* Altered mental status Respiratory depression Cardiac conduction defects Cardiac dysrhythmias† Seizures Hypotension unresponsive to fluids *Presence of any one of these signs at presentation or within 6 hours of the ingestion warrants admission. † Presence of sinus tachycardia alone may warrant prolonged observation. See text for further explanation.

Qualitative toxicology testing demonstrating absence of CAs can provide additional support for discharging young children with questionable unintentional ingestions who remain asymptomatic earlier than 6 hours. Certainly for any patient, if there are any concerns about the accuracy of the ingestion history, psychosocial issues, or other coingestants with the potential for delayed toxicity, medical admission is warranted.

Inpatient Cardiac Monitoring The duration of cardiac monitoring in any patient initially exhibiting signs of major clinical toxicity is dependent on many factors. Certainly the duration of CA cardiotoxicity and neurotoxicity may be prolonged as might be expected from the long serum half-life of CAs, in those patients who are slow hydroxylators, or in the presence of a coingestant that alters the metabolism of CAs or causes cardiac or neurologic toxicity. Recommendations from the older literature for 48–72 hours of ICU monitoring even in mild CA ingestions stem from isolated case reports of late-onset dysrhythmias, CNS effects, and sudden deaths.46,48,116,138 However, review of these cases shows inadequate gastric decontamination, inadequate therapeutic interventions, and significant ongoing complications of overdose. Several retrospective studies demonstrate that late, unexpected complications in CA overdoses (such as seizures, dysrhythmias, and death) do not occur in patients who had few or no major signs of toxicity at presentation or a normal level of consciousness and normal ECG for 24 hours.27,40,53,119,152 All fatalities due directly to CA toxicity occur in the first 12–24 hours. Using normalization of ECG abnormalities as an endpoint for therapy and discharge is problematic and subject to discussion. Previous studies document the variable resolution and normalization of QRS prolongation and T40-ms axis rotation.111,143 Small numbers of patients, inconsistent therapeutic interventions, and infrequent intervals at which serial ECGs were obtained flawed these studies. In a prospective observational study of 36 patients who had at least three ECGs in the first 8 hours, conduction abnormalities, specifically QRS interval prolongation and T40-ms axis rotation, varied widely in the time required for resolution, ranging from hours to days.87 More importantly, these two parameters remained persistently abnormal despite standard therapeutic interventions, including GI decontamination and sodium bicarbonate therapy. Clinical improvement including mental status and hypotension occurred both before and during resolution of ECG abnormalities. Although this study was limited by the lack of premorbid baseline ECGs available for comparison, the data support the clinical impression that such patients are not at an increased risk for development of late complications. Based on the available literature, it is reasonable to recommend that after the mental status and blood pressure have normalized, patients should be monitored an additional 24 hours off all therapy, including alkalinization, antidysrhythmics, and inotropics/ vasopressors. If the patient shows improvement of ECG abnormalities with the above criteria, the patient may be discharged to a monitored bed on the ward with a low risk of further complications.

SUMMARY Cyclic antidepressant poisoning continues to be a cause of serious morbidity and mortality worldwide. The distinctive characteristics

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of these drugs can cause significant central nervous system and cardiovascular toxicity, the latter being responsible for the mortality as a result of overdose of these drugs. Cardiovascular toxicity ranges from mild conduction abnormalities and sinus tachycardia to wide-complex tachycardia, hypotension, and asystole. Central nervous system toxicity may include delirium, lethargy, seizures, and coma. The ECG is a simple, readily available diagnostic test that can predict the development of significant toxicity, particularly seizures and/or dysrhythmias. Management strategies are based primarily on the pathophysiology of these drugs’ toxicities—namely, sodium channel blockade in the myocardium. Alkalinization and sodium loading with sodium bicarbonate and isotonic saline are the principal modes of specific therapy for cardiovascular toxicity. Investigational immunotherapy with TCA antibodies has shown promising results in animal and initial clinical trials. Guidelines for observing or admitting patients to the hospital may be based on initial clinical presentation and/or development of clinical symptomatology and ECG changes.

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58

SEROTONIN REUPTAKE INHIBITORS AND ATYPICAL ANTIDEPRESSANTS Christine M. Stork

Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) data 1987–1996, and the U.S. Food and Drug Administration adverse event database through 1997, there were 57 SSRI-related deaths reported, only 6 of which could be attributed to the SSRI alone.8 In those same years, there were more than 107,000 exposures to SSRIs reported to the AAPCC TESS (p. 1752 and Chap. 116).

A 38-year-old female presented to the Emergency Department (ED) after a history of antidepressant overdose. She was drowsy, but initially responded to voice. The vital signs were blood pressure, 110/60 mm Hg; pulse, 110 beats/min; respiratory rate, 13 breaths/min; and temperature, 37°C (98.6°F). The physical examination was noncontributory with 4-mm reactive pupils, normal mucous membrane findings, and positive bowel sounds. The patient’s ECG demonstrated a sinus tachycardia with a QRS duration of 90 msec. The patient received 1 dose of oral activated charcoal. During observation, the patient experienced a brief 30-second generalized seizure. Repeat vital signs included blood pressure, 90 mm Hg by palpation; pulse, 120 beats/min; respiratory rate, 18 breaths/min; and temperature, 37.5°C (99.5°F). After an intravenous infusion of 2 L of 0.9% sodium chloride, her blood pressure returned to 120/60 mm Hg. The patient’s electrocardiogram (ECG) remained unchanged. A 4-hour acetaminophen level was reported as negative, and the patient’s mental status improved over the next 16 hours. A relative revealed that the patient had access to venlafaxine.

PHARMACOLOGY The modulation of serotonin neurotransmission has a definitive role in the treatment of depression.113 However, the exact etiology of depression and the mechanism by which increased serotonergic neurotransmission attenuates symptoms remain unclear. Some postulated causes of depression include decreased overall serotonin neuronal storage, increased serotonin receptor sensitivity, and, finally, serotonin overactivity resulting in depressed dopamine neurotransmission.113,132,144,146 The SSRIs are distinct psychopharmaceutical agents capable of specifically inhibiting the reuptake of serotonin.6 Their selectivity for serotonin reuptake may be structurally related to the p-trifluoromethyl substitution in some of these agents147 (Fig. 58–1). By inhibiting serotonin reuptake, these drugs potentiate the activity of neuronally released serotonin and may subsequently alter the sensitivity of serotonin receptors. In addition, increased serotonergic activity, particularly at 5-HT2A receptors, may result in antidepressant activity through reduction of dopaminergic release.146 Unlike tricyclic antidepressants and other atypical antidepressants, SSRIs have little direct interaction with cholinergic receptors, γ-amino butyric acid (GABA) receptors, sodium channels, or adrenergic reuptake (Table 58–2).

Many antidepressants inhibit the reuptake of serotonin as a means to achieve their therapeutic effect. The class of selective serotonin reuptake inhibitors (SSRIs) includes citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (Fig. 58–1). Table 58–1 lists the pharmacology, therapeutic doses, and metabolism of the currently available SSRIs and other atypical antidepressants.

HISTORY AND EPIDEMIOLOGY Initially marketed in the early 1980s, SSRIs are currently considered first-line therapy for the treatment of depressive disorders.92 Since the finding that SSRIs are as effective as the tricyclic antidepressants for the treatment of major depression, they have become the largest prescribed class of medication for its treatment.108,127 SSRIs are also used to treat obsessive/compulsive disorders, panic disorder, alcoholism, obesity, and various other medical and psychologic disorders.36,95 SSRIs differ from previously used antidepressants in that they have fewer adverse effects, particularly with respect to those characteristics that limit patient compliance, such as weight gain and anticholinergic effects37 (Chap. 57). The relative safety of the SSRIs after overdose, when compared with traditional antidepressants, makes them desirable. This is particularly important prior to the onset of their therapeutic benefit, which can be delayed for up to 30 days. According to a study that summarized reports of SSRI toxicity using Medline 1985–1996, the American Association of

PHARMACOKINETICS AND TOXICOKINETICS The SSRIs display diverse elimination patterns and have numerous active metabolites, which substantially increase both the duration of therapeutic effectiveness and the time during which drug interactions and adverse drug reactions can occur (Table 58–1). Important pharmacokinetic and pharmacodynamic drug interactions are reported with therapeutic dosing. (Pharmacodynamic interactions are listed under “Serotonin Syndrome,” later in this chapter.) The SSRIs and their active metabolites are both substrates for and potent inhibitors of cytochrome P450 (CYP) isoenzymes.57,114 For example, fluoxetine, fluvoxamine, citalopram,

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Figure 58–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

The structures of common selective serotonin reuptake inhibitors.

venlafaxine, mirtazapine, paroxetine, and sertraline are substrates for the CYP2D6 isoenzyme. Additionally, many of these also inhibit CYP2D6 (Table 58–1). The ability to inhibit CYP2D6 is greatest with paroxetine, followed by norfluoxetine, and finally fluoxetine.27 The consequences of these interactions are manifest when the metabolism of drugs and toxins that rely on this isoenzyme for metabolic transformation is altered. This includes the aforementioned SSRIs that is substrates for this system. Chapter 11 discusses other cytochrome inhibitions.

whereas the development of ECG abnormalities was delayed for as long as 24 hours following ingestion.105 Although the mechanisms are unclear, experimental models suggest that the didesmethylcitalopram metabolite of citalopram prolongs the QT interval duration, whereas high levels of both the parent drug and this metabolite result in seizures and ventricular dysrhythmias.13,21 In human case reports concurrent exposure to other drugs capable of producing these effects, such as tricyclic antidepressants, was not excluded by laboratory studies. Until further information is available, all patients exposed to citalopram should be carefully monitored for the development of ECG abnormalities and seizures.

OVERDOSE PATHOPHYSIOLOGY The effects that occur following overdose are a direct extension of the pharmacologic activity of SSRIs in therapeutic doses. Excess serotonergic stimulation is prominent and nonselective.

CLINICAL MANIFESTATIONS The acute manifestations of SSRI overdose include nausea, vomiting, dizziness, blurred vision, and, less commonly, central nervous system (CNS) depression and sinus tachycardia.14,15 Hyponatremia, seizures, delayed seizures, and QRS complex prolongation are also reported, but are rare with most SSRIs, even after large overdoses15,56,72 (Table 58–3). Citalopram causes a widening of QT complexes and seizures in a dose-related manner. These effects typically occur in patients acutely exposed to more than 600 mg of citalopram, or in those with serum levels greater than 40 times the expected therapeutic levels.58,104,105 In one case series, seizures were an early finding,

MANAGEMENT Treatment of patients with SSRI overdose is largely supportive. Dextrose and thiamine should be given to patients presenting with an alteration in mental status as indicated. Although cardiac manifestations after SSRI overdose are rare, a 12-lead ECG should be obtained to identify the effects of other, more life-threatening antidepressants to which the patient may have access (Chap. 57). Serum electrolytes and an acetaminophen level, and in females, a pregnancy test, may be useful for monitoring and treatment of patients with intentional overdose. After the patient is stabilized, oral activated charcoal (1 g/kg) in a slurry may be useful to adsorb drug remaining in the gastrointestinal tract. Because of the potential for unexpected changes in mental status, syrup of ipecac should not be used in the management of these patients. Overdoses solely of SSRIs are rarely lifethreatening; therefore, orogastric lavage is not generally indicated.

CHAPTER 58

TABLE 58–1.

SEROTONIN REUPTAKE INHIBITORS AND ATYPICAL ANTIDEPRESSANTS

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Drug Mechanism and Information for SSRIs and Atypical Antidepressants

Metabolized Primarily by CYP

Major Active Metabolites

Major Metabolite t1⁄2

Drug (d) or Metabolite (m) Inhibits CYP (strong inhibitors are bold)

33–37

2C19, 3A4, 2D6

?

None

14–100

24–144

2C9, 2D6

Monodesmethylcitalopram, didesmethylcitalopram Norfluoxetine

4–16 d

25 8–28 20

15–23 2.9–44 24

1A2, 2D6 2D6 2C9, 2B6, 2C19, 2D6, 3A

None None Desmethylsertraline

None None 62–104 h

2D6 (d,m), 2C19 (d,m), 2D6 (d, m), 3A4 (m) 1A2, 2C9, 2C19, 3A4 2D6 2C19 (d,m)

Atypical Antidepressants Serotonin Reuptake Inhibitors (SRIs) with
-Adrenergic Antagonism: Trazodone (Desyrel) 50–600

0.47–1

3–9

2D6

?

None

Nefazodone (Serzone)

300–600

0.22–0.87

3.5

3A4

Metachlorophenylpiperazine Triazoledione, hydroxynefazodone

2–33 h

3A4 (d,m[hydroxynefazodone])

SRI with Inhibition of Reuptake of Norepinephrine and Dopamine: Venlafaxine (Effexor)

75–375

6–7

3–4

2D6

O-desmethylvenlafaxine, depends on 3A4, and 2C19 for metabolism

10 h

None

SRI with
2-Adrenergic Antagonism Mirtazapine (Remeron)

15–45

?

20–40

3A4

Desmethylmirtazapine

?

None

SRI with Inhibition of Reuptake of Biogenic Amines or Dopamine Bupropion (Wellbutrin, Zyban)

150–450

20

9.6–20.9

2B6

Hydroxybupropion

24–37 h

None

Drug Mechanism and Example

Typical Daily Dose range (mg)

Vd (L/kg)

t1⁄2 (hr)

Selective Serotonin Reuptake Inhibitors (SSRIs) Citalopram (Celexa)

20–60

12–15

Fluoxetine (Prozac)

10–80

Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft)

100–300 10–50 50–200

Patients with small unintentional overdoses of SSRIs are not expected to develop significant signs and symptoms of poisoning. Those patients, frequently children, with well-defined small unintentional oral ingestions may be managed in the home with close observation.94

ADVERSE EFFECTS AFTER THERAPEUTIC DOSES Adverse effects commonly attributed to therapeutic doses of SSRIs include gastrointestinal symptoms (anorexia, nausea, vomiting, diarrhea), sexual dysfunction in both males and females, headache, insomnia, jitteriness, dizziness, and fatigue.149 Less common adverse effects include sedation, particularly following

citalopram and paroxetine as a result of their weak anticholinergic activity, and anxiety following fluoxetine treatment.86 Movement disorders, most commonly akathisia and dystonia, also occur after SSRI use.1,44,46,87 These extrapyramidal side effects may be related to the complex interplay between serotonergic and dopaminergic activity. Predisposing factors for the development of movement disorders include preexisting neuromuscular disease and concomitant use of dopamine antagonists such as antipsychotics.81 The syndrome of inappropriate antidiuretic hormone (SIADH), in which severe hyponatremia may occur rapidly, is associated with SSRI use. In an animal model, the effect appears to be serotonin mediated with a dose-related increase in serum cortisol concentration, potentiation of oxitriptan-induced elevations in serum cortisol concentrations, and increased adrenocorticotropin

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TABLE 58–2.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Receptor Activity of SSRIs and Atypical Antidepressants

Drug SSRIs Citalopram (Celexa) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Atypical Antidepressants Bupropion (Wellbutrin, Zyban) Duloxetine (investigational) Mirtazapine (Remeron) Nefazodone (Serzone) Reboxetine (Edronax, Vestra) Trazodone (Desyrel) Venlafaxine (Effexor)

Mechanism

Peripheral
-Adrenergic Agonism

Serotonin Agonism

Dopamine Agonism

SSRI, antimuscarinic SSRI SSRI SSRI, antimuscarinic SSRI

++++ ++++ ++++ ++++ ++++

0 0 0 0 0

0 0 0 0 0

Inhibits reuptake of biogenic amines SRI, Norepinephrine reuptake inhibitor α2-adrenergic antagonism, 5HT2/5HT3 SRI, 5HT2 receptor antagonism Selective Norepinephrine reuptake inhibitor SRI, α-adrenergic antagonist SRI, norepinephrine and dopamine reuptake inhibitor

+++

+++

+++

++++

0

++

++++ ++++

0 0

+++ 0

0 ++++

0 0

++++ +

++++

0

++

SRRI: selective serotonin reuptake inhibitor; SRI: serotonin reuptake inhibitor; +: weak if any agonism; ++: weak agonism; +++: strong agonism; ++++: very strong agonism; 0: no effect.

(ACTH) and vasopressin concentrations.40 A review of the literature identified females over age 70 who are concomitantly receiving diuretic therapy to be at greatest risk of SIADH.77 The onset of symptoms can occur from 3 days to 4 months after the initiation of therapy, but most often occurs within the first 3 weeks of therapy.148 Serotonin-mediated platelet dysfunction is also reported.69

Serotonin Syndrome The SSRIs are associated with the development of the serotonin syndrome. This syndrome is also referred to as the serotonin behavioral or hyperactivity syndrome.54 First described in animals, serotonin excess causes hyperactivity, forepaw-treading, headweaving, hind-limb abduction, and an arched tail, in addition to

TABLE 58–3. A Predictive Analysis of the Relative Potential for Seizures and QRS Prolongation of SSRIs and Atypical Antidepressants Drug Classic SSRIs Citalopram (Celexa) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Others Bupropion (Wellbutrin, Zyban) Duloxetine (Investigational) Mirtazapine (Remeron) Nefazodone (Serzone) Reboxetine (Edronax, Vestra) Trazodone (Desyrel) Venlafaxine (Effexor)

Seizures

QRS Prolongation

+++ + + + +

+++ + + + +

++++ ++++ Unknown + ++++ + ++++

+ Unknown ++ 0 Unknown 0 +++

0: does not cause; +: very rarely if ever causes; ++: rarely causes; +++: causes; ++++: very commonly causes.

tremor, rigidity, salivation, flushing, myoclonus, and seizures. In humans, the serotonin syndrome was first described in patients treated with monoamine oxidase inhibitors (MAOIs) who were given other drugs that enhance serotonergic activity.25,101,131 It is characterized by an altered mental status, autonomic instability, and neuromuscular abnormalities resulting in hyperthermia.88,97 However, ingestion of an MAOI is not required for this syndrome to develop, and its initiation is unpredictable (Table 58–4). A prospective study of depressed inpatients given clomipramine demonstrated that 16 of 38 patients experienced symptoms consistent with the serotonin syndrome.84 All except two cases spontaneously resolved within 1 week without discontinuation of therapy. A study of 38 cases led to suggested diagnostic criteria for the serotonin syndrome. When other etiologies are excluded and an antipsychotic agent is not being concomitantly used, three of the following clinical findings should be present for a diagnosis of serotonin syndrome: altered mental status, agitation, myoclonus, hyperreflexia, diaphoresis, tremor, diarrhea, and incoordination.137 These criteria, although not validated in human trials, can serve as a guide when evaluating potential cases of serotonin syndrome. Untreated patients may develop lactic acidosis, rhabdomyolysis, myoglobinuria, renal and hepatic dysfunction, disseminated intravascular coagulation, or adult respiratory distress syndrome.89,137 The pathophysiologic mechanism of the serotonin syndrome is not completely understood, but involves excessive selective stimulation of serotonin 5-HT1A receptors. Serotonin 5-HT2A agonism was initially thought to be involved as well. However, animal models found that specific stimulation of 5-HT1A receptors resulted in signs and symptoms of serotonin syndrome even when 5HT2A receptors were inactivated.30 The 5-HT1D receptors, stimulated with antimigraine drugs such as sumatriptan, are not implicated in cases of serotonin syndrome. Cases of serotonin syndrome are associated with many agents that increase synaptic serotonin or enhance 5-HT1A receptor stimulation.

CHAPTER 58

TABLE 58–4.

SEROTONIN REUPTAKE INHIBITORS AND ATYPICAL ANTIDEPRESSANTS

Potential Causes of Serotonin Syndrome

Drugs That Inhibit the Breakdown of Serotonin Monamine oxidase inhibitors (nonselective) Phenelzine, moclobemide, clorgyline, isocarboxyzid 16,22,25,38,51,53,65,76,107,115,128,130,133,139,140 Ayahuasca preparations—psychoactive beverage for religious purposes in the Amazon and Orinoco River Basins (harmine and harmaline)22 Drugs That Block Reuptake of Serotonin Dextromethorphan115 Meperidine51 SSRIs Fluoxetine, citalopram, paroxetine, fluvoxamine, sertraline4,9,11,16,26,34,38,45,49,53,55,61,71,85,93,102,107,111,119,128,129,136 Clomipramine79,107,117,133 Nefazodone18,71 Pentazocine61 Trazodone45,52,99,110,111 Venlafaxine29,65,80 Cocaine140—weak reuptake inhibitor Serotonin Precursors or Agonists Buspirone4,52 Lithium79,93,99 131,136 L-Tryptophan Lysergic acid diethylamide (LSD)126 Valproic acid18 Drugs That Enhance Serotonin Release MDMA (ecstasy)76,130 Mirtazapine11

The serotonin syndrome occurs most commonly following the use of combinations of serotonergic agents. This syndrome is also reported in patients following a single dose, high therapeutic doses, or overdoses of certain serotonergic agents in adults and children.29, 49,75,80,85,102,110,117 Although selective MAO enzyme subtype A (MAO-A) inhibitor drug combinations at therapeutic doses are infrequently reported to cause serotonin syndrome, there are sporadic reports implicating selegiline or moclobemide when given in combination with SSRIs.33,91 The serotonin syndrome may also occur following the discontinuation of therapy of one serotonergic agent when an insufficient lag time occurs before initiating alternative therapy.119,120 Some reasons for the development of the serotonin syndrome under these circumstances include residual pharmacologic effect, receptor down- or up-regulation, and the presence of active metabolites. For example, fluoxetine metabolism results in an active metabolite, norfluoxetime, with comparable pharmacologic effects and a half-life substantially longer than that of the parent drug. Residual effects of this metabolite may result in serotonin syndrome when another serotonergic agent, usually another antidepressant, is initiated prior to the complete elimination of norfluoxetine.26 Treatment for the serotonin syndrome begins with supportive care and a focus on decreasing muscle rigidity. Because this muscular rigidity is thought to be responsible for hyperthermia and death, rapid external cooling in conjunction with the aggressive use of benzodiazepines should limit the complications associated with prolonged hyperthermia. In severe cases, neuromuscular blockade should be considered to achieve rapid muscle relaxation.

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The time course of the serotonin syndrome is variable and related to the time required to decrease drug levels of the offending agents. The serotonin syndrome resolves in most patients within 24 hours after removal of the offending drug, but can be prolonged when caused by drugs with long half-lives, protracted duration of effects, or active metabolites. Several case reports suggest the successful use of the antihistamine, cyproheptadine (4 mg po) acting as a nonspecific antagonist at 5-HT1A and 5-HT2 receptors.55,82 The patients typically had mild to moderate symptoms of serotonin syndrome and were not hyperthermic. It is uncertain whether these patients would have responded to supportive care. However, pretreatment with nonspecific serotonin antagonists and serotonin 5-HT1A-receptor antagonists prevents the development of the serotonin syndrome in animals.48,67,135 Other drugs that are anecdotally reported to be successful in the treatment of symptoms caused by the serotonin syndrome include methysergide (2 mg twice daily), chlorpromazine, and propranolol.50,52,59,121 Because all of these agents are of unproven utility, aggressive cooling and sedation with a benzodiazepine remain the basis of therapy.

Differential Diagnosis of the Serotonin Syndrome from the Neuroleptic Malignant Syndrome There are many overlapping features between the serotonin syndrome and the neuroleptic malignant syndrome (NMS) (Chap. 59). Some authors call these “spectrum disorders” that can be caused by drugs with both antidopaminergic and/or proserotonergic effects.90,150 Altered mental status, autonomic instability, and changes in neuromuscular tone that may result in hyperthermia characterize both syndromes. However, the implicated agents and pathophysiologic mechanisms are distinct. The development of NMS involves rapid blockade of dopaminergic neurons in the central nervous system, whereas the serotonin syndrome appears to result from acute overstimulation of serotonin receptors (5-HT1A). 5-HT2A agonism results in an overall decrease in the release of neuronal dopamine, and some authors describe NMS with the use of serotonin-enhancing drugs. However, the levels of measured dopamine and serotonin metabolites in NMS patients support the hypothesis of central dopaminergic hypoactivity that is unrelated to increased serotonergic activity.5,98 In addition to the associated medications, the time courses of the two syndromes are substantially different. Signs and symptoms of the serotonin syndrome develop within minutes to hours after exposure to the offending agent, whereas NMS typically develops days to weeks after daily exposure to the drug in question.53 Also, after symptoms develop and offending drugs are discontinued, the NMS can last for as long as a week, whereas the serotonin syndrome usually resolves within 24 hours. Patients with serotonin syndrome are also more likely to present with hyperreflexia and myoclonus, rather than with acute muscular “lead pipe” rigidity that occurs in those patients with NMS.53,78

ATYPICAL ANTIDEPRESSANTS Atypical antidepressants are defined as not belonging to a set classification of antidepressants. As such, they are not selective serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. In general, the atypical antidepressants are

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newer antidepressants that are developed in an attempt to decrease the undesirable side effects of traditional antidepressants.

Serotonin/Norepinephrine Reuptake Inhibitors

In addition to inhibiting the reuptake of serotonin, venlafaxine inhibits the reuptake of norepinephrine and dopamine. Venlafaxine produces a rapid down-regulation of central
-adrenergic receptors, which may result in a faster onset of antidepressant effect.124 Patients acutely exposed to venlafaxine may present with nausea, vomiting, dizziness, tachycardia, central nervous system depression, hypotension, hyperthermia, hepatic enzyme elevations, and seizures.68,145 QRS prolongation and ventricular tachycardia have resulted in death.7,12,118,153 Although there are no clinical data on effectiveness, sodium bicarbonate may be theoretically helpful in attenuating these cardiotoxic effects. Similar investigational drugs are duloxetine and milnacipran,19 which inhibit the reuptake of serotonin and norepinephrine. Overdose information is lacking, but clinical effects would be expected to be similar to venlafaxine overdose.

Bupropion is a unicyclic antidepressant. The exact pharmacologic mechanism of bupropion’s action is unclear, but both the parent drug and an active metabolite may inhibit the reuptake of biogenic amines. Extended-release formulations of bupropion are frequently employed as adjuncts to enhance smoking cessation therapy.70 At doses greater than 450–500 mg/d, there is a substantial risk of seizures.31,73 Acute large overdoses may result in seizure activity with and without QRS complex prolongation.20,63,64,103,125,134,138 In some cases, these effects were delayed for up 10 hours, particularly after ingestion of sustained-release preparations.62 Symptoms were reported to continue for up to 48 hours. Several studies suggest that the seizures following either bupropion overdose or high therapeutic doses are caused by the metabolite hydroxybupropion.39,106 Elevated hydroxybupropion levels were documented after seizures when bupropion levels were no longer detectable.31,39,116 Treatment, when required for seizures, should be supportive and include the judicious use of benzodiazepines, followed by barbiturates. If QRS prolongation occurs, the patient should be treated with sodium bicarbonate (Antidote in Depth: Sodium Bicarbonate). Other serious adverse effects reported after bupropion use include hepatic dysfunction, rhabdomyolysis, and isolated reports of dyskinesia, altered vestibular and sensory function, and serum sickness.28,43,141,151

Norepinephrine Reuptake Inhibitors

Reboxetine is a selective norepinephrine reuptake inhibitor.143 Lack of experience precludes an analysis of overdose data. However, toxicity can be extrapolated from adverse effects reported in clinical trials and from experience with other drugs possessing similar pharmacologic characteristics. In particular, overdosed patients should be carefully monitored for tachycardia, hypotension, and the development of seizures.

Trazodone is a serotonin agonist that acts through inhibition of serotonin reuptake. In addition, trazodone may have some peripheral -adrenergic antagonist activity. Central nervous system depression and orthostatic hypotension are the most common complications after acute overdose of trazodone.42 Trazodone is rarely reported to cause SIADH. This effect may be responsible for seizures, which are also rarely reported after acute overdose.6,142 Priapism, reported with the therapeutic use of trazodone, may occasionally occur after overdose23,42 (Chap. 30). Overdose management includes supportive care and fluids and vasopressors, if necessary.

Other Reuptake Inhibitors

Nefazodone inhibits the reuptake of serotonin and is an antagonist of serotonin 5-HT2 receptors.3 Chronic therapeutic use of nefazodone over 14–24 weeks is reported to result rarely in centrilobular hepatic necrosis.2 Experience with this drug in acute overdose is limited. Single cases of acute overdose show limited toxicity

CHAPTER 58

SEROTONIN REUPTAKE INHIBITORS AND ATYPICAL ANTIDEPRESSANTS

that includes CNS depression and hypotension, similar to trazodone.24,41 Careful clinical monitoring is advised until more acute overdose information is available.

The mechanism of action of mirtazapine is unique in that it increases neuronal norepinephrine and serotonin through 2adrenergic antagonism.32 Mirtazapine also blocks some subtypes of 5-HT receptors, including 5-HT2 and 5-HT3, which appear to have antidepressive effects.100 The main effects that occur after acute overdoses of mirtazapine include the alteration of mental status and tachycardia.17 Large overdoses or coingestants may be responsible for reports of respiratory depression and prolongation of the QT interval.17,47,66,112 Because more overdose data are required before a precise constellation of symptoms can be attributed to this drug, careful clinical monitoring is advised. In therapeutic usage, mirtazapine caused a single case of reversible agranulocytosis.96

871

leading to alterations in serotonergic activity, including interactions with other neurotransmitters (γ-aminobutyric acid (GABA), norepinephrine, and dopamine); or biologic/cognitive sensitivity in individual patients.123 Although postulated, antimuscarinic withdrawal seems an unlikely cause because in a human model, the antimuscarinic effects of desipramine failed to protect against paroxetine withdrawal.35 Treatment of patients exhibiting discontinuation symptoms should include supportive care and the reinitiation of the discontinued drug, if reinitiation of the drug is not contraindicated. The drug should then be tapered at a rate that allows for improved patient tolerance. Many other antidepressants discussed in this chapter are also reported to result in discontinuation reactions. Symptoms appear similar to those reported after discontinuation of SSRIs and are treated in a similar manner10,74 (Chap. 72).

SUMMARY The toxicity of SSRIs or atypical antidepressants following acute overdose is usually not life-threatening, although a few agents produce seizures or cardiac toxicity. Treatment is generally supportive for all of these agents. There are, however, significant drug interactions and adverse drug reactions associated with serotonin reuptake inhibitors that may lead to acute life-threatening events. In addition, the management of these patients is frequently complicated because they are also likely to have concomitant access to more life-threatening antidepressants such as TCAs and MAOIs.

REFERENCES

DRUG DISCONTINUATION SYNDROME A drug discontinuation syndrome manifested by withdrawal manifestations is pharmacologically based. Like classic drug withdrawal, this syndrome also includes symptoms resulting from psychological withdrawal. Drug discontinuation syndromes are commonly reported after withdrawal of conventional antidepressants, including tricyclic antidepressants and monoamine oxidase inhibitors83 (Chaps. 57 and 60). Selective serotonin reuptake inhibitors are reported to cause a discontinuation syndrome that typically begins within 5 days after drug discontinuation and that may last up to 3 weeks.60 The most frequently reported symptoms include dizziness, lethargy, paresthesias, nausea, vivid dreams, irritability, and depressed mood.122,152 The risk factors associated with the development of a discontinuation syndrome are not fully clarified, although it is more common with SSRIs with a shorter elimination half-life (paroxetine > fluvoxamine > sertraline > fluoxetine). In addition, those SSRIs with high-potency serotonin reuptake inhibition are more frequently implicated (paroxetine > sertraline > clomipramine > fluoxetine > venlafaxine > trazodone). Of the SSRIs, paroxetine most often results in discontinuation symptoms, which are estimated to occur at a rate of 300 cases per million prescriptions. Fluoxetine discontinuation syndrome occurred significantly less frequently at two cases per million prescriptions.109 Fluoxetine’s long elimination half-life and its active metabolite, norfluoxetine, probably decrease the incidence of discontinuation syndrome by providing a tapered effect after cessation. The biochemical basis of the discontinuation syndrome is hypothesized to be a result of serotonin receptor down-regulation

1. Adler L, Angrist B: Paroxetine and akathisia. Biol Psychiatry 1995; 37:336–337. 2. Aranda-Michel J, Koehler A, Bejoaano PA, et al: Nefazodoneinduced liver failure: Report of three cases. Ann Intern Med 1999; 130:285–288. 3. Augustin BG, Cold JA, Jann MW: Venlafaxine and nefazodone, two pharmacologically distinct antidepressants. Pharmacotherapy 1997; 17:511–530. 4. Baetz M, Malcolm D: Serotonin syndrome from fluvoxamine and buspirone. Can J Psychiatry 1995;40:428–429. 5. Bakheit AMO, Beehan PO, Prach AT, et al: A syndrome identical to the neuroleptic malignant syndrome induced by LSD and alcohol. Br J Addiction 1990;85:150–151. 6. Baldessarini RJ: Drugs and the treatment of psychiatric disorders. In: Hardman JG, Limbird LE, Molinoff PB, et al, eds: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996, pp. 431–459. 7. Banham NDG: Fatal venlafaxine overdose. Med J Aust 1998;169: 445–448. 8. Barbey JT, Roose SP: SSRI safety in overdose. J Clin Psychiatry 1998:59(Suppl 15):42–48. 9. Bastani JB, Troester MM, Bastani AJ: Serotonin syndrome and fluvoxamine: A case study. Nebr Med J 1996;81:107–109. 10. Benazzi F: Mirtazapine withdrawal symptoms [letter]. Can J Psychiatry 1998;43:525. 11. Benazzi F: Serotonin syndrome with mirtazapine-fluoxetine combination [letter]. Int J Geriatr Psychiatry 1998;13:493–496. 12. Blythe D, Hackett LP: Cardiovascular and neurological toxicity of venlafaxine. Hum Exp Toxicol 1999;18:309–313. 13. Boeck V, Fredricson OK, Svendsen O: Studies on acute toxicity and drug levels of citalopram in the dog. Acta Pharmacol Toxicol 1982; 50:169–174.

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14. Borys DJ, Setzer SC, Ling LJ, et al: Acute fluoxetine overdose: Report of 234 cases. Am J Emerg Med 1992;10;115–120. 15. Braitberg G, Curry SC: Seizure after isolated fluoxetine overdose. Ann Emerg Med 1995;26:234–237. 16. Brannan SK, Talley BJ, Bowden CL: Sertraline and isocarboxazid cause of serotonin syndrome [letter]. J Clin Psychopharmacol 1994; 14:144–145. 17. Bremner JD, Wingard P, Walshe TA: Safety of mirtazapine in overdose. J Clin Psychiatry 1998;59:233–235. 18. Brazelton T, Blanc PD, Olson KR, Peak DA: Toxic effects of nefazodone [letter]. Ann Emerg Med 1997;20:550–551. 19. Briley M, Prost JF, Moret C: Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol 1996;11(Suppl 4):9–14. 20. Bryant SG, Guernsey BG, Ingrim NB: Review of bupropion. Clin Pharm 1983;2:525–537. 21. Burgh Van Der M: Citalopram product monograph. Copenhagen, Denmark, H Lundbeck A/S, 1994, ISBN 87–88085–00–7. 22. Callaway JC, Grob CS: Ayahuasca preparations and serotonin reuptake inhibitors: A potential combination for severe adverse reactions. J Psychoactive Drugs 1998;30:367–369. 23. Carson CC III, Mino RD: Priapism associated with trazodone therapy. J Urol 1988;139:369–370. 24. Catalano G, Catalano MC, Tumarkin NBB: Nefazodone overdose: A case report. Clin Neuropharmacol 1999;22:63–65. 25. Cohen RM, Pickar D, Murphy DL: Myoclonus associated hypomania during MAO-inhibitor treatment. Am J Psychiatry 1980;137: 105–106. 26. Coplan JD, Gorman JM: Detectable levels of fluoxetine metabolites after discontinuation: An unexpected serotonin syndrome [letter]. Am J Psychiatry 1993;150:837. 27. Crewe HK, Lennard MS, Tucker GT, et al: The effect of selective serotonin reuptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992;34: 262–265. 28. Daniella D, Esquenazi J: Rhabdomyolysis associated with bupropion treatment [letter]. J Clin Psychopharmacol 1999;19:185–186. 29. Daniels RJ: Serotonin syndrome due to venlafaxine overdose. J Accid Emerg Med 1998;15:333–337. 30. Darmani NA, Zhao E: Production of serotonin syndrome by 8-OH DPAT in Cryptotis parva. Physiol Behavior 1998;65:327–331. 31. Davidson J: Seizures and bupropion: A review. J Clin Psychiatry 1989;50:256–261. 32. deBoer T: The pharmacologic profile of mirtazapine. J Clin Psychiatry 1996;57(Suppl 4):19–25. 33. Dingenmanse J, Wallnofer A, Gieschke R, et al: Pharmacokinetic and pharmacodynamic interactions between fluoxetine and moclobemide in the investigation of development of the “serotonin syndrome.” Clin Pharmacol Ther 1998;63:403–413. 34. Dursun SM, Mathew VM, Reveley MA: Toxic serotonin syndrome after fluoxetine plus carbamazepine [letter]. Lancet 1993;342: 442–443. 35. Fava GA, Grandi S: Withdrawal syndromes after paroxetine and sertraline discontinuation [letter]. J Clin Psychopharmacol 1995;15: 374–375. 36. Ferguson JM, Feighrer JP: Fluoxetine-induced weight loss in overweight non-depressed humans. Int J Obesity 1987;11:163–170. 37. Finley PR: Selective serotonin reuptake inhibitors: Pharmacologic profiles and potential therapeutic distinctions. Ann Pharmacother 1994;28:1359–1369. 38. Fitzsimmons CR, Metha S: Serotonin syndrome caused by overdose with paroxetine and moclobemide. J Accid Emerg Med 1999;16: 293–295. 39. Friel PN, Logan BK, Fligner CL: Three fatal drug overdoses involving bupropion. J Anal Toxicol 1993;17:436–438. 40. Fuller R: Serotonergic stimulation of pituitary-adrenocortical function in rats. Neuroendocrinology 1985;32:118–120. 41. Gaffney PN, Schuckman HA, Beeson MS: Nefazodone overdose. Ann Pharmacother 1998;32:1249–1250.

42. Gamble DE, Peterson LG: Trazodone overdose: Four years of experience from voluntary reports. J Clin Psychiatry 1986;47:544–546. 43. Gardos G: Reversible dyskinesia during bupropion therapy. J Clin Psychiatry 1997;58:218. 44. George M, Trimble M: Dystonic reaction associated with fluvoxamine. J Clin Psychopharmacol 1993;13:220–221. 45. George TP, Godleski LS: Possible serotonin syndrome with trazodone addition to fluoxetine [letter]. Biol Psychiatry 1996;39: 384–385. 46. Gerber PE, Lynd LD: Selective serotonin reuptake inhibitor induced movement disorders. Ann Pharmacother 1998;32:692–698. 47. Gerritsen AW: Safety in overdose of mirtazapine: A case report [letter]. J Clin Psychiatry 1997;58:271. 48. Gerson SC, Baldessarini RJ: Motor effects of serotonin in the central nervous system. Life Sci 1980;27:1435–1451. 49. Gill M, LoVecchio F, Selden B: Serotonin syndrome in a child after a single dose of fluvoxamine. Ann Emerg Med 1999;33:457–459. 50. Gillman PK: The serotonin syndrome and its treatment. J Psychopharmacol 1999;12:100–109. 51. Gillman PK: Possible serotonin syndrome with moclobemide and pethidine [letter]. Med J Aust 1995;162:554. 52. Goldberg RJ, Huk M: Serotonin syndrome from trazodone and buspirone [letter]. Psychosomatics 1992;33:235–236. 53. Graber MA, Hoens TB, Perry PJ: Sertraline-phenelzine drug interaction: A serotonin syndrome reaction. Ann Pharmacother 1994;28: 732–735. 54. Grahame-Smith DC: Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with monoamine oxidase inhibitor and L-tryptophan. J Neurochem 1971;18:1053–1066. 55. Graudins A, Stearman A, Chan B: Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med 1998;16:615–619. 56. Graudins A, Vossler C, Wang R: Fluoxetine-induced cardiotoxicity with response to bicarbonate therapy. Am J Emerg Med 1997;15: 501–503. 57. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI: Human cytochromes and some newer antidepressants: Kinetics, metabolism, and drug interactions. J Clin Psychopharmacol 1999;19(Suppl 1): 23–35. 58. Grundemar L, Wohlfart B, Lagerstedt C, et al: Symptoms and signs of severe citalopram overdose [letter]. Lancet 1997;349:1602. 59. Guze BH, Baxter LR Jr: The serotonin syndrome: Case responsive to propranolol [letter]. J Clin Psychopharmacol 1986;6:119–120. 60. Haddad P: Newer antidepressants and the discontinuation syndrome. J Clin Psychiatry 1997;58(Suppl 70):17–22. 61. Hansen TE, Dieter K, Keepers GA: Interaction of fluoxetine and pentazocine. Am J Psychiatry 1990;147:949–950. 62. Harmon T, Jurta D, Krenzelok E: Delayed seizures from sustainedrelease bupropion overdose [abstract]. J Toxicol Clin Toxicol 1998;36:522. 63. Harris CR, Gualtieri J, Stark G: Fatal bupropion overdose. J Toxicol Clin Toxicol 1997;25:321–324. 64. Hebert S: Bupropion (Zyban, sustained-release tablets): Reported adverse reactions. Canadian Med Assoc J 1999;160:1050–1051. 65. Heisler MA, Guidry JR, Arnecke B: Serotonin syndrome induced by administration of venlafaxine and phenelzine [letter]. Ann Pharmacother 1996;30:84. 66. Hoes MJ, Zeijpveld JHB: First report of mirtazapine overdose [letter]. Int Clin Psychopharmacol 1996;11:147. 67. Hoes MJ, Zeijpveld JH: Mirtazapine as treatment for serotonin syndrome [letter]. Pharmacopsychiatry 1996;29:81. 68. Holliday SM, Benfield P: Venlafaxine: A review of its pharmacology and therapeutic potential in depression. Drugs 1995;49:280–294. 69. Humphries JE, Wheby MS, Vandenberg SR: Fluoxetine and the bleeding time. Arch Pathol Lab Med 1990;114:727–728. 70. Hurt RD, Sachs DPL, Glover ED, et al: A comparison of sustainedrelease bupropion and placebo for smoking cessation. N Engl J Med 1997;337:1195–1202.

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71. John L, Perreault MM, Tao T, Blew PG: Serotonin syndrome associated with nefazodone and paroxetine. Ann Emerg Med 1997;29: 287–289. 72. Johnsen CR. Hoejlyng N: Hyponatremia following acute overdose with paroxetine. Internat J Clin Pharmacol Ther 1998;36:333–335. 73. Johnson JA, Lineberry CG, Ascher JA, et al: A 102-center prospective study of seizure in association with bupropion. J Clin Psychiatry 1991;52:450–456. 74. Johnson H, Bouman WP, Lawton J: Withdrawal reaction associated with venlafaxine. BMJ 1998;317:787. 75. Kaminski CA, Robbins MS, Weibley RE: Sertraline intoxication in a child. Ann Emerg Med 1994;23:1371–1374. 76. Kaskey GB: Possible interaction between MAOI and “ecstasy.” Am J Psychiatry 1992;149:411–412. 77. Kirchner V, Silver LE, Kelly CA: Selective serotonin reuptake inhibitors and hyponatremia: Review and proposed mechanisms in the elderly. J Psychopharmacol 1998;12:396–400. 78. Kline SS, Mauro LS, Scala-Barnett DM, Zick D: Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharmacol 1989;8:510–514. 79. Kojima H, Terao T, Yoshimura R: Serotonin syndrome during clomipramine and lithium treatment [letter]. Am J Psychiatry 1993; 150:1897. 80. Kolecki P: Isolated venlafaxine-induced serotonin syndrome. J Emerg Med 1997;15:491–493. 81. Lane RM: SSRI-induced extrapyramidal side effects and akathisia: Implications for treatment. J Psychopharmacol 1998;12:192–214. 82. Lappin R, Auchincloss E: Treatment of serotonin syndrome with cyproheptadine. N Engl J Med 1994;331:1021–1022. 83. Lejoyeux M, Ades J: Antidepressant discontinuation: A review of the literature. J Clin Psychiatry 1997;58(Suppl 7):11–16. 84. Lejoyeux M, Roullion F, Ades J: Prospective evaluation of the serotonin syndrome in depressed inpatients treated with clomipramine. Acta Psychiatr Scand 1993;88:369–371. 85. Lenzi A, Raffaelli S, Marazziti D: Serotonin syndrome-like symptoms in patients with obsessive-compulsive disorder, following inappropriate increase in fluvoxamine dosage. Pharmacopsychiatry 1993; 26:100–101. 86. Levinson ML, Lipsy RJ, Fuller DK: Adverse effects and drug interactions associated with fluoxetine therapy. Ann Pharmacother 1991; 25:657–661. 87. Lewis CF, DeQuardo JR, Rajiv T: Dystonia associated with trazodone and sertraline. J Clin Psychopharmacol 1997;17:64–65. 88. Martin TG: Serotonin syndrome. Ann Emerg Med 1996;28: 520–526. 89. Miller F, Friedman R, Tanenbaum J, Griffin A: Disseminated intravascular coagulation and acute myoglobinuric renal failure: A consequence of the serotonin syndrome [letter]. J Clin Psychopharmacol 1991;11:277–279. 90. Miyaoka H, Kamijima K: Encephalopathy during amitriptyline therapy: Are neuroleptic malignant syndrome and serotonin syndrome spectrum disorders? Int Clin Psychopharmacol 1995;10:265–267. 91. Montastruc JL, Charnontin B, Senard JM, et al: Pseudophaeochromocytoma in parkinsonian patients treated with fluoxetine plus selegiline [letter]. Lancet 1993;341:555. 92. Montgomery SA: Development of new treatments for depression. J Clin Psychiatry 1985;46:3–6. 93. Muly EC, McDonald W, Steffens D, Book S: Serotonin syndrome produced by a combination of fluoxetine and lithium [letter]. Am J Psychiatry 1993;150:1565. 94. Myers LB, Krenzelok EP: Paroxetine (Paxil) overdose: A pediatric focus. Vet Human Toxicol 1997;39:86–88. 95. Naranjo CA, Bremner KE: Clinical pharmacology of serotonin-altering medication for decreasing alcohol consumption. Alcohol Alcohol 1993;2:221–229. 96. Nelson JC: Safety and tolerability of the new antidepressants. J Clin Psychiatry 1997;58(Suppl 6):26–31.

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97. Nierenberg DW, Semprebon M: The central nervous system serotonin syndrome. Clin Pharmacol Ther 1993;53:84–88. 98. Nisijima K, Ishiguro T: Cerebrospinal fluid levels of monoamine metabolites and gamma-aminobutyric acid in neuroleptic malignant syndrome. J Psychiatry 1995;29:233–244. 99. Nisijima K, Shimizu M, Abe T, Ishiguro T: A case of serotonin syndrome induced by concomitant treatment with low-dose trazodone and amitriptyline and lithium. Int Clin Psychopharmacol 1996;11; 289–290. 100. Nutt D: Mirtazapine: Pharmacology in relation to adverse effects. Acta Psychiatr Scand 1997;96(Suppl 39):31–37. 101. Oates JA, Sjoerdsma A: Neurologic effects of tryptophan in patients receiving monamine oxidase inhibitor. Neurology 1960;10: 1076– 1078. 102. Pao M, Tipnis T: Serotonin syndrome after sertraline overdose in a 5-year-old girl. Arch Pediatr Adolesc Med 1997;151:1064–1067. 103. Paris PA, Saucier JR: ECG conduction delays associated with massive bupropion overdose. J Toxicol Clin Toxicol 1998;36: 595–598. 104. Personne M, Persson H, Sjoberg G: Citalopram toxicity. Lancet 1997;350:518–519. 105. Personne M, Sjoberg G, Persson H: Citalopram overdose—Review of cases treated in Swedish hospitals. J Toxicol Clin Toxicol 1997; 35:237–240. 106. Popli AP, Tanquary J, Lamparella V, Masand PS: Bupropion and anticonvulsant drug interactions. Ann Clin Psychiatry 1995;7:90–101. 107. Power BM, Pinder M, Hackett LP, Ilett KF: Fatal serotonin syndrome following a combined overdose of moclobemide, clomipramine and fluoxetine. Anaesth Intensive Care 1995;23:499–502. 108. Preskorn SH, Burke MJ: Somatic therapy for major depressive disorder: Selection of an antidepressant. J Clin Psychiatry 1992;53:5–18. 109. Price JS, Waller PC, Wood SM, et al: A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors, including the investigation of symptoms occurring on withdrawal. Br J Clin Pharmacol 1996;42:757–763. 110. Rao R: Serotonin syndrome associated with trazodone [letter]. Int J Geriatric Psychiatry 1997;12:129–132. 111. Reeves RR, Bullen JA: Serotonin syndrome produced by paroxetine and low-dose trazodone [letter]. Psychosomatics 1995;36:159–160. 112. Retz W, Maier S, Maris F, Rosler M: Non-fatal mirtazapine overdose. Int Clin Psychopharmacol 1998;12:277–279. 113. Richelson E: Biologic basis of depression and therapeutic relevance. J Clin Psychiatry 1991;52(Suppl 6):4–10. 114. Richelson E: Pharmacokinetic drug interactions of new antidepressants: A review of the effects on the metabolism of other drugs. Mayo Clin Proc 1997;72:835–847. 115. Rivers N, Horner B: Possible lethal interaction between Nardil and dextromethorphan [letter]. Can Med Assoc J 1970;103:85. 116. Rohrig TP, Ray NG: Tissue distribution of bupropion in a fatal overdose. J Anal Toxicol 1992;16:343–345. 117. Rosebush PI, Margetts P, Mazurek MF: Serotonin syndrome as a result of clomipramine monotherapy. J Clin Psychopharmacother 1999;19:285–287. 118. Rudolph RL, Derivan AT: The safety and tolerability of venlafaxine hydrochloride: Analysis of the clinical trials database. J Clin Psychopharmacol 1996;16(Suppl 2):54–61. 119. Ruiz R: Fluoxetine and the serotonin syndrome. Ann Emerg Med 1994;24:983–985. 120. Safferman AZ, Masiar SJ: Central nervous system toxicity after abrupt monoamine oxidase inhibitor switch: A case report. Ann Pharmacother 1992;26:337–338. 121. Sandyk R: L-Dopa-induced serotonin syndrome in a parkinsonian patient on bromocriptine [letter]. J Clin Psychopharmacol 1986;6: 194–195. 122. Schatzberg AF, Haddad P, Kaplan EM, et al: Serotonin reuptake discontinuation syndrome: A hypothetical definition. J Clin Psychiatry 1997;58(Suppl 8):5–10.

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ANTIPSYCHOTICS Frank LoVecchio / Neal A. Lewin

hours after admission, he was transferred from the ICU to the psychiatric service for his depression.

A lethargic 40-year-old man was brought to the Emergency Department (ED) by paramedics. He was discovered slumped over a park bench with an empty pill container at his side. Bystanders at the scene stated that the patient had a history of chronic alcoholism, and had been hospitalized several times for “hallucinations.” There was no other medical history available. His vital signs were blood pressure, 90/50 mm Hg; pulse, 118 beats/min and regular; respirations, 10 breaths/min and regular; and rectal temperature, 95°F (35°C). The patient’s skin revealed signs of compression where it was in contact with the park bench. There was no evidence of head trauma. Numerous carious teeth and gingivitis were noted. A gag reflex could not be elicited. His pupils were 4 mm, equal, and responsive to light. Oculocephalic reflexes were present. The optic discs were within normal limits. Coarse rales and rhonchi were heard over the right lower lung area. Heart sounds were normal with no audible murmurs. The patient’s abdomen was distended with ascites and no palpable masses. Bowel sounds were diminished but present. Rectal examination was negative for occult blood. There was mild pitting edema in the extremities. Pulses were palpable and equal bilaterally. The patient was unresponsive to deep pain. Reflexes were normal and equal bilaterally. Plantar flexion was present bilaterally. There were no localizing neurologic findings. As his airway and breathing were being assessed, bedside blood glucose was noted to be 130 mg/dL. Two successive 2-mg IV boluses of naloxone were administered with no subsequent response. Thiamine 100-mg was also given intravenously. The patient was successfully intubated with a cuffed 8.0-mm endotracheal tube and supplemental oxygen was administered. A 2-L intravenous infusion of 0.9% sodium chloride solution was administered rapidly and the blood pressure rose to 110/80 mm Hg. The initial room air arterial blood gas values were pH, 7.28; PCO2, 53 mm Hg; and PO2, 70 mm Hg. Blood samples were sent for electrolytes, glucose, serum calcium, acetaminophen, creatine phosphokinase (CPK), and complete blood count. A nasogastric tube was inserted and 75 g of activated charcoal was instilled into the stomach. An electrocardiogram (ECG) revealed a sinus tachycardia with a prolonged QT interval and QRS duration of 110 msec. An abdominal radiograph suggested radiopaque material in the upper small bowel, and a chest radiograph demonstrated a right lower lobe infiltrate. The patient received broad-spectrum intravenous antibiotics following appropriate cultures. A bolus of 100 mEq of sodium bicarbonate (8.4%) was administered because of the slightly prolonged QRS interval. Shortly after its administration the QRS duration decreased to 90 msec. When the patient awoke 24 hours later in the intensive care unit (ICU), he admitted to ingesting a 1-month supply of mesoridazine pills. A CPK level peaked at 6500 U/L 20 hours after admission. Fifty

HISTORY AND EPIDEMIOLOGY Antipsychotic medication use has increased since their introduction in the 1950s.9 More adverse reactions to psychotropic medications are to be anticipated with increased utilization, broader indications, and newer products. Newer products are a direct result of improved knowledge of pharmacologic mechanisms of these agents. These advances have stimulated research in identifying pathophysiologic changes of psychiatric diseases and the introduction of numerous “atypical” antipsychotics. Mood and behavior modification in human beings was first attempted hundreds of years ago. One of the first formal reports occurred in 1845 when Moreau proposed a hashish model for mental illness research. Thirty years later, Freud presented his cocaine papers, followed shortly thereafter by Kraepelin, who founded the first laboratory of clinical pharmacology in Germany. In 1931, Rauwolfia serpentina was used in the treatment of insanity. Shortly thereafter, amphetamine-induced psychosis was used in an animal model to study psychosis. In 1943, Hofmann synthesized lysergic acid diethylamide (LSD).42 Treatment of psychosis with lithium salts was first reported in 1949, and chlorpromazine was synthesized the following year. The term tranquilizer was introduced shortly thereafter and was used to describe the psychic effects of reserpine. The years that followed led to the serendipitous recognition of monoamine oxidase inhibitor and antidepressant properties in antituberculous drugs such as iproniazid. Haloperidol was synthesized in 1958. In the next decades, research into the biologic basis of mental illness flourished.42 This past decade saw the emergence of newer antipsychotics, which carry with them a hope of improved clinical effectiveness and decreased toxicity. In addition to the treatment of the psychoses (schizophrenia and psychotic depression) antipsychotics are increasingly being used for nonpsychiatric conditions. Antipsychotics may be used for the chemical restraint of agitated patients, to control nausea and emesis, for relief of pain and/or nausea accompanying migraines, for the inhibition of hiccups, and for the management of various involuntary motor disorders such as Tourette syndrome or Huntington chorea.48 This chapter identifies the antipsychotic agents that are commonly used for the treatment of psychiatric illness and their adverse effects, as well as the manifestations of intentional and unintentional overdose.

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PHARMACOLOGY Classification of Antipsychotic Medications In part because of their long and charged history, the terminology of the agents used in the management of psychosis is unfortunately complex. Antipsychotic agents encompass all drugs used in the resolution of psychosis and include both the neuroleptics and atypical antipsychotics. Neuroleptics, formerly called “major tranquilizers,” are able to suppress spontaneous movements, but the term specifically contrasts the effects of agents such as chlorpromazine with those of the classic central nervous system depressants (ie, “minor tranquilizers”). These effects include the development of extrapyramidal movement disorders as well as the maintenance of spinal reflexes and antinociceptive-avoidance behaviors. It is currently appreciated that all neuroleptics have antipsychotic effects, but not all antipsychotics have neuroleptic effects. The term antipsychotic is a more general and hopeful term. We will attempt to exclusively use this term in this chapter, except where widespread use prohibits this clarification. Prototypical antipsychotic agents include haloperidol and chlorpromazine. Sedation and antianxiety (sometimes difficult to notice in agitated patients) are common effects with antipsychotics. With the introduction of newer heterocyclic agents or atypical antipsychotics, such as clozapine and olanzapine, the use of the term neuroleptic is inappropriate for these medications because clozapine has well-defined antipsychotic effects with minimal extrapyramidal effects.32,75 Antipsychotics are divided into seven major classes: phenothiazines, thioxanthenes, butyrophenones, diphenylbutylpiperidines, dibenzodiazepines, dibenzoxazepines, and indoles (Table 59–1). The phenothiazines, commonly used in the treatment of various psychiatric disorders, have a basic three-ring structure (Fig. 59–1). Substitutions at position 2 and the nitrogen atom at position 10 in

TABLE 59–1.

the middle ring yield compounds that can be divided into three major classes: the aliphatic (eg, chlorpromazine), piperidine (eg, thioridazine), and piperazine (eg, perphenazine) derivatives.9 All three groups have similar central and peripheral dopaminergicreceptor blockade actions. The thioxanthenes are derivatives of the phenothiazines. A carbon atom replaces the nitrogen at position 10, with a double bond to the side chain. The thioxanthenes and the butyrophenones (such as haloperidol) are pharmacologically similar to the phenothiazines. Atypical antipsychotics can be partitioned into various categories: (a) substantial selectivity for a dopamine receptor subtype, (b) significant selectivity for a nondopaminergic receptor, (c) atypical actions secondary to concomitant actions at two or more receptors, and (d) different functional effects when binding to the same receptor isoform in different cell types.42,99a The phenothiazines have various inhibitory effects on a variety of receptors, including dopaminergic, cholinergic,
1- and
2-adrenergic, histaminic, and diverse serotonergic receptors.9 Antipsychotic activity results from the dopamine-receptor-blocking activity in the limbic system and is probably mediated by serotonergic receptors. Excessive dopaminergic activity in the limbic system produces psychosis, such as schizophrenia, and addictivedrug-craving behavior. The two basal ganglia sites identified as most important in dopaminergic effects are the substantia nigra, which is important in movement control, and the nucleus accumbens, which controls emotion and cognitive function.10 Excessive dopaminergic activity in other areas, such as the striatum, may produce tics, acute choreoathetosis, or Tourette syndrome. Diminished dopaminergic activity in the basal ganglia produces various extrapyramidal disorders such as acute dystonias and parkinsonism.81 Further research will delineate which dopamine subtype receptors are responsible for manifestation and reversal of specific symptomatology. There are six distinct dopamine receptor subtypes: D1,

Pharmacologic Classification of Typical and Atypical Antipsychotic Agents

Generic Name

Class

Sedation

D2 Antagonism

Phenothiazine Aliphatic Aliphatic Piperazine Piperazine Piperazine Piperazine Piperidine Piperidine Thioxanthene Butyrophenone Butyrophenone Diphenylbutylpiperidine Dihydroindolone Dibenzoxazepine

+++ + + ++ ++ + +++ + ++ +++ ++ +++ ++ +

+ +++ +++ ++ ++ +++ + + +++ +++ ++ +++ ++ ++

Dibenzodiazepine Thienobenzodiazepine Dibenzothiazepine Benzisoxazole

++ ++ ++ ++

+ + + +

Typical antipsychotics Chlorpromazine Triflupromazine Fluphenazine Perphenazine Prochlorperazine Trifluoperazine Thioridazine Mesoridazine Thiothixene Haloperidol Droperidol Pimozide Molindone Loxapine Atypical antipsychotics Clozapine Olanzapine Quetiapine Risperidone +++, strong; ++, moderate; +, weak.

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Figure 59–1.

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The structures of common antipsychotic drugs.

D2A, D2B, D3, D4, and D5 (Table 59–2). Most clinically effective antipsychotic agents have a high affinity for D2 and D3 receptors. A strong correlation exists between clinical potencies of antipsychotic drugs and their ability to antagonize D2 receptors.96,97 Some antipsychotics, such as the thioxanthenes and phenothiazines, bind with high affinity to D1, D2, D3, and D4 receptors (Table 59–2). The heterocyclic substituted agents haloperidol and pimozide are high-

affinity antagonists for D2 and D3 dopamine receptors72 and have variable affinity for D4. The D3 receptors are present in limbic areas of the CNS, and agents acting here would have fewer extrapyramidal effects than on dopamine receptors in the basal ganglia.44 The effect of blocking D1 or D5 receptors remains unclear.49 Central glutamatergic effects show a net decrease following the administration of antipsychotics. The exact mechanism is unclear,

TABLE 59–2. Effects of Antipsychotics on Postsynaptic Dopamine Receptors and Serotonin Receptors

Effect on cyclic AMP Agonists Dopamine Apomorphine Antagonists Phenothiazines Thioxanthenes Butyrophenones Clozapine Olanzapine Risperidone Quetiapine Sertindole

D1 and D5

D2

D2b

D3 and D4

Increases

Decreases

Increases phosphoinositide

Full agonist (weak) Partial agonist (weak)

Full agonist (potent) Full agonist (potent)

? ?

? ?

Potent Potent Weak Inactive Weak D1 Weak D1 Weak D1 Weak D1

Potent Potent Potent Weak Moderate Moderate Moderate Moderate

? ? ? Weak ? ? ? ?

? ? Potent ? ? ? ?

5-HT

5-HT2A 5-HT2A, C 5-HT2A; weak 5-HT1A, C, D Weak 5-HT1A 5-HT2A

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with current theories suggesting that nigrostriatal dopamine neurons are antagonized by striatonigral GABA pathways. An atypical antipsychotic agent with low risk of producing extrapyramidal reactions, such as clozapine, has a low affinity for D2 receptors, but is also an active
-adrenergic antagonist. Clozapine and risperidone also have affinities for 5-HT2 serotonin receptors. Clozapine has selectivity for D4 dopamine receptors as well, but the significance of this subtype in the basal ganglia remains unknown. Although much of the information is unclear, the mechanism and receptor activities of some of the newer antipsychotics are discussed individually. Olanzapine, a thienobenzodiazepine, has a potent affinity for D1, D2, D4, 5-HT2A, 5-HT2C, 5-HT3,
1-adrenergic, histamine H1, and muscarinic receptor subtypes. In comparison to other typical agents, olanzapine has less affinity for 5-HT1 subtypes, GABA, adrenergic receptors, and benzodiazepine binding sites. Compared to clozapine, olanzapine has a high affinity for the dopamine D4 receptor and less
2-adrenoceptor activity. Olanzapine has a different binding profile from that seen with haloperidol, risperidone, and quetiapine. Quetiapine is a dibenzothiazepine with affinity to 5-HT2 and dopamine D2 receptors. Quetiapine has affinity for H1 and
1- and
2-adrenergic receptors, and mild affinity for dopamine D1 receptors. In comparison to clozapine, quetiapine possesses less affinity for muscarinic cholinergic and benzodiazepine binding sites. Quetiapine and risperidone have stronger affinity for 5-HT2 receptors than for D2 receptors. Quetiapine has weak dopamine D2 receptor affinity, akin to clozapine, whereas risperidone has higher dopamine D2 receptor affinity, like haloperidol. Risperidone is an benzisoxazole with greater affinity for the 5-HT2 receptor in comparison to the D2 receptor. Absolute affinity is high at both receptors. Risperidone is also a potent antagonist of
1- and
2-adrenergic and H1 receptors. Risperidone has low to moderate affinity for 5-HT1C, 5-HT1D, and 5-HT1A receptors weak affinity for dopamine D1 receptors. Risperidone has no affinity for cholinergic muscarinic or 1- and 2-adrenergic receptors.42 Sertindole is predominantly a 5-HT2 antagonist with antagonist activity at
1-adrenergic and dopamine D2 and D1 receptors. Sertindole has a low affinity for 5-HT1A,
2-adrenergic, -adrenergic, H1, and muscarinic receptors. Sertindole binds with high affinity to fewer receptors than either risperidone or clozapine. However, like risperidone and clozapine, sertindole binds with high affinity to D2, 5-HT2, and
1-adrenergic receptors. Sertindole has no affinity for histamine receptors because risperidone and clozapine have high affinities. Clozapine also binds to muscarinic receptors with high affinity. Sertindole is more selective for the mesolimbic dopamine neurons than it is for the nigrostriatal dopaminergic neurons.42

PHARMACOKINETICS AND TOXICOKINETICS The phenothiazines can be administered orally, intramuscularly, rectally, or intravenously. Gastrointestinal (GI) absorption is diminished because of drug binding in the intestinal wall.49 Intramuscular absorption is variable, and some phenothiazines, such as chlorpromazine, may cause hypotension when administered intravenously or intramuscularly.101 Chlorpromazine is mainly absorbed in the jejunum in a pH-dependent fashion; thus, concomitant therapy with H2 antagonists results in decreased steady-

state plasma chlorpromazine levels.47 Chlorpromazine undergoes a substantial first-pass metabolism with oral dosing, which can be obviated by substituting parenteral dosing. In general, the butyrophenones undergo less first-pass degradation. Peak chlorpromazine plasma levels are attained within 2–4 hours of oral administration of therapeutic doses.20 In plasma, 99% of chlorpromazine is bound to albumin.20 Biotransformation of this drug occurs in the liver by demethylation and hydroxylation.20,22,73 There are more than 15 metabolites of this drug, half of which are excreted in the urine and stool. Several of the breakdown products, such as 7-hydroxychlorpromazine, have antipsychotic effects,73,86 whereas others, such as chlorpromazine sulfoxide, are inactive.59 The nonphenothiazine antipsychotics, such as the butyrophenones and the thioxanthenes, have no active metabolites. Half of the excretion of the phenothiazines occurs by conjugation of oxidized and hydroxylated metabolites with glucuronic acids and sulfates, after which the conjugated metabolites are excreted by the kidneys.47,49 The remainder of phenothiazine excretion occurs via the enterohepatic system. Metabolism of the phenothiazines by the liver microsomes may be enhanced by such cytochrome P450 enzyme inducers as barbiturates or rifampin.21,37,50,70 Both concomitant lithium and antipsychotic therapy and cytochrome P450 enzyme drug interactions result in diverse neurotoxic manifestations.11,24,37,79,95,106 Cardiac dysrhythmias are reported when lithium is discontinued following combined therapy with lithium and phenothiazines.93,101 Phenothiazine metabolites are lipophilic and have large volumes of distribution. Hence the breakdown products may be found in the urine up to 6 weeks after the last dose of the parent compound. There is little correlation between dose, serum level, and antipsychotic effect of phenothiazines.21,77 Tolerance to the sedative and hypotensive effects occurs after several weeks of therapy. In general, optimum antipsychotic effects require approximately 1 month of therapy. Interestingly, chronic therapy with a constant dose results in lowered plasma levels. However, in spite of the lowered plasma levels of phenothiazines, tolerance to their antipsychotic effects typically does not occur for months.

PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS Toxicity of the antipsychotic agents can be broadly categorized into CNS and non-CNS effects (Table 59–3).90 Toxic manifestations may occur with therapeutic doses, but are usually found in patients who have taken a consequential overdose or initiated therapy with a new drug but with totally different manifestations. The most common non-CNS complication is orthostatic hypotension, which commonly occurs during the initiation of therapy. The most likely cause of orthostatic hypotension is peripheral
-adrenergic blockade with contributing factors being direct vasodilation, central vasomotor reflex depression, and direct myocardial depression.71 The depressant action of phenothiazines on the heart is similar to that of the IA antidysrhythmic agents or tricyclic antidepressants. Through sodium and potassium channel blockade these drugs prolong the QRS and QTc intervals, respectively, and cause repolarization abnormalities (Chap. 52).50,105 Supraventricular and ventricular tachydysrhythmias are also reported, but the majority of patients have sinus tachycardia and aberrant conductions simi-

CHAPTER 59

TABLE 59–3.

Toxic Effects of Antipsychotic Agents

Cardiovascular

Central nervous system

Endocrine

Gastrointestinal Genitourinary

Ophthalmic

Prolonged QT, QRS and PR intervals Nonspecific ST- and T-wave changes, Right-axis deviation (terminal 40 msec prolongation) Myocardial depression, orthostatic hypotension Akathisia Decreased sweating Decreased vasomotor reflexes Dystonia and related movement disorders Hyperthermia Potentially lower seizure threshold Impaired memory Parkinsonism or parkinson-like symptoms “Rabbit syndrome” (perioral tremor) Somnolence, coma Tardive dyskinesia Amenorrhea and irregular menses Decreased ADH secretion Decreased gonadotrophins, ACTH, and growth hormone Increased prolactin secretion Dry buccal membranes Decreased gastrointestinal motility Ejaculation dysfunction Priapism Urinary retention Miosis Mydriasis Blurred vision

lar to the tricyclic antidepressants (Chap. 57).23,66,71 Of all the phenothiazines, thioridazine and mesoridazine are associated with the greatest cardiotoxicity because of their degree of sodium channel and potassium efflux blockade.71 High-dose haloperidol and droperidol both orally and parenterally, is also associated with cardiac dysrhythmias including prolonged QTc-associated torsades de pointes.14,33,46,52,66,80,108 Respiratory effects are extremely rare. If they do occur, they are related to CNS depression. The most commonly reported adverse effects of the antipsychotic medications involve the CNS and are generally reversible.107 Sedation almost always accompanies the induction of antipsychotic therapy and tolerance to this effect develops within months. This effect led to the earlier classification of this group of agents as tranquilizers. Clinical experience with overdose of the newer atypical agents is limited. Clozapine, with its profound anticholinergic effects, results in central nervous system depression and seizures,94 but appears to be unlikely to cause cardiac conduction disturbances or agranulocytosis following acute ingestion. Clozapine has been associated with a case of nephritis.30 Reports thus far with risperidone, olanzapine, and quetiapine suggest that patients should be monitored for obtundation, respiratory depression, and cardiac conduction abnormalities. A prospective poison center–based study with 31 presumed risperidone ingestions resulted in lethargy (23%) as the most common symptom with 1 death in a patient who also ingested imipramine.1 Olanzapine has been associated with the neuroleptic malignant syndrome and lethargy.35 Coma is reported after quetiapine ingestion.45

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Movement Disorders More troubling to the patient than sedation are the movement disorders. Three acute movement disorders occur within 1–60 days of initiating therapy: acute dystonia, parkinsonism, and akathisia (Table 59–4). An additional movement disorder, which occurs months to years after initiating therapy, is tardive dyskinesia6,62–64 (Chap. 19). Normal motor movement patterns depend on a delicate balance between dopamine and acetylcholine in the extrapyramidal system. Excessive stimulation of the cholinergic fibers that project from the basal ganglia to the thalamus results in hyperkinesis. The pathophysiology of acute dystonic reactions is not fully elucidated but at least a portion involves interference of neurotransmitters in the basal ganglia. Dopamine is an excitatory neurotransmitter, whereas GABA and acetylcholine, and to a lesser degree serotonin, act as inhibitors. Nigrostriatal dopamine neurons are antagonized by striatonigral GABA neurons and presynaptic serotonin receptors and inhibited by cholinergic striatal interneurons. Antipsychotics antagonize D2 receptors, thus resulting in amplified acetylcholine release. Ironically, an acute dystonic reaction may be a result of enhanced dopamine discharge into supersensitive postsynaptic receptors. Acute administration of antipsychotics provokes increased dopamine synthesis and release from nigrostriatal neurons and postsynaptic receptor supersensitivity. These are compensatory attempts to surmount postsynaptic D2 blockade. As drug concentrations decrease over hours to days, a state of dopamine surplus occurs and heightened muscular activity (dystonia) results. Acute dystonic reactions typically occur within 48–72 hours of a single dose and are more common in males and children treated with butyrophenones and piperazines. The reactions may include oculogyric crisis (upward gaze paralysis); jaw, tongue, lip, and throat spasms; torticollis (neck twisting); retrocollis (back of neck spasm); opisthotonos (scoliosis); buccolingual (facial) grimacing; tortipelvis (abdominal wall spasm); and laryngeal dystonia, which is potentially life-threatening.27,62,87 The anatomic localization for these effects varies according to individual susceptibility and cortical involvement. Significant hyperthermia may rarely be associated with dystonic reactions. Symptoms rapidly resolve with parenteral antihistamines, anticholinergics, or benzodiazepines. Recommended treatments in adults and children are diphenhydramine (Benadryl) IV or IM 1 mg/kg or benztropine mesylate (Cogentin) IV or IM 1–2 mg in adults and children older than 12 years of age. Intravenous administration has a more rapid onset. Diazepam 0.1 mg/kg IV may be used instead of anticholinergic agents when anticholinergics have failed or in agitated febrile patients who may have impaired thermoregulatory control.6 Acute treatment should be followed with several days of oral benztropine mesylate (Cogentin) 1–2 mg twice daily, or diphenhydramine 1 mg/kg up to 50 mg four times daily.68 If long-term therapy is needed, benztropine mesylate is the agent of choice. Rarely, patients may feign a movement disorder in order to receive their anticholinergic drug of choice.25,83 The reason for the abuse of anticholinergics is unclear, but likely includes euphoria supported by the increased serotonin effects of Cogentin. Those over 40 year of age are more susceptible to the adverse effects of the antipsychotic agents, other than dystonic reactions, especially tardive dyskinesia (TD).89 The prevalence of TD in patients older than 40 years of age is 3 times its prevalence in those patients who are younger than 40 years of age.

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TABLE 59–4.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Extrapyramidal Adverse Effects of Antipsychotic Agents

Effect and Time of Maximal Risk

Characteristics

Mechanism

Treatment

Dystonia (acute) (1–5 days)

Oculogyric crisis; torticollis; retrocollis; tortipelvis

Anticholinergics (diphenhydramine, benzotropine); benzodiazepines

Akathisia (5–60 days)

Restlessness; inability to sit

Unknown; dopamine vs cholinergic imbalance; serotonin and GABA effects Unknown

Parkinsonism (5–30 days)

Bradykinesia; shuffling gait; resting tremor; rigidity; masked facies; perioral tremor (“rabbit” syndrome) Rigidity; autonomic dysfunction (unstable blood pressure); hyperthermia; altered mental status; catatonia; increased CPK

Neuroleptic malignant syndrome (days to weeks)

Tardive dyskinesia (months to years)

Involuntary buccolinguomasticatory movements; choreoathetoid movements

Another toxic CNS effect of antipsychotic medications is akathisia, the subjective sensation of restlessness or muscle discomfort.10 The severity and persistence of dyskinesia and akathisia increases with age.10,89 Affected patients are usually elderly and may appear agitated, have restless legs, and are unable to sit still. Objective symptoms can persist. At times the patient may act violently. This symptom usually occurs early in treatment (5–60 days), especially with dosage increase. These symptoms are alleviated by reduction of the phenothiazine dose or by the addition of lorazepam, propranolol, or, to a lesser extent, antiparkinsonian drugs.88 Parkinsonism (bradykinesia) is another CNS effect of antipsychotic therapy.29 In fact, it is the most common extrapyramidal effect, particularly in elderly women. Antipsychotic-induced parkinsonism occurs in 90% of susceptible patients within 72 days of initiating antipsychotic therapy and is characterized by a shuffling gait, resting tremor, rigidity, sialorrhea, pill rolling that is typically worse at rest, a masklike expression, fine-movement muscle weakness, postural instability, and bradykinesia. An atypical syndrome of perioral tremor (rabbit syndrome) may merely be a late parkinsonian variant.56 The incidence of bradykinesia increases with age, but patients rarely develop symptoms if they have been maintained on the same dose for 3 months or more. When symptoms develop, they may be attenuated by reduction of dosage or by addition of antiparkinsonian agents.4 The most serious CNS toxic effect of antipsychotics is tardive dyskinesia, with a reported incidence ranging from 3% to 50%.6 Its development appears to be much less frequent with use of the atypical antipsychotic agents. Also called permanent dyskinesia, tardive dyskinesia is characterized by involuntary, repetitive movements of the face, tongue, and lips (buccolinguomasticatory syndrome). Movements of the tongue typically appear first. Orofacial manifestations are more common in the elderly, whereas truncal movements are more common in young adults. The extremities and/or trunk may manifest choreoathetoid movements. Voluntary activity of the involved muscles may reduce the frequency of repetitive cycles and sleep typically abolishes all abnormal move-

Antagonism of dopamine

Antagonism of dopamine

Excess dopaminergic activity

Reduction in dose of antipsychotic agent; anticholinergics; benzodiazepines Reduction in dose of antipsychotic agent; anticholinergics

Limit hyperthermia (rapid cooling); benzodiazepines; neuromuscular blockade; central dopamine agonists ? benefit (bromocriptine, amantadine) Stop offending drug; addition of or increase in antipsychotic dose; cholinergic agents

ments. Individuals on long-acting intramuscular depot therapy are more apt to develop the syndrome. Women who have been on butyrophenones or phenothiazine therapy for several years are more likely to develop the disorder perhaps secondary to higher doses if adjusted for weight. Tardive dyskinesia may first appear when drug dosage reductions are attempted after several years of therapy. Chronic dopamine receptor blockade results in receptor upregulation and increased dopamine secretion.44,97 Reduction of phenothiazine dose may thus cause the movement disorder. Similarly, administration of L-dopa, the dopamine precursor, exacerbates the syndrome.54 The exact neuropathology of tardive dyskinesia is unknown. It is hypothesized that compensatory increases in dopamine neurotransmitter function may be involved. This hypothesis is supported by dissimilar therapeutic responses in patients with Parkinson disease from patients with tardive dyskinesia. In contrast to the similar responses of patients with choreoathetotic dyskinesias (ie, Huntington disease), other factors play a role as neuropathologic examination of patients with tardive dyskinesia does not reveal striatal damage. In addition, primate studies reveal that haloperidol, an agent commonly implicated in tardive dyskinesia, and its analogue (tetrahydropyridine) are metabolized to the potentially neurotoxic pyridinium metabolites haloperidol pyridinium (HPP+) and reduced pyridinium (RHPP+), respectively.7,54 These metabolites are believed to cause nigrostriatal toxicity by inhibiting mitochondrial respiration and are similar to MPP+ (1-methyl-4phenylpyridium), a structurally related pyridinium neurotoxic metabolite of MPTP (Chap. 62). HPP+ in rats is also a potent cytotoxin for dopaminergic and serotonergic neurons. Although the results are not confirmed in human beings, the authors suggest a potential link between HPP+ and RHPP+ neurotoxicity, which may result in tardive dyskinesias in haloperidol-treated patients. Tardive dyskinesia may be permanent or show minimal improvement despite treatment. Preventive therapy in the form of “drug holidays” (periods of abstinence from drugs), which was thought to avert this complication, may not be as successful as previously reported.68 Avoidance of high-dose, long-term daily

CHAPTER 59

therapy may also decrease its incidence.56 Increase in dosage of antipsychotic medication may alleviate the symptoms. Haloperidol is commonly used for this purpose because of its potent blockade of dopamine receptors. In some patients, symptoms progressively disappear after stopping the antipsychotic agents, but psychotic symptoms may return. Piperazine phenothiazines or butyrophenones with little anticholinergic effect may be helpful in managing the psychosis, but not the tardive dyskinesia.62–64 Other medications have been used for the treatment of tardive dyskinesia with limited efficacy. Not only do anticholinergic medications not improve tardive dyskinesia, but they may, in fact, exacerbate the condition, as well as cause a psychosis. This would be the expected result if the postulated mechanism of dopaminergic overactivity with subsequent cholinergic underactivity were valid. Anticholinergics agents are commonly prescribed with antipsychotics to prevent parkinsonism, but some experts have expressed concern in that anticholinergics facilitate the development of tardive dyskinesia.62–64 Another treatment approach is to decrease receptor stimulation by decreasing the amount of neurotransmitter available. Reserpine and meclofenoxate deplete catecholamine storage in synaptic vesicles by preventing reuptake of dopamine, thereby decreasing the amount of neurotransmitter available; however, long-term studies have not supported this therapy.38,51,55,57,58 Cholinergic stimulation using an anticholinesterase such as physostigmine may also help the ameliorate tardive dyskinesia.105 The administration of choline, a precursor of acetylcholine, and lecithin, a dietary source of choline, has similarly exhibited shortterm beneficial effects on the tardive dyskinesia.4

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) is characterized by hyperthermia, muscle rigidity, other extrapyramidal effects, autonomic dysfunction, and altered consciousness.43,60,61,67,69 NMS is a rare sequela of antipsychotic treatment, with an estimated frequency of 0.02–2.4%.57 Antipsychotics associated with NMS include phenothiazines, butyrophenones, thioxanthenes, loxapine, and olanzapine,10 although all dopamine antagonists can potentially cause the syndrome. Of these, the medications with greater antidopaminergic activity seem to have a greater potential for causing NMS.99 This syndrome is an idiosyncratic, rare, and potentially fatal reaction, which usually occurs in the course of treatment with antipsychotic drugs. Typically, there is a history of a high initial dose with rapid escalation in dose.39,98 A syndrome similar to NMS is described with the withdrawal of dopamine agonists in parkinsonian patients using lithium.39,40,82,102 It has also been described with newer agents.34 The mortality of this disorder was as high as 76% before 1976, but has since declined to about 20%, partly as a result of early recognition and rapid institution of appropriate therapy.92 The current mortality is unknown. The central dopamine blockade of NMS results in disequilibrium characterized by a constellation of clinical features including hyperthermia, muscle rigidity, autonomic instability, and alteration in mental status.92 Unlike a febrile response to an underlying infection, where there is a hypothalamic-controlled elevation of the temperature set point, this is not the case in NMS-induced hyperthermia; therefore, the use of antipyretics is unwarranted.60 The temperature rise can be mild or marked and is believed be caused by a combination of an altered dopamine response in the hypothalamus and amplified heat production from muscle hyperactiv-

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ity.26,94 The type of muscular activity accompanying or leading to NMS can vary and includes akinesia, choreoathetosis, tremors, myoclonus, dystonia, dyskinesia, dysphagia, dysarthria, opisthotonus, and “lead pipe” rigidity.40 Alterations in mental status range from confusion and agitation to frank coma. There is no specific laboratory test for NMS, but abnormal findings, such as leukocytosis and creatine phosphokinase, and creatinine elevations are common. The diagnosis of NMS is difficult to establish and is exclusionary. An essential point in the history is a recent change in antipsychotic dose or the addition of another dopamine antagonist. The differential diagnosis includes meningoencephalitis, tetanus, malignant hyperthermia, lethal catatonia, heatstroke, thyroid storm, serotonin syndrome, pheochromocytoma, strychnine poisoning, and toxicity from a variety of drugs, including anticholinergic poisoning. Perhaps the two syndromes most difficult to distinguish from NMS are serotonin syndrome and lethal catatonia, as all three feature fever and muscle rigidity. Malignant hyperthermia (Chap. 54) is associated with a history of anesthetic agent use, whereas lethal catatonia follows a period of manic hyperactivity and does not feature autonomic instability. If all of the manifestations of NMS are present, medical stabilization and rapid cooling takes precedence over the establishment of the diagnosis. Treatment of NMS includes rapid external cooling with ice and intravenous benzodiazepines to decrease muscle rigidity, and discontinuation of antipsychotic agents.94,103 In case reports, bromocriptine and amantadine are reported to be effective in treating NMS, presumably secondary to their central dopamine agonist effects.5,41,78,81,85,104 However, significant clinical improvement typically does not occur for up to 3 days after initiation of these dopaminergic agents and therefore they are of limited use.104 Dantrolene sodium, which inhibits the release of calcium from the sarcoplasmic reticulum, is reported as a treatment for NMS.76,86 Dantrolene, a skeletal muscle relaxant is specifically indicated in the treatment of malignant hyperthermia. However, although its use is anecdotally reported in the treatment of NMS, it should not be considered as initial therapy. This is because NMS primarily involves the CNS, and there is no derangement of calcium transport in the skeletal muscle as in malignant hyperthermia.67,104 Case reports suggest that the combination of pancuronium and sodium nitroprusside is effective in treating NMS.16,91 The rationale for using a nondepolarizing agent such as pancuronium is that the muscle paralysis it causes would eliminate further muscle-induced heat generation. However, the use of nitroprusside to reverse any vasoconstriction is controversial and offers no clear advantage to supportive care. In addition, anticholinergic agents are ineffective in NMS and may contribute to increased morbidity and mortality. The initial management of NMS should consist of good supportive care, aimed primarily at arresting muscle hyperactivity, and evaluation for other potentially life-threatening medical etiologies of hyperthermia. Intubation should be considered, and aggressive muscle relaxation should be pursued with intravenous benzodiazepines and a nondepolarizing agent as indicated. The offending pharmacologic agent should be discontinued. Based solely on the pathophysiology of the syndrome of central dopamine depletion, specific therapy with bromocriptine (2.5–5 mg PO tid), a dopamine agonist, is advocated for NMS. Most importantly, no agent should be considered a substitute for good supportive care. Aggressive supportive care has led to a reduction in mortality from NMS, as demonstrated by a prospective controlled clinical trial in which supportive therapy statistically reduced the duration

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of illness and incidence of complications compared to dantrolene or bromocriptine.85 The clinical course of NMS lasts usually about 10 days, and antipsychotic agents should not be restarted while symptoms of NMS persist. If antipsychotics are necessary, they should not be reintroduced until 1–2 weeks after symptoms resolve. The antipsychotic chosen should be from a different class than the one that precipitated NMS and should have minimal extrapyramidal effects. The atypical antipsychotic agents clozapine, risperidone, olanzapine, and quetiapine are recommended under these circumstances.75

DIAGNOSTIC TESTS Plasma levels of antipsychotics do not correlate well with clinical signs and symptoms.21,71,76,79 Historically, positive urine phenothiazine colorimetric testing, using the Forrest test, ferric chloride test, or Phenistix reagent strip test, can suggest the presence of phenothiazines.36 An abdominal radiograph may help confirm a deliberate overdose, as some solid dosage forms of phenothiazines are radiopaque. However, radiographic findings are neither sensitive nor specific for the presence of phenothiazines. An electrocardiogram should be performed to look for cardiac abnormalities as discussed above.

MANAGEMENT Patients with isolated acute antipsychotic ingestions generally have uncomplicated clinical courses. Deaths are rare and are most frequently associated with thioridazine and mesoridazine overdose,8,18 or with overdoses of antipsychotics in combination with other drugs. In the management of patients with this overdose, sympathomimetic agents should be reserved for hypotensive patients refractory to intravenous fluids. Studies suggest that catecholamines modify impulse conduction, permitting reentry of delayed impulse within the conduction system and promoting dysrhythmias.18,74 Activated charcoal administered orally or via a nasogastric tube may be appropriate as a therapeutic intervention. Emesis, lavage, multiple-dose activated charcoal, cathartics, orogastric lavage, or gastric emptying is not ordinarily recommended for isolated antipsychotic overdoses for the risks of these agents or procedures outweigh the benefits. Because of the substantial protein binding and large volumes of distribution, hemoperfusion and hemodialysis are of no benefit in antipsychotic agent overdoses.20 Tachycardia is best managed with fluid resuscitation.71 If a vasopressor is needed to manage refractory hypotension, a mixed
- and -adrenergic receptor agonist such as dopamine should be avoided. Because the phenothiazines are potent
-adrenergic antagonists, -adrenergic stimulation may enhance peripheral vasodilation, further exacerbating the blockade-induced vasodilation and hypotension. Direct-acting, as opposed to indirect-acting,
-adrenergic receptor agonists are preferred. The
-adrenergic receptor agonists phenylephrine, norepinephrine, and metaraminol are more appropriate drugs in this setting.13 Hemodynamic monitoring will be required in hypotensive patients. Dysrhythmias are most common with overdose of the piperidine class and are also seen with the butyrophenone agent haloperidol.1–3,28 Electrocardiographic abnormalities should be

treated, particularly if hemodynamic instability results.15,21,31,53 These manifestations are similar to those of cyclic antidepressantinduced cardiac toxicity. For this reason, sodium bicarbonate may be an appropriate intervention to treat the Na+ channel blockade–related cardiac toxicity from this drug (Antidotes in Depth: Sodium Bicarbonate). Supraventricular dysrhythmias can usually be managed supportively. Ventricular dysrhythmias should be treated with sodium bicarbonate and/or lidocaine. Class IA and IC antidysrhythmic agents are contraindicated because of their sodium channel–blocking effects. If torsades de pointes (polymorphic ventricular tachycardia) is present, magnesium, isoproterenol, or a pacemaker may be an effective treatment. Treatment with physostigmine salicylate reverses central as well as peripheral anticholinergic abnormalities caused by phenothiazines (Antidotes in Depth: Physostigmine). However, because these clinical effects are rarely life-threatening and physostigmine may further impair cardiac conduction, its use is not typically recommended following antipsychotic drug overdose.103

SUMMARY The use of antipsychotics has increased since their introduction in the 1950s. Adverse reactions are common, as are serious sequelae of intentional and unintentional overdoses. Physicians must be knowledgeable about the pharmacology of these agents and be aware of treatment modalities to be able to manage these potentially dangerous reactions.

ACKNOWLEDGMENTS Eddy A. Bresnitz, MD, and Richard Y. Wang, MD, contributed to this chapter in a previous edition.

REFERENCES 1. Acri AA, Hentretig FM: Effects of risperidone in overdose. Am J Emerg Med 1998;16:498–501. 2. Aherwadkar SJ, Efendigil MC, Coulshed N: Chlorpromazine therapy and associated acute disturbances of cardiac rhythm. Br Heart J 1974;36:1251–1252. 3. Agelink MW, Majewski T, Wurthmann C, et al. Effects of newer atypical antipsychotics on autonomic neurocardiac function: A comparison between amisulpride, olanzapine, sertindole, and clozapine. J Clin Psychopharmacol. 2001;21:8–13 4. Akiyama K: Algorithms for antipsychotic-associated tardive movement disorders. Psychiatry Clin Neurosci 1999;53:S23–S29. 5. Amdurski S: A therapeutic trial of amantadine in haloperidol induced malignant antipsychotic syndrome [letter]. Curr Ther Res 1983;33:225. 6. American Psychiatric Association Task Force on Late Neurological Effects of Antipsychotic Drugs: Tardive dyskinesia. Am J Psychiatry 1980;137:1163–1172. 7. Avent KM, Etsuko U, Eyles DW, et al: Haloperidol and its tetrahydropyridine derivative (HPTP) are metabolized to potentially neurotoxic pyridinium species in the baboon. Life Sci 1996;59: 1473–1482. 8. Baker PB, Merigian KS, Roberts JR, et al: Hyperthermia, hypertension, hypertonia and coma in a massive thioridazine overdose. Am J Emerg Med 1988;6:346–349. 9. Andersson C, Chakos M, Mailman R, et al: Emerging roles for the novel antipsychotics medications in the treatment of schizophrenia. Psychiatr Clin North Am 1998;21:151–179.

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10. Apple JE, Van Hauer G: Antipsychotic malignant syndrome associated with olanzapine therapy. Psychosomatics 1999;40:267–268. 11. Battaglia J, Thornton L, Young C: Loxapine-lorazepam-induced hypotension and stupor [letter]. J Clin Psychopharmacol 1989;9: 227–228. 12. Bausher J, Goldstein HS, Aronson MD, et al: Case report: “Pseudogiant-p waves” and pericardial friction rub following chlorpromazine therapy. Am J Med Sci 1976;272:357–359. 13. Benowitz NL, Rosenberg J, Becker CE: Cardiopulmonary catastrophes in drug-overdosed patients. Med Clin North Am 1979;63: 127–140. 14. Bett JHN, Holt GW: Malignant ventricular tachyarrhythmia and Haldol. Br Med J 1983;287:1264. 15. Bigger JT: Cardiac electrophysiologic effects of moricizine hydrochloride. Am J Cardiol 1990;65:15D–20D. 16. Blue MG, Schneider SM, Noro S, et al: Successful treatment of NMS with sodium nitroprusside. Ann Intern Med 1986;104:56–57. 17. Caligiuri MR, Jeste DV, Lacro JP: Antipsychotic-Induced movement disorders in the elderly: Epidemiology and treatment recommendations [review]. Drugs Aging 2000;17:363–384. 18. Chouinard G, Ghadirian AM, Jones BD: Death attributed to ventricular arrhythmia induced by thioridazine in combination with a single Contact capsule. Can Med Assoc J 1978;119:729–730. 19. Conley RR, Metzer HY: Adverse events related to olanzapine [review]. J Clin Psychiatry 2000;61(Suppl 8):26–30. 20. Curry SH: Relation between binding to plasma protein, apparent volume of distribution, and rate constants of disposition and elimination for chlorpromazine in three species. J Pharm Pharmacol 1972;24: 818–819. 21. Curry SH, Davis JM, Janowsky DS, et al: Factors affecting chlorpromazine plasma levels in psychiatric patients. Arch Gen Psychiatry 1970;22:209–215. 22. Dahl SG, Strandjord RE: Pharmacokinetics of chlorpromazine after single and chronic dosage. Clin Pharmacol Ther 1976;21:437–438. 23. De Ponti F, Poluzzi E, Montanaro N, Ferguson J: QTc and psychotropic [letter]. Lancet 2000;356:75–76. 24. de la Gandara J, Dominguez RA: Lithium and loxapine: A potential interaction [letter]. J Clin Psychiatry 1988;49:126. 25. Demetropoulos S, Schauben JL: Acute dystonic reactions from “street Valium.” J Emerg Med 1987;5:293–297. 26. Diamond BI, Borison RL: Basic and clinical studies of antipsychotic-induced supersensitivity psychosis and dyskinesia. Psychopharmacol Bull 1986;22:900–905. 27. Diamond SG, Markham CH, Baloh RW: Vestibular involvement in spasmodic torticollis: An old hypothesis with new data from otolith testing. Adv Otorhinolaryngol 1988;42:219–223. 28. Dorson PG, Crismon ML: Chlorpromazine accumulation and sudden death in a patient with renal insufficiency. Drug Intell Clin Pharm 1988;22:776–778. 29. Duvoisin R: History of parkinsonism. Pharmacol Ther 1987;32: 1–17. 30. Elias TJ, Bannister KM, Clarkson AR, et al: Clozapine-induced acute interstitial nephritis. Lancet 1999;354:1180–1181. 31. Ereshefsky L: Pharmacokinetics and drug interactions: Update for new antipsychotics [review]. J Clin Psychiatry 1996;57(Suppl 11): 12–25. 32. Ereshefsky L, Watanabe MD, Tran-Johnson TK: Clozapine: An atypical antipsychotic agent. Clin Pharm 1989; 8:691–709. 33. Fayer SA: Torsade de pointes ventricular tachyarrhythmia associated with haloperidol. J Clin Psychopharmacol 1986;6:375–376. 34. Filice GA, McDougall BC, Ercan-Fang N, et al: Antipsychotic malignant syndrome associated with olanzapine. Ann Pharmacother 1998;32:1158–1159. 35. Fogel J, Diaz JE: Olanzapine overdose [letter]. Ann Emerg Med 1998;32:275–276. 36. Forrest FM, Forrest IS, Mason AS: Review of rapid urine tests for phenothiazine and related drugs. Am J Psychiatry 1961;118: 300–307.

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37. Forrest FM, Forrest IS, Serra MT: Modification of chlorpromazine metabolism by some other drugs frequently administered to psychiatric patients. Biol Psychiatry 1970;2:53–58. 38. Friedman JH: A case of progressive hemichorea responsive to highdose reserpine. J Clin Psychiatry 1986;47:149–150. 39. Friedman JH, Feinberg SS, Feldman RG: A antipsychotic malignantlike syndrome due to levodopa therapy withdrawal. JAMA 1985; 254:2792–2795. 40. Fuller MA, Sajatovic M: Neurotoxicity resulting from a combination of lithium and loxapine. J Clin Psychiatry 1989;50:187–190. 41. Gangadhar BN, Desain G, Channabasarnana SM: Amantadine in the antipsychotic malignant syndrome. J Clin Psychiatry 1984;45: 526–529. 42. Baldessarini RJ: Drugs and the treatment of psychiatric disorders: Psychosis and anxiety. In: Hardman JG, Limbird LE, Molinoff PB, et al, eds: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw Hill, 1996, pp. 399–430. 43. Guze BH, Baxter JR: Antipsychotic malignant syndrome. N Engl J Med 1985;313:163–166. 44. Hacksell U, Jackson DM, Mohell N: Does dopamine receptor subtype selectivity of antipsychotic agents provide useful leads for development of novel therapeutic agents? Pharmacol Toxicol 1995; 76:320–324. 45. Harmon TJ, Benitez JG, Krenzelok EP, et al: Loss of consciousness from acute quetiapine overdose. J Toxicol Clin Toxicol 1998;36: 599–602. 46. Henderson RA, Lane S, Henry JA: Life-threatening ventricular arrhythmia (torsade de pointes) after haloperidol overdose. Hum Exp Toxicol 1991;10:59–62. 47. Hicks R, Dysken MW, Davis JM, et al: The pharmacokinetics of psychotropic medication in the elderly: A review. J Clin Psychiatry 1981;42:374–385. 48. Hollister LE: Clinical Use of Psychotherapeutic Drugs. Springfield, IL, Charles C. Thomas, 1973. 49. Horacek J: Novel antipsychotics and extrapyramidal side effects. Theory and reality. Pharmacopsychiatry 2000;33(Suppl 1):34–42. 50. Howes CA, Pullar T, Sourindhrin I, et al: Reduced steady-state plasma concentrations of chlorpromazine and indomethacin in patients receiving cimetidine. Eur J Clin Pharmacol 1983;24:99–102. 51. Huang CC: Reserpine and alpha methyldopa in the treatment of tardive dyskinesia. Psychopharmacology 1981;33:359–362. 52. Hunt N, Stern TA: The association between intravenous haloperidol and torsade de pointes. Psychosomatics 1995;36:541–549. 53. Huston JF, Bell GE: The effect of thioridazine and chlorpromazine on the electrocardiogram. JAMA 1966;198:134–138. 54. Igarashi K, Matsubata K, Kasuya F, et al: Effect of a pyridinium metabolite derived from haloperidol on the activities of striatal tyrosine hydroxylase in freely moving rats. Neurosci Lett 1996;214: 183–186. 55. Izumi K, Tominaga H, Koja T, et al: Meclofenoxate therapy in tardive dyskinesia: A preliminary report. Biol Psychiatry 1986;21: 151–160. 56. Jeste DV, Wyatt RJ: Therapeutic strategies against tardive dyskinesia: Two decades of experience. Arch Gen Psychiatry 1982;39: 803–816. 57. Jeste DV, Wyatt RJ: In search of treatment for tardive dyskinesia: A review of the literature. Schizophr Bull 1979;5:251–293. 58. Jus K, Jus A, Gautier J, et al: Studies of the actions of certain pharmacological agents on tardive dyskinesia and on the rabbit syndrome. Int J Clin Pharmacol 1974;9:138–145. 59. Kaul PN, Whitfield LR, Clark ML: Chlorpromazine metabolism. VIII: Blood levels of chlorpromazine and its sulfoxide in schizophrenic patients. J Pharm Sci 1976;65:694–697. 60. Keck PE, Caroff SN, McElroy SL: Antipsychotic malignant syndrome and malignant hyperthermia: End of a controversy [review]? J Neuropsychiatry Clin Neurosci 1995;7:135–144. 61. Keck PE, Pope HG, Cohen BM, et al: Risk factors for antipsychotic malignant syndrome. Arch Gen Psychiatry 1989;46:914–918.

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62. Klawans HL: Tardive dyskinesia: Review and update. Am J Psychiatry 1980;137:900–905. 63. Klawan HL, Tanner CM, Goetz CG: Epidemiology and pathophysiology of tardive dyskinesias [review]. Adv Neurol 1988;49:185–197. 64. Kobayashi RM: Drug therapy of tardive dyskinesia. N Engl J Med 1977;296:257–259. 65. Koek RJ, Pe EH: Acute laryngeal dystonic reactions to antipsychotics. Psychosomatics 1989;30:359–364. 66. Kriwisky M, Perry GY, Tarchitsky D, et al: Haloperidol-induced torsade de pointes. Chest 1990;98:482–484. 67. Lazarus A, Caroff SN, Mann SC: Beyond NMS: Management after the acute episode. Psychiatry Ann 1991;21:165–174. 68. Leckman JF, Peterson BS, Pauls DL, Cohen DG: Tic disorders. Psychiatr Clin North Am 1997;20(4):839–881. 69. Levenson JL: Antipsychotic malignant syndrome. Am J Psychiatry 1985;142:1137–1145. 70. Loga S, Curry SH, Lader M: Interactions of orphenadrine and phenobarbitone with chlorpromazine: Plasma concentrations and effects in man. Br J Clin Pharmacol 1975;2:197–208. 71. Lutz EG: Cardiotoxic effects of psychotropic drugs. J Med Soc NJ 1976;73:105–112. 72. Maclaren DC, Gambhir SS, Satamurthy N, et al: Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals. Gene Ther 1999;6:785–791. 73. Manian AA, Efran DH, Goldberg ME, et al: A comparative pharmacological study of a series of monohydroxylated and methoxylated chlorpromazine derivatives. Life Sci 1965;4:2425–2438. 74. Marrs-Simon P, Zell-Kanter M, Kendzierski DL, et al: Cardiotoxic manifestations of mesoridazine overdose. Ann Emerg Med 1988;17: 1074–1078. 75. Matz R, Rich W, Oh D, et al: Clozapine: A potential antipsychotic agent without extrapyramidal manifestations. Curr Ther Res 1974; 16:687–695. 76. May DC, Morris SW, Stewart RM, et al: Antipsychotic malignant syndrome: Response to dantrolene sodium. Ann Intern Med 1982; 98:183–184. 77. May PRA, Van Putten T, Jenden DJ, et al: Chlorpromazine levels and the outcome of treatment in schizophrenic patients. Arch Gen Psychiatry 1981;38:202–207. 78. McCarron MM, Boettger ML, Peck JJ: A case of antipsychotic malignant syndrome successfully treated with amantadine. J Clin Psychiatry 1982;43:381–382. 79. McIntyre WT, Gershon S: Interpatient variations in antipsychotic therapy. J Clin Psychiatry 1985;46:3–16. 80. Mehta D, Mehta SH, Petit J, et al: Cardiac arrhythmia and Haldol. Am J Psychiatry 1979;136:1468–1469. 81. Moore NA: Behavioural pharmacology of the new generation of antipsychotic agents [review]. Br J Psychiatry Suppl 1999;38:5–11. 82. Mueller PS, Vester JW, Fermaglich J: Antipsychotic malignant syndrome-like state following a withdrawal of anti-parkinsonian drugs. J Nerv Ment Dis 1981;169:324–327. 83. Pullen GP, Best NR, Maguire J: Anticholinergic drug abuse: A common problem. Br Med J 1984;289:612–613. 84. Rivera-Calimlim L, Kerzner B, Karch FE: Effect of lithium on plasma chlorpromazine levels. Clin Pharmacol Ther 1978;23: 451–455. 85. Rosebush PI, Stewart T, Mazurek MF: The treatment of antipsychotic malignant syndrome: Are dantrolene and bromocriptine useful adjuncts to supportive care? Br J Psychiatry 1991;159:709–712. 86. Rosenberg MR, Green M: Antipsychotic malignant syndrome. Arch Intern Med 1989;149:1927–1931.

87. Russell SA, Henner HM, Herson KJ, Stremski ES: Upper airway compromise in acute chlorpromazine ingestion. Am J Emerg Med 1996;14:467–468. 88. Sachdev P, Loneragan C: Intravenous benztropine and propranolol in tardive akathisia. Psychopharmacolgy 1993;1:119–122. 89. Saltz BL, Woemer MG, Kane JM, et al: Prospective study of tardive dyskinesia incidence in the elderly. JAMA 1991;266:2402–2406. 90. Saltz BL, Woemer MG, Robinson DG, et al: Side effects of antipsychotic drugs. Avoiding and minimizing their impact in elderly patients. Postgrad Med 2000;107:169–172, 175–178. 91. Sangal R, Dimitrijevic R: Antipsychotic malignant syndrome: Successful treatment with pancuronium. JAMA 1985;254:2795–2796. 92. Sekine Y, Rikihisa T, Ogata H, et al: Correlations between in vitro affinity of antipsychotics to various central neurotransmitter receptors and clinical incidence of their adverse drug reactions. Eur J Clin Pharmacol 1999;55:583–587. 93. Shalev A, Hermesh H, Munitz H: Mortality from antipsychotic malignant syndrome. J Clin Psychiatry 1989;50:18–25. 94. Shalev A, Munitz H: The antipsychotic malignant syndrome: Agent and host interaction. Acta Psychiatr Scand 1986;73:337–347. 95. Silvestri RC, Bromfield EB, Khoshbin S: Clozapine-induced seizures and EEG abnormalities in ambulatory psychiatric patients. Ann Pharmacother 1988;32:1147–1151. 96. Sletten I, Pichardo J, Korol B, et al: The effect of chlorpromazine on lithium excretion in psychiatric subjects. Curr Ther Res 1966;8: 441–446. 97. Snyder SH: Receptors, neurotransmitters and drug responses. N Engl J Med 1979;300:465–472. 98. Snyder SH: Antischizophrenic drugs and the dopamine receptor. Drug Ther 1978;3:29–34. 99. Srinivassan AV, Murugapappan M, Krishnamurthy SG, et al: Antipsychotic malignant syndrome. J Neurol Neurosurg Psychiatry 1990;53:514–516. 99a. Stahl SM: What makes an antipsychotic atypical? J Clin Psychiatry 1999;60:3–13. 100. Swett C, Cole JO, Hartz SC, et al: Hypotension due to chlorpromazine: Relation to cigarette smoking. Arch Gen Psychiatry 1977; 34:661–663. 101. Toru M, Matsuda O, Maleiguchi K, et al: Antipsychotic malignant syndrome-like state following a withdrawal of antiparkinsonian drugs. J Nerv Ment Dis 1981;169:324–327. 102. Vassallo SU, Delaney KA: Pharmacologic effects on thermoregulation: Mechanisms of drug-related heatstroke. J Toxicol Clin Toxicol 1989;27:199–224. 103. Verhoeven WMA, Elderson A, Westernberg HC: Antipsychotic malignant syndrome: Successful treatment with bromocriptine. Biol Psychiatry 1985;20:680–684. 104. Ward A, Chaffman MO, Sorkin EM: Dantrolene: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the antipsychotic malignant syndrome and an update of its use in muscle spasticity. Drugs 1986; 32:130–168. 105. Wech R, Chue P: Antipsychotic agents and QT changes [review]. J Psychiatry Neurosci. 2000;25:154–160. 106. Yassa R: A case of lithium chlorpromazine interaction. J Clin Psychiatry 1966;47:90–91. 107. Zaratzian VL: Psychotropic drugs: Neurotoxicity. Clin Toxicol 1980;17:231–270. 108. Zee-Cheng C, Mueller CE, Seifert CF, Gibbs HR: Haloperidol and torsade de pointes [letter]. Ann Intern Med 1985;102:418.

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MONOAMINE OXIDASE INHIBITORS Lada Kokan

drug interactions, and in the 1970s, the MAOIs were largely replaced by tricyclic antidepressants.3 In the 1980s, there was a resurgence of MAOI use in the treatment of refractory depression, phobias, and anxiety disorders.10,38 This trend corresponded to the reappearance of MAOI toxicity reports in the literature.39,63 Subsequently, their use again declined following the appearance of the less toxic selective serotonin reuptake inhibitors (SSRIs) for treatment of depression. Recently, the emergence of a new generation of reversible and selective MAOIs again brings the MAOIs into focus. The new MAOIs are notably safer in overdose and have limited food and drug reactions.

A 28-year-old woman ran into the Emergency Department (ED) clutching the back of her head, screaming that her head was going to explode. A brief history revealed that she was maintained on tranylcypromine for depression. Fifteen minutes before the onset of the headache she had been eating dinner in a restaurant and had eaten a salad with a yogurt dressing. The initial evaluation revealed an alert, oriented, but agitated patient who was holding her head with both hands and had her eyes shut tightly. She was flushed and mildly diaphoretic. Her initial blood pressure was 200/110 mm Hg; her pulse was 90 beats/min and irregular; her respiratory rate was 28 breaths/min; and her temperature was 99°F (37.2°C). Cardiac auscultation suggested bigeminy. A neurologic evaluation revealed equal round and reactive pupils. She complained of photophobia. She was moving all four extremities equally and had no gross sensory deficits. The remainder of her physical evaluation was unremarkable. The cardiac monitor now demonstrated that the patient was in a normal sinus rhythm at a rate of 92 beats/min. Simultaneous with the placement of a peripheral intravenous (IV) line, the patient received 10 mg nifedipine sublingually.* She then vomited a large amount of undigested food. Repeat blood pressure was 190/100 mm Hg. The patient continued to complain of a severe throbbing occipital headache. Over 20 minutes the blood pressure stabilized at 130/80 mm Hg with some resolution of the headache. On further questioning, the patient denied the ingestion of cheese or wine and denied the use of illicit drugs, specifically amphetamines or cocaine although she had used cocaine in the past. Because of the persistence of a mild headache and the risk of intracranial hemorrhage, a noncontrast head CT scan was obtained; it was normal. Although a lumbar puncture was considered, it was not performed as the patient’s symptoms resolved completely with observation. Her mental status, vital signs, and neurologic examination remained normal subsequently and she was discharged home. Her hypertensive MAOI interaction was likely caused by an unrecognized dietary indiscretion or undisclosed sympathetic drug use because the yogurt salad dressing is a food low in tyramine.

EPIDEMIOLOGY Few recent fatalities from MAOIs have been reported to the American Association of Poison Control Centers (p. 1752 and Chap. 116). MAOI use has declined as patients chosen for treatment are more carefully selected and greater care is taken to avoid interactions. The new generations of selective and reversible MAOIs are safer and are being prescribed more frequently than the older MAOIs. Extensive experience with the reversible MAOIs in Europe and Canada demonstrates that they have a wider therapeutic window and much less potential for food and drug interactions than the older nonselective MAOIs. However, the irreversible MAOIs are still used and mortality has been reported from acute ingestions of as little as 170–680 mg of tranylcypromine and 375–1500 mg of phenelzine.70 In contrast, ingestion of 85% inhibition of platelet MAO enzymatic activity and continues to rise linearly above this level of inhibition.25,26,52

Figure 60–1. The sympathetic nerve terminal. Norepinephrine (NE) is synthesized in the sympathetic nerve cell and stored in vesicles. An action potential causes the vesicles to migrate to and fuse with the presynaptic membrane. NE diffuses across the synaptic cleft and binds with and activates postsynaptic α- and β-adrenergic receptors. NE is then taken back up into the neuron by the monoamine reuptake pump and repackaged into vesicles. NE that is taken up by the neuron but escapes repackaging is inactivated by mitochondrial monoamine oxidase (MAO). NE that diffuses away from the synaptic cleft is inactivated by catechol-O-methyl transferase (COMT). (Reprinted, with permission, from Lefkowitz RJ, Hoffman BB, Taylor P: Drugs acting at synaptic and neuroeffector junctional sites. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds: Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 8th ed. New York, Pergamon Press, 1990, pp. 84–121.)

There are two MAO enzyme subtypes, MAO-A and MAO-B. They are differentiated by their location in tissues, by the substrates that they preferentially degrade, and by their inhibitors3 (Table 60–1). MAO-A is found in the liver, in the gastrointestinal tract, and in monoaminergic neurons. Hepatic MAO-A is important in inactivating ingested monoamines such as tyramine, which can cause a significant systemic reaction if not inactivated by MAO-A in the gastrointestinal tract. The tyramine or “aged cheese” reaction is a food interaction that results when patients taking MAOIs ingest monoamines that cannot be metabolized by their inactivated MAO. The clinical manifestations of this reaction are discussed in more detail later in this chapter. Other substrates degraded primarily by MAO-A include epinephrine, norepinephrine, metanephrine, and serotonin, accounting for the negligible oral bioavailability of these monoamines. Circulating monoamines are also inactivated in the liver. The MAO-B isoenzyme is found primarily in the brain and in platelets. Serotonergic neurons contain both MAO-A and MAO-B. Substrates degraded by MAO-B include dopamine,
-phenylethylamine, phenylethanolamine, and benzylamine.3 The active form of the enzyme MAO is a dimer consisting of two subunits. Each subunit is covalently bound with one flavin adenine dinucleotide (FAD), and has a molecular weight of approximately 60,000 daltons. Monoamine oxidase uses oxidative deamination to inactivate its substrates in two steps. First the monoamine is oxidized and FAD is reduced. Hydrolysis of the intermediate imine results in an aldehyde and FADH2. In the second step FADH2 is oxidized by O2, forming H2O2 as a by-product.18 Substrates metabolized by both MAO subtypes include tyramine, dopamine, octopamine, and tryptamine.73 Table 60–1 compares the various types of MAO inhibitors. The nonselective MAOIs inhibit the MAO enzyme irreversibly. This means that new MAO must be synthesized before enzyme function can resume because of irreversible covalent binding to the enzyme, resulting in a prolonged pharmacologic halflife lasting several days to up to 2 weeks. Thus, until sufficient MAO is synthesized to metabolize monoamines normally, the patients taking irreversible MAOIs are at risk for significant morbidity and even mortality from drug-drug or drug-food interactions. Therefore, patients taking these drugs must be placed on a restrictive diet to avoid drug-food interactions and their use of prescription and nonprescription drugs must be closely monitored to avoid drug-drug interactions. For the same reason, severe morbidity and mortality are common after MAOI overdose. Selegiline (Deprenyl, Eldepryl) is used for the treatment of Parkinson disease.43 It is an irreversible inhibitor that selectively inhibits MAO-B at doses of less than 20 mg/d. Above this dose MAOI selectivity is lost, and findings in selegiline overdose may resemble those of the nonselective, irreversible MAOIs. An additional pharmacologic feature of selegiline is that it is metabolized to amphetamine and methamphetamine. This can result in hypomanic symptoms at therapeutic doses, as well as a hyperadrenergic state in overdose. Patients taking selegiline may also test positive for amphetamines on drug tests because of the metabolites. The newer MAOIs, such as moclobemide, reversibly bind MAO in a competitive manner. Because the enzyme is bound reversibly and competitively by these drugs, some MAO is still available to metabolize ingested monoamines rapidly after moclobemide ingestion. This inhibition is competitive so that MAO

CHAPTER 60

TABLE 60–1.

MONOAMINE OXIDASE INHIBITORS

887

Types of Monamine Oxidase MAO-A

MAO-B

Substrates

Serotonin Epinephrine Norepinephrine Metanephrine Tryptamine Dopamine Octopamine

Benzylamine Phenylethylamine Tyramine β-Phenylethylamine Tryptamine Dopamine Octopamine

Location

Gastrointestinal tract Liver Exocrine pancreas Monoaminergic neurons Serotonergic neurons

Brain Platelets Pancreatic islets Serotonergic neurons

Inhibitors: Irreversible

Clorgyline Tranylcypromine* Phenelzine* Isocarboxazid*

Selegiline*† Pargyline* Tranylcypromine* Phenelzine* Isocarboxazid*

Moclobemide Brofaromine Cimoxatone Toloxatone Harmaline

Lazabemide

Reversible

*Currently available in the United States. † Selective at doses up to 20 mg.

function can resume in hours in contrast to the older irreversible MAOIs, which require days, rather than hours, to replete deactivated MAO enzyme. Consequently, these reversible inhibitors of MAOI-A (RIMAs) are much safer in overdose, require fewer food restrictions,1,18,32,43,46 and have much less potential for drug interactions. Drug-drug interactions, although less common with RIMAs than with the older MAOIs, have been reported at therapeutic doses as well as in overdose.47 These drugs include moclobemide (Manerex), brofaromine, cimoxatone, toloxatone, and befloxatone, and are not yet available in the United States. Table 60–1 classifies the older irreversible MAOIs and the newer MAOIs, which inhibit the enzyme reversibly. It also classifies the selective and nonselective MAOIs. By classifying a given MAOI as reversible/irreversible and selective/nonselective to MAO-A or MAO-B, one can define much about the drug’s pharmacology, toxicity, and interactions with food and drugs. These concepts are further discussed below. Some less commonly encountered MAOIs include procarbazine (Matulane), which is a weak MAOI used as an antitumor agent for Hodgkin disease.23 Clorgyline is an irreversible inhibitor of MAO-A.73 The enzymatic inhibitory action of MAOIs precedes their clinical effects by as long as 2 weeks,3 an effect that is also seen with tricyclic antidepressants. The reason for this is not well characterized but may be related to down-regulation of CNS postsynaptic serotonin or its receptor. Several weeks after the initiation of MAO therapy, multiple changes in the CNS occur that affect neurotransmission. The number of
-adrenergic receptors decreases, and the activity of
-adrenergic, 1- and 2-adrenergic, and 5-HT1

and 5-HT2 receptors decreases.45 Dopamine receptors are unaffected.73 The initial increase in monoamine levels and the delayed receptor down-regulation may both contribute to the antidepressant activity of MAOIs via a mechanism of action that is not yet fully understood. Other enzyme systems inhibited by MAOIs include diamine oxidase, pyridoxal phosphokinase, ceruloplasmin, dopa decarboxylase, L-glutamic acid decarboxylase, and other pyridoxine (B6)-containing enzyme systems.21 The clinical implications of the inhibition of these diverse enzyme systems other than MAO are poorly understood.

PHARMACOKINETICS AND TOXICOKINETICS MAOIs are only available in oral form at present. They are well absorbed orally and peak levels are reached within 2–3 hours. MAOIs are hepatically metabolized primarily by acetylation and are excreted in the urine.3 The therapeutic and toxic effects of MAOIs, however, lag behind their absorption and excretion characteristics, as discussed in the sections on pharmacology and clinical manifestations of overdose. Recent studies with transdermal administration of selegiline show signs of clinical effectiveness in some patients within 1 week of administration.13 Further clinical trials are ongoing with this method of administration that may challenge some of the currently proposed mechanisms of action and pharmacokinetics of MAOIs.13

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Some MAOIs are structurally related to amphetamine and have amphetaminelike activity unrelated to the inhibition of MAO (Fig. 60–2).35 In addition, selegiline is metabolized to amphetamine and methamphetamine.

MONOAMINE OXIDASE INHIBITOR OVERDOSE The significant morbidity and mortality characteristic of overdose with the older irreversible MAOIs must be differentiated from that following overdose with the newer reversible MAOIs or RIMAs. The RIMAs have a much greater therapeutic window than the irreversible MAOIs, so that overdose with RIMAs characteristically results in a relatively benign course if no other drugs are ingested. Drug-drug interactions resulting in the serotonin syndrome greatly increase the danger from overdose with either type of MAOI. Overdose from irreversible MAOIs is characterized by a spectrum of sympathetic hyperactivity that is followed by cardiovascular collapse in severe cases. These effects are attributed to the same elevation of monoaminergic neurotransmitter levels and amphetaminelike activity35 that confers to MAOIs their antidepressant activity. Thus, presynaptic monoamines are released, stimulating postsynaptic adrenergic and serotonergic receptors and initiating a multiorgan sympathetic response. In addition, because of the lack of active MAO enzyme, the released monoamines are not adequately metabolized and the sympathetic response is greatly exaggerated. In a limited or early phase of overdose with irreversible MAOIs, the patient typically appears irritable, anxious, flushed, diaphoretic, and tachycardic, and may complain of a headache. Characteristic symptoms of more severe overdose include hyperthermia, hypertonia, seizures, and marked hypertension. These severe cases may progress to cardiovascular collapse with hypotension and dysrhythmias, obtundation, and disseminated intravascular coagulopathy as the body’s catecholamine stores are depleted and multiorgan failure occurs. Other symptoms may include tachypnea, nystagmus, mydriasis, hallucinations, trismus,

Figure 60–2. The structural similarities between amphetamine and the monoamine oxidase inhibitors.

neuromuscular irritability, agitation, and delirium.19,39 A predominance of sympathetic hyperactivity is expected to be associated with MAOIs that have amphetaminelike characteristics (see Fig. 60–2). Secondary problems resulting from CNS and hemodynamic hyperactivity may include rhabdomyolysis, renal failure, dehydration, intracranial hemorrhage, and ischemia (Chap. 18). There are many reports of delay in the onset of significant symptoms for as long as 12–32 hours after irreversible MAOI overdose.4,39,42 In contrast, the reversible inhibitors of MAO appear to be much less toxic in overdose. For example, moclobemide, a reversible inhibitor of MAO-A, has been ingested in doses of as much as 8000 mg, or 25 times the therapeutic dose, without causing significant toxicity. At doses as high as 8000 mg, fatigue, agitation, tachycardia, and hypertension were noted.47 When interpreting the significance of these case reports, one must note that the patients who ingested the largest amount of moclobemide were lavaged early in their course; thus less drug may have been absorbed systemically, contributing to a more benign course. Whether the reversibility or some other pharmacologic property is responsible for this improved toxicity profile is unclear. Therapy of patients with MAOI overdose should focus on emergency treatment of the airway followed by stabilization of the heart rate and blood pressure, and, subsequently, hyperthermia, seizures, and muscular rigidity.19,39 Gastric decontamination should proceed after the patient is stabilized. This is especially important with overdose from irreversible MAOIs, which are characterized by a high potential for mortality and a delayed onset of clinical deterioration. Because fluctuation of vital signs is characteristic of MAOI overdose, hemodynamic monitoring should be instituted even in patients who are initially stable. When supporting the patient’s vital signs, preference should be given to titratable drugs with a rapid onset and termination of action because of the potential for rapid hemodynamic changes. Sodium nitroprusside and nitroglycerine are used to treat hypertension and can be rapidly stopped if hypotension develops. The short-acting -adrenergic antagonist phentolamine given at 2–5 mg IV can also effectively control hypertension. However,
-adrenergic antagonists are not recommended for control of hypertension in this setting because of the potential for unopposed -adrenergic effects, such as vasoconstriction, exacerbating the hypertension. Both - and
-blocking antihypertensives are difficult to titrate and therefore increase the risk of iatrogenic hypotension in those patients with potentially unstable blood pressure. Although dopamine is the most familiar inotrope, it is not recommended in this situation because of its indirect effects on catecholamine release (see “Adverse Drug Events” below). Norepinephrine, a direct-acting agent, may be required in a hypotensive patient with an MAOI overdose who fails to respond to fluid therapy because the patient is likely to become catecholamine depleted.47 Hyperthermia must be aggressively treated (Chap. 18). The use of ice baths, cold water, and fans is the mainstay of treatment. Benzodiazepines help control muscular rigidity, seizures, and agitation that may be contributing to the hyperthermia and tachycardia. Phenobarbital and neuromuscular blocking agents may also be required for patients with ongoing seizures.19,47 Vitamin B6 should be given to replete potentially depleted stores in patients with refractory seizures, particularly if a hydrazine-derived MAOI such as phenelzine has been ingested. However, seizures are often con-

CHAPTER 60

trolled with first-line measures (Chap. 41 and Antidotes in Depth: Pyridoxine.). Neuromuscular blockers are also essential for control of rigidity and hyperthermia if first-line treatment is unsuccessful. Dantrolene has been used in case reports to control neuromuscular rigidity and hyperthermia associated with MAOI overdose.19,34 However, it should not be considered the standard of care, which remains the benzodiazepines and neuromuscular blocking agents.19,34 Atrial and ventricular dysrhythmias are a grave sign following MAOI overdose and are difficult to treat. Although standard Advanced Cardiac Life Support (ACLS) protocols should be followed, amiodarone use in this setting is unstudied. Theoretically, bretylium use could further deplete catecholamine stores, but this drug is not available. After the initial components of patient stabilization have been completed, gastric decontamination should be performed.19,39 Because of the potential for life-threatening toxicity in patients with MAOI overdose, even those with a delayed presentation should probably be given 1 g/kg activated charcoal and should also be lavaged with an orogastric lavage tube if there is potential for removing unabsorbed drug. Finally, consideration should be given to the potential for mixed overdoses and concomitant medical problems. These should be diagnosed and treated in the usual manner. Other treatment may be required for secondary problems associated with MAOI overdose. These include specific and symptomatic treatment of rhabdomyolysis, renal failure, diffuse intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), myocardial infarction, and intracranial hemorrhage.39 Asymptomatic patients with presumed MAOI overdose require 24 hours of monitoring and observation in the intensive care unit.

SEROTONIN SYNDROME The serotonin syndrome is discussed in great detail in Chap. 58. The serotonin syndrome is also discussed below because of the importance of the MAOI-associated serotonin syndrome and because of its similarity to other MAOI drug interactions and overdoses. Clinically, the serotonin syndrome is characterized by an altered mental status, hyperthermia, neuromuscular dysfunction (such as rigidity), and autonomic dysfunction (such as hypertension and/or hypotension and tachycardia).60 Symptoms may also include shivering, disorientation, trismus, akathisia, coma, seizures, and later complications such as disseminated intravascular coagulation.59,60 Any patient taking an MAOI is at risk of developing the serotonin syndrome if the individual coingests an SSRI or another drug that raises CNS serotonin levels.9,12,36,40 The reaction is not dose-dependent. Coingestion of a single dose of any prescription or nonprescription medicine that has the ability to elevate serotonin levels can result in symptoms. The half-life of the drugs involved determines the duration of risk for the development of the syndrome. The serotonin syndrome is thought to result from overstimulation of CNS serotonin receptors, primarily 5-HT1A. MAO degradation is normally an important pathway for degradation and control

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of CNS serotonin levels. Because other pathways are also involved, and because we neither measure total serotonin degradation nor CNS serotonin levels, the development of the serotonin syndrome is difficult to predict. However, the inhibition of enzymatic degradation by MAOIs may lead to increased serotonin levels, contributing to the serotonin syndrome, particularly when combined with drugs that are likely to raise serotonin levels via other pathways, such as inhibited serotonin reuptake by tricyclic antidepressants (see below). Experimentally, the ability of various agents to cause hyperthermia in rabbits pretreated with an MAOI has been found to be in direct proportion to each agent’s ability to block the reuptake of serotonin.58 Both reversible and irreversible as well as selective and nonselective MAOIs are implicated.49 Nevertheless, in this respect as in overdose, moclobemide and the other reversible MAOIs appear to have a greater margin of safety and they appear to be safer than the older MAOIs to combine with SSRIs.2 There are reports of the serotonin syndrome developing both with a combination of therapeutic agents and in overdose of moclobemide combined with SSRIs,2,40,47,49,59 but these syndromes are mild with few fatalities reported.47,59 Although MAOIs and tricyclic antidepressants are sometimes used in combination for depressed patients,74 this combination places patients at risk of developing the serotonin syndrome50 as a consequence of the ability of tricyclics to inhibit serotonin reuptake. The degree of reuptake inhibition varies among the tricyclic antidepressants. Other drugs that can inhibit serotonin reuptake, and that might result in the serotonin syndrome if combined with MAOIs, include meperidine (Demerol) and dextromethorphan, which is found in many nonprescription antitussives.14 In contrast, morphine lacks the serotonin-potentiating effects in an animal model,64 and in humans appears to be safe to use in combination with MAOIs.58 Treatment of the serotonin syndrome is similar in many respects to the treatment for MAOI overdose. Initial treatment focuses on control of the airway and vital signs. Attention should be focused on control of hyperthermia. An emphasis should be placed on hemodynamic monitoring and the use of titratable drugs that can be rapidly reversed when treating autonomic dysfunction such as hypertension. After the patient is stabilized, gastric decontamination may be undertaken with activated charcoal. Gastric lavage probably has no role in patients who have developed signs and symptoms of the serotonin syndrome as by this time the drug is probably no longer in the stomach and has been distributed in the body. Because of the long half-lives of the parent SSRI drug or active metabolite, a patient should discontinue SSRI therapy for at least 2 weeks, while the SSRI is “washed out” and levels fall, before initiating MAOI therapy so as to avoid an MAOI-SSRI interaction.12 Fluoxetine has the longest half-life; in this case, the manufacturer recommends a 5-week washout period.12 Similarly, at least 2 weeks is recommended before initiating SSRI therapy in a patient who had been taking the older MAOIs. A washout period is less important after therapy with the newer reversible MAOIs such as moclobemide.68 When switching from a tricyclic antidepressant to an MAOI, the standard recommendation is to wait 7–10 days between drugs. However, the prescribing practice of some psychiatrists is to switch from a tricyclic antidepressant (TCA) to an MAOI over a shorter period of time33; the community standard is in evolution.

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TYRAMINE-RELATED MAOI-FOOD INTERACTIONS Food interactions occur when pharmacologically active dietary monoamines such as tyramine, phenylethylamine, and histamine are ingested by patients taking MAOIs (Table 60–2).56,66 These monoamines are normally degraded by gastrointestinal and liver MAO-A before they enter the systemic circulation. However, with MAO inhibition, large quantities of monoamines may be absorbed in the systemic circulation. Protein-rich foods are particularly likely to contain decarboxylating bacteria that convert amino acids into pharmacologically active monoamines.7,56 Tyramine acts in a manner similar to the indirect-acting sympathetic agents (Fig. 60–1). Stored norepinephrine is released into the nerve terminal, resulting in a hypertensive crisis.16,27 Ingestion of as little as 6 mg of tyramine may result in a significant vasopressor effect in the MAO-inhibited patient.30 This is 1–10% of the dose normally needed to achieve a vasopressor effect. Analysis of the tyramine content of food and beverages reveals that the amine composition of foods varies greatly even when the same type of cheese from different sources is analyzed.16 Less danger of a tyramine reaction occurs with the use of the reversible inhibitors of MAO (RIMAs), and patients taking these drugs can have an unrestricted diet.28,68 Because of the reversible nature of MAO inhibition by these MAOIs, tyramine can compete effectively for MAO, more tyramine is degraded, and there is much less danger of a hypertensive reaction following ingestion of tyramine-rich foods.28,57,65 Symptoms of MAOI-food interactions reflect the hyperadrenergic state created by the nonmetabolized dietary monoamines. They include hypertension, tachycardia, and headache in early or minor reactions. Additional symptoms may include bradycardia, flushing, an altered mental status and seizures as well as secondary sequelae from uncontrolled hypertension, such as myocardial infarction and intracranial hemorrhage. However, these

TABLE 60–2. Dietary Considerations for Patients Taking MAOIs High tyramine content Aged, mature cheeses (65–1500 mg/kg) Smoked, pickled, aged, putrefying meats or fish (0–470 mg/kg) Yeast and meat extracts (65–2250 mg/kg), including marmite Red wines (1.5–12 mg/kg) Broad beans Moderate tyramine content Meat extracts (100–300 mg/kg) Pasteurized light and pale beers Ripe avocados Low tyramine content Distilled alcohol Cottage cheese, cream cheese Sour cream Chocolate, caffeine-containing beverages Fruit Soy sauce Yogurt Patients should avoid high tyramine content meals and eat small quantities of meals containing moderate amounts of tyramine. Patients may eat foods low in tyramine content.

monoamines have a short half-life and the direct effects will have a rapid onset and abate within several hours. Normotensive patients who experience severe hypertension after dietary interactions may be treated with the use of an -adrenergic antagonist such as 2–5 mg IV of phentolamine.27 Titratable drugs, such as nitroprusside, are an excellent choice to allow to enable controlled lowering of the blood pressure. Treatment of individual symptoms in patients with MAOI-food interaction is similar to the symptomatic and supportive care described for MAOI overdose. However, these patients usually have early clinical manifestations rather than the delayed presentations characteristic of MAOI overdose. Therefore, patients with MAOIfood interactions may not require hospital admission if the interaction has been mild, resolution of symptoms has been complete, and the patient can be observed in the ED for 4–8 hours. Patients with an altered mental status, seizures, or suspected intracranial hemorrhage must be managed accordingly, have appropriate diagnostic studies, and be hospitalized for further studies and observation. Table 60–3 compares the characteristics of MAOI overdose with symptoms following interactions of MAOIs with foods and indirect-acting sympathomimetic agents. It is notable that the syndromes overlap greatly. In fact, despite a few clinical differences, the most reliable way to tell them apart is by history.

ADVERSE DRUG EVENTS There are several important adverse reactions that may occur during therapeutic use of MAOIs. Hepatotoxicity caused by hydrazine MAOIs is rare but serious, and has led to the discontinuation of the use of iproniazid.6 Such hepatotoxicity results from cellular damage to the hepatic parenchyma and is rare with the MAOIs in current use. However, fatal hepatitis has also been reported after chronic therapeutic use of the reversible MAO-A inhibitor toloxatone. Peripheral neuropathy from vitamin B6 depletion by the hydrazines can also occur. Orthostatic hypotension is common with pargyline.6 The mechanism is thought to involve an alteration in synaptic amine stores in adrenergic neurons. Norepinephrine is replaced by the less potent dopamine, resulting in decreased adrenergic vasomotor tone. As an extension of their therapeutic effects, MAOIs may cause agitation and hypomanic behavior, insomnia, tremors and hyperhidrosis in therapeutic doses.3 A variety of other effects, such as dry mouth, blurred vision, dizziness, difficulty with urination and ejaculation, and constipation, may also occur, particularly with phenelzine and tranylcypromine, especially when doses exceed 45 mg/d.6 Drug interactions with sympathomimetic agents are predictable and may occur when a patient taking an MAOI also takes one of the several types of drugs mentioned in Table 60–4.4,40 Drug interactions may occur when the drug combinations are taken in therapeutic doses or in overdose. As with other MAOI-related interactions, they are more likely to occur in patients taking the older, nonspecific, irreversible inhibitors of MAO than with the RIMAs.28,68 The serotonin syndrome has been discussed above. Other major types of drug interactions result from the indirect-acting sympathomimetic agents or from interactions caused by alteration of hepatic metabolism. Indirect-acting sympathomimetic agents (Table 60–4) release norepinephrine stored in the peripheral sympathetic nerve terminal27 (Fig. 60–1). Patients taking MAOIs have increased presynap-

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TABLE 60–3.

Interaction Between Monoamine and Food or Drugs

MAOI Overdose

Onset of symptoms Minutes to hours

Minutes to hours

Up to 24 hours

Signs and symptoms

Hypertension or hypotension Hyperthermia Muscle rigidity Disorientation Shivering Seizures

Severe hypertension Tachycardia or bradycardia Headache Flushing Seizures Intracranial hemorrhage

Hypertension or hypotension Diaphoresis Neuromuscular hyperactivity Opsoclonus Obtundation Seizures Intracranial hemorrhage Cardiovascular collapse

Symptom duration

Hours

Hours

Days

tic stores of norepinephrine because its degradation by MAO is inhibited. In a patient taking an MAOI, the norepinephrine release that is triggered by an indirect-acting sympathetic agent may result in a hyperadrenergic syndrome when a large amount of released norepinephrine stimulates postsynaptic - and
-adrenergic and serotonergic receptors. In contrast, direct-acting sympathetic agents such as epinephrine, norepinephrine, and isoproterenol are not potentiated by MAO inhibition and are relatively safely used in patients on MAOIs.20,70 Rather than release a stored pool of norepinephrine, the direct-acting sympathetic agents bind directly with postsynaptic - and
-adrenergic receptors and are not primarily degraded by MAO. Direct-acting and parenterally administered adrenergic agents are primarily cleared by cell reuptake and catecholO-methyltransferase (COMT), a synaptic enzyme that is not inhibited by MAOIs.37 The hyperadrenergic syndrome that results from the interaction of an MAOI and an indirect-acting sympathetic drug may be difficult to distinguish from MAOI overdose or the serotonin syndrome. Fortunately, treatment is very similar and is based upon the same principles of supportive care of specific symptoms. Symp-

Sympathomimetic Agents

Indirect acting* Amphetamine Hydroxyamphetamine Benzphetamine Ritodrine Methamphetamine Phenylpropanolamine Fenfluarmine Propylhexedrine Phentermine Tyramine

891

Characteristics of MAOI Reactions

Serotonin Syndrome

TABLE 60–4.

MONOAMINE OXIDASE INHIBITORS

Direct acting Epinephrine Norepinephrine Isoetharine Ethylnorepinephrine Isoproterenol Methoxamine Phenylephrine Albuterol Both direct and indirect acting* Dopamine Metaraminol Ephedrine Mephentermine

*High risk for adverse drug events with MAOIs.

toms typically start within 4–8 hours of ingestion. Mild symptoms can include hypertension, tachycardia or reflex bradycardia, and headache. Severe reactions may occur with hyperthermia, an altered mental status, seizures, intracranial hemorrhage, and death. Animal studies of MAOI-theophylline interactions implicate serotonin potentiation by theophylline via adenylate cyclase.5,69 Human reports of interactions between MAOIs and theophylline are limited to reports with multiple coingestants that are known to interact with MAOIs. Many cases of toxic reactions are reported in patients who were treated with MAOIs and given tryptophan for depression51,67 or levodopa for Parkinson’s disease.55,65 The reaction appears to be similar to the tyramine-MAOI food interaction and includes hypertension, facial flushing, and a sensation of warmth. This reaction has been attributed to the administration of precursor amino acids in the setting of decreased degradation24 (Table 60–3). Although there have been no reports of fatalities, these combinations should be avoided or used only with great caution. The use of selegiline, the specific inhibitor of MAO-B, with levodopa is considered safe in therapeutic doses. Animal studies and human reports describe a potentiation of the hypoglycemic effects of insulin and sulfonylureas in the presence of MAO inhibition.8 Tranylcypromine is a potent insulin secretagogue.8 Persistent hypoglycemia with the use of selegiline is also reported.55 Doses of hypoglycemic agents should be appropriately adjusted in patients on MAOIs because of the increased risk of hypoglycemic episodes. This hypoglycemic effect has not been observed with moclobemide.28,68 The MAOIs inhibit the mixed-function oxidase enzyme system of P450 that metabolizes and inactivates pentobarbital, amobarbital, and hexobarbital.22 Doses of barbiturates should therefore be adjusted when MAOIs are used simultaneously. Similarly, the sedating effects of codeine may also be prolonged and potentiated in MAO-inhibited patients. Drugs in other classes that may necessitate dose adjustment because of prolonged and intensified effects in the setting of MAO inhibition include general anesthetics, sedatives, antihistamines, ethanol, and anticholinergic agents.3 When switching from one MAOI to another, a waiting period of 14 days is recommended to avoid hypertensive reactions that have been reported when switching from pargyline to tranyl-

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cypromine. In some patients, more rapid switching or simultaneous administration may be safe.72 However, it is impossible to predict who will have an adverse reaction and who will not. Recently, attention has been drawn to the herbal medication St. John’s wort, which is thought to be a weak MAO inhibitor and to increase CNS serotonin levels.44,48,53 Although the mechanism of action requires further study, the concomitant use of St. John’s wort with MAOIs should be avoided in order to avoid potentially harmful interactions. In general, a patient on MAOIs should not use nonprescription medications without seeking the advice of a physician or pharmacist in order to avoid the potential for drug-drug interactions.

SUMMARY MAOIs have been largely replaced by different classes of antidepressants with potentially less food and drug interactions. Fortunately, the newer, reversible MAOIs are emerging as safer drugs that will not necessitate dietary restrictions and that have less frequent drug-drug interactions. The newer indications for MAOI administration, such as anxiety and phobias, will lead to an increasing popularity of MAOIs and to their broader use. The complex pharmacology of MAOIs remains pertinent as treatment modalities in psychopharmacology evolve.

ACKNOWLEDGMENTS Diane Sauter contributed to this chapter in a previous edition. Thanks to Doson Chua B.Sc. (Pharm) for assistance with research.

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57. Silverstone T: New aspects in the treatment of depression. Int Clin Psychopharmacol 1992;6(Suppl 5):41–44. 58. Sinclair JG, Lo GF: The blockade of serotonin uptake and the meperidine monoamine oxidase inhibitor interaction. Proc West Pharmacol Soc 1977;20:373–374. 59. Singer PP, Graham RJ: An uncommon fatality due to moclobemide and paroxetine. J Anal Tox 1997;21:518–520. 60. Smilkstein MJ, Smolinske SC, Rumack BH: A case of MAO inhibitor/MDMA interaction. Agony after ecstasy. J Toxicol Clin Toxicol 1987;25:149–159. 61. Stack CG, Rogers P, Linter PK: Monoamine oxidase inhibitors and anaesthesia. Br J Anaesth 1988;60:222–227. 62. Stark DCC: Effects of giving vasopressors to patients on MAO inhibitors. Lancet 1962;2:1405–1406. 63. Sternbach H: The serotonin syndrome. Am J Psychiatry 1991;148: 705–713. 64. Tanks CM, Lloyd AT: Hazards with monoamine oxidase inhibitors. Br Med J 1965;1:589. 65. Teychenne PF, Calne DB, Lewis PJ, et al: Interactions of levodopa with inhibitors of monoamine oxidase and L-aromatic acid decarboxylase. Clin Pharmacol Ther 1975;18:273–277. 66. Thakore J, Dinan TG, Kelleher M: Alcohol-free beer and the irreversible monoamine oxidase inhibitors. Int Clin Psychopharmacol 1992;7:59–60. 67. Thomas JM, Rubin EH: Case report of a toxic reaction from a combination of tryptophan and phenelzine. Am J Psychiatry 1984;141: 281–283. 68. Tiller JWG, Johnson GFS, Franz CP, et al: Moclobemide for depression: An Australian psychiatric practice study. J Clin Psychopharmacol 1995;15:31S–34S. 69. Tobin AB, Osborne NN: Evidence for the presence of serotonin receptors negatively coupled to adenylate cyclase in the rabbit iris-ciliary body. J Neurochem 1989;53:686–691. 70. Tolefson GD: Monoamine oxidase inhibitors: A review. J Clin Psychol 1983;44:280–287. 71. Trinker FR, Flearn HJ, McCullock NW, et al: Experimental observations on the effects of adrenaline after treatment with antidepressant monoamine oxidase inhibitors (MAOI) drugs. Austr Dent J 1967; 12:297–303. 72. True L, Alexander B, Carter B: Switching monoamine oxidase inhibitors. Drug Intell Clin Pharm 1985;19:825–827. 73. Wells DG, Bjorksten AR: Monoamine oxidase inhibitors revisited. Can J Anaesth 1989;36:64–74. 74. White K, Pistole T, Boyd JL: Combined monoamine oxidase inhibitor-tricyclic antidepressant treatment: A pilot study. Am J Psychiatry 1980;137:1422–1425.

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LITHIUM Glendon C. Henry

Lithium MW = 6.94 daltons Lithium levels (serum): Therapeutic level for bipolar depression = 0.6–1.2 mEq/L (mmol/L) Action level Acute toxicity = >4.0 mEq/L (mmol/L) Chronic toxicity = >1.5 mEq/L (mmol/L) Values greater than or equal to the action level necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical condition of the patient.

ST segment and T-wave changes, and U waves. The chest radiograph was normal. A lumbar puncture was performed and all chemical and cytologic studies of the cerebrospinal fluid (CSF) were normal. Shortly thereafter, a serum lithium level of 3.6 mEq/L was reported by the laboratory. Other pertinent laboratory studies included a blood urea nitrogen (BUN) of 40 mg/dL and a creatinine of 1.9 mg/dL. Following consultation with a nephrologist, hemodialysis was performed for 4 hours at a blood flow rate of 250 mL/min. During the procedure the patient became more alert and responsive. Her lithium level immediately postdialysis was reported as 0.6 mEq/L, but this rose to 2.1 mEq/L 4 hours later. A second hemodialysis treatment was performed the following day, and the patient’s posttreatment and subsequent lithium levels remained below 0.1 mEq/L. She was now communicative and reported that her physician had started her on an angiotensin-converting enzyme (ACE) inhibitor 2 weeks earlier for mild hypertension. She denied acute ingestion or suicidal ideations and was discharged on a lower maintenance dose of lithium with close followup.

A 36-year-old woman was rushed to the Emergency Department (ED) by her family because of a change in mental status. The patient was stuporous, but when aroused, she had slurred speech and complained of blurred vision. She was unable to provide any additional history at that time. According to the family and a clinic psychiatrist, the woman had manifested emotional problems for years and had been treated by numerous psychiatrists. The patient’s purse contained bottles of phenothiazines, tricyclic antidepressants, lithium carbonate, and several analgesic combinations. On examination, the patient was unkempt, diaphoretic, and poorly nourished. Her vital signs were blood pressure, 140/85 mm Hg; pulse, 110 beats/min; respirations, 18 breaths/min; temperature, 37.3°C (99.1°F); and oxygen saturation, 94% on room air. She had poor dentition and her mouth smelled of fresh vomitus. Horizontal nystagmus was present. Her chest was normal to auscultation and percussion, heart rate was regular, and there were no murmurs, thrills, heaves, or gallops. Abdominal examination revealed hyperactive bowel sounds. Rectal examination revealed good sphincter tone, with no occult blood in the stool. During the neurologic examination the patient became agitated with stimulation. She had a mild tremor and fasciculations in both upper extremities. There was no motor weakness, but the deeptendon reflexes were hyperactive. Clonus of both lower extremities was noted and choreoathetoid movements were observed twice during the examination. All cranial nerves were normal, with the exception of the previously noted horizontal nystagmus. Low-flow oxygen was administered, and cardiac monitoring initiated. A largebore intravenous catheter was inserted, and blood specimens were obtained for electrolytes, renal function, complete blood count (CBC), arterial blood gases (ABG), and serum lithium level. A bedside glucose determination was 120 mg/dL. The patient was administered 100 mg of thiamine HCl intravenously without response and an ampule of multivitamins was added to the first liter of 0.9% sodium chloride. The patient’s clinical condition did not change. The electrocardiogram (ECG) demonstrated a sinus tachycardia at 110 beats/min with normal P-R and QRS intervals, nonspecific

HISTORY Lithium is the lightest metal known; it is a cation with an atomic number of 3 and a valence of +1. It is in the same column of the periodic table as sodium and potassium; thus, many of its actions are similar to those of sodium and potassium (Chap. 12). Although first prescribed as an antidepressant in 1970, lithium’s use in medicine began much earlier.1 In the mid-19th century, because of the solubility of lithium urate, various lithium salts were used in the treatment of gouty arthritis and nephrolithiasis. At one time, it was a constituent in the soft drink Seven-Up. Later, lithium chloride was popularized as a table-salt substitute for the treatment of hypertensive patients.1 However, in 1949, several deaths were attributed to lithium toxicity, leading the FDA to ban its use as a salt substitute. Ironically, this was about the time that a beneficial role for lithium

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in the treatment of mania was discovered. In 1970, lithium was recognized as the treatment of choice for patients with bipolar disorders. In addition to its role in treating bipolar disorders, lithium carbonate is also prescribed in the prophylaxis and treatment of cluster headaches,39 and as a “cell stimulator” in neutropenic patients.44,52,54

PHARMACOLOGY Lithium’s precise mechanism of action has not been fully elucidated. The actions of lithium are similar to those of sodium and potassium, with which it shares the same valence. The ionic radius of lithium is similar to that of magnesium; therefore, it may substitute for this ion as well.47 Although lithium may alter some of the functions of magnesium and serve as a false ion for either sodium or potassium, its main effect may not be secondary to its substitution for any of these ions, but rather from its effect on phosphatidylinositol metabolism via a second messenger. After inositol is activated by a surface agonist,9,19,53 it interacts with G proteins that then stimulate phospholipase C to cleave intracellular phosphatidylinositol to intracellular messengers 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate.14,38 The latter is a direct stimulator for the release of intracellular calcium, while the former is an activator of protein kinase C. This is important because inositol does not cross the blood-brain barrier; thus, its concentration in the brain is maintained by regeneration and breakdown of phosphorylated components.3,57 Lithium may inhibit the enzyme inositol monophosphatase, leading to an increase in inositol monophosphate and to a decrease in free inositol and the intermediate phosphatidylinositol 4,5-bisphosphate.13,14,38 The final common pathway is a decrease in free brain inositol concentration, which is believed to result in both the desired and the adverse effects produced. Although this mechanism seems reasonable, lithium may also alter other pathways and its effects on protein kinase C and G proteins may be just as important as the depletion of inositol.47 Norepinephrine activity may also be attenuated by lithium via a second messenger, cAMP.7 Although its interactions with cAMP have been extensively evaluated, no definitive mechanism of action is yet elucidated. Its interactions with magnesium metabolism may play a vital role.48 The numerous chemical interactions may explain various alterations in biologic functions brought about by lithium as well as its potential role in treating diverse disease processes. Lithium may also effect neurotransmitters. It seems to increase the synthesis and turnover of serotonin,46 while producing a downregulation of the 5-HT1A receptors in the hippocampus49 by diminishing serotonin binding to its receptors.38 Although not as well established, lithium may also have an effect on the down-regulation of the
- and -adrenergic receptors.46 Similar net effects on dopaminergic receptors may occur because lithium may prevent up-regulation at the D2 receptors.2,75 Lithium may cause other disorders such as nephrogenic diabetes insipidus18,25 and hypothyroidism.23 Diabetes insipidus may be the most problematic of all the complications induced by lithium because its development will invariably lead to further toxicity. Lithium may decrease cyclic adenosine monophosphate (cAMP) production in the renal collecting ducts by blocking the action of antidiuretic hormone (ADH)-sensitive adenylate cyclase, which produces a decrease in water reabsorption and polyuria. It

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may also impair the expression or function of aquaporins, or water channels, in the renal tubules. The drug-induced diabetes insipidus creates a hyperosmolar state, which causes increased ADH secretion secondary to pituitary stimulation. This stimulation induces urinary prostaglandin secretion, which blocks ADH-sensitive cyclase, thereby decreasing water reabsorption.18,25,28 Fortunately in the majority of the cases, the diabetes insipidus is reversible upon discontinuing lithium therapy. Lithium is selectively concentrated in the thyroid gland, where long-term exposure produces hypothyroidism. The etiology of the hypothyroidism may be multifactorial and includes blocking of iodine uptake by the gland, reduced release of T3 and T4, or even decreased sensitivity of the gland to TSH.58 In addition, lithium prevents the conversion of T4 to T3 and is associated with the formation of antithyroid antibodies. It is said that nearly one-third of all patients on chronic lithium therapy will have an increase in TSH, with one-third to one-half of those patients developing hypothyroidism.

TOXICOKINETICS Immediate-release lithium is absorbed from the gastrointestinal tract within 1–2 hours, with peak levels achieved at 2–4 hours. Following ingestion of sustained-release preparations, initial absorption may be delayed for 6–12 hours with absorption completed after an additional 8 hours. In overdose, peak absorption may be delayed even longer. Lithium has a volume of distribution of 0.6–0.9 L/kg, which is slightly larger than total body water. Lithium is excreted via the kidney (95%), and its clearance is dependent on the glomerular filtration rate (GFR). Patients with a decreased GFR are at higher risk for toxicity.63 Normally, 80% of the lithium handled by the kidney is reabsorbed, while 20% is excreted in the urine unchanged.31,63,66,67 Lithium was believed to be solely reabsorbed in the proximal tubules following filtration,51 but recent evidence suggests that some lithium is also reabsorbed in the loop of Henle, as well as in the distal tubules.7,16,37 About 5% of lithium is secreted in sweat and saliva, and a small percentage is excreted in breast milk in the lactating female.73 After absorption, lithium undergoes a slow distribution as it traverses cell membranes in therapeutic and toxic doses.34 Lithium enters the liver and kidney rapidly, while its passage into muscle, bone, and brain is much slower.34 As lithium enters these outer compartments, its volume of distribution approaches 0.9 L/kg. The therapeutic elimination half-life for lithium is about 20–24 hours, but may be prolonged beyond that in patients who receive lithium therapy for extended periods of time or in those patients with reduced renal function.30 The CSF lithium levels range from 40% to 80% of that in the serum. Unfortunately, CSF levels do not correlate either with serum levels, therapeutic effect, or toxicity.57,74

CLINICAL MANIFESTATIONS Signs and symptoms of chronic lithium toxicity are quite distinct from those resulting from single acute ingestions (Table 61–1). Similar to patients who ingest other metal salts, those patients with acute lithium overdose typically manifest early gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Neurologic findings are delayed. Cardiovascular complaints, such as light-

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TABLE 61–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Toxicity of Lithium Acute

Chronic Myocarditis

Cutaneous

Prolonged QT interval ST- and T-wave abnormalities None

Renal

Concentrating defects

Gastrointestinal

Nausea Vomiting Leukocytosis

Cardiovascular

Hematologic Neurologic Mild Moderate

Severe

Endocrine Congenital

Weakness, lightheadedness, fine tremor Muscle twitching, tinnitus, drowsiness, hyperreflexia, slurred speech, apathy Confusion, clonus, coma, seizure, extrapyramidal symptoms (choreoathetoid movements) None None

Dermatitis, ulcers, localized edema Nephrogenic diabetes insipidus Interstitial nephritis Renal failure Minimal Aplastic anemia Same Same

Parkinson disease, psychosis, memory deficits, idiopathic intracranial hypertension Hypothyroidism Hypothyroidism

headedness, dizziness, and orthostatic hypotension, are usually the result of excessive fluid loss rather than from a direct cardiotoxic effect. Electrocardiographic manifestations such as nonspecific T-wave changes may develop and are usually benign.22 Although reported in the literature, malignant dysrhythmias and severe cardiac dysfunction are very rare.68 Neurologic abnormalities are the major manifestations of both acute and chronic lithium toxicity.50,59,60 In the acute setting, the initial finding may be merely a fine tremor of the hands. As toxicity progresses, the patient will develop hyperreflexia followed by fasciculations, muscular irritability, choreoathetosis, clonus, agitation, and altered mental status. Confusion may be followed by lethargy, coma, and seizures. Dysarthria, nystagmus, and truncal ataxia may also occur.21,50,55,70 The electroencephalogram (EEG) may show diffuse slowing.59,61 Although the progression of these signs or symptoms may be orderly, the levels do not necessarily correlate with the toxic manifestations, which may be explained by the slow distribution time for lithium.26,57,75 Patients with chronic lithium toxicity rarely notice or manifest gastrointestinal symptoms and usually present with altered mental status. Toxicity typically results from either a dosing error, such as the continuation of high lithium doses following the control of a manic episode, or as a result of other predisposing factors, such as drug interactions, sodium restriction, or a decrease in renal lithium excretion. Numerous agents, such as the nonsteroidal anti-inflammatory agents, ACE inhibitors, serotonin reuptake inhibitors (SSRIs), and antipsychotic agents, may elevate lithium levels. Patients with a history of cardiovascular disease and anyone who uses a diuretic chronically are at increased risk for toxicity. Impaired elimination results from intrinsic renal dysfunction or diuretic therapy causing natruresis. Prerenal azotemia, or any condition that predisposes to a relative decrease in intravascular

volume or sodium, leads to a concomitant increased reabsorption of both sodium and lithium, as noted previously. The toxicity of the patient chronically poisoned by lithium is almost exclusively neurologic and resembles the later stages of acute toxicity. An explanation for the difference in time between acute and chronic poisoning presentations is that with chronic use there is a high total body burden of lithium and therefore any additional increase in lithium intake results in immediate toxicity. By comparison, in the acute setting, there is a substantial delay in tissue distribution prior to the development of therapeutic or toxic effects. Patients receiving chronic lithium therapy who also acutely ingest an excessive amount of lithium (“acute or chronic overdose”) may be the most difficult to accurately diagnose and to properly manage because they may manifest signs and symptoms of both acute and chronic toxicity. Although neurologic signs may be present in this situation of a chronic overdose, acute gastrointestinal symptoms also occur, and toxicity may be more severe and prolonged (Table 61–1). Patients who initially appear well may subsequently develop seizures and altered mental status.50 Prolonged exposure of the central nervous system to excess lithium can cause permanent neurologic sequelae, even when enhanced extracorporeal clearance methods such as hemodialysis are used.33,65 Long-term exposure to sustained toxic levels may result in memory deficits, neuromuscular weakness, change in personality, or tremors.29,42,65,72 Hyperthermia is a grave marker of central nervous system (CNS) toxicity, necessitating immediate intervention. In addition, there are several reports linking lithium with the neuroleptic malignant syndrome (Chap. 18). Unfortunately, all of these cases describe patients who had ingested multiple agents, including at least one antipsychotic. There are no reports of NMS induced by lithium as the sole agent.4,17 Lithium is frequently added after an antipsychotic is initiated and therefore it is difficult to determine what role lithium itself actually plays in this disorder.

DIAGNOSTIC TESTING Laboratory studies should be sent for electrolytes, renal function, and a serum lithium level.36,64 Not only will the renal function studies offer insight into the etiology of toxicity, but they will help predict the response to conservative therapy. A second and perhaps serial lithium levels are essential to assess both for ongoing absorption and for response to therapy. When polyuria or hypernatremia is present, simultaneous determinations of the serum and urine osmolarity may assist with the diagnosis of nephrogenic diabetes insipidus. Although not necessarily indicated, a leukocytosis is expected if a CBC is obtained. Similarly, thyroid function studies should be determined when clinical signs of hypothyroidism are suspected. The electrocardiograph should be performed while continuous monitoring is established. Continuous monitoring of the urine output may necessitate insertion of a Foley catheter in patients with significant toxicity.

MANAGEMENT As in all toxicologic emergencies, it is important to define the nature of the patient’s ingestion. It must be determined whether the ingestion is intentional or unintentional, whether one or more

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agents were ingested, and whether the agents are sustained- or regular-release products. With regard to lithium, it is essential to determine whether the ingestion is acute or chronic, or an acute ingestion following chronic treatment. These characteristics of the history may alter how the patient is treated and the eventual outcome. A risk assessment should be performed when the number of ingested pills is known. Each 300-mg lithium carbonate tablet contains approximately 8 mEq of lithium. Assuming a volume of distribution of nearly 1 L/kg and complete absorption for an 80-kg adult, each 300-mg tablet is expected to raise the serum lithium level approximately 0.1 mEq/L. The patient’s airway, breathing, and circulation must be assured; although lithium toxicity does not usually affect the airway or breathing, other coingestants may. Cardiovascular compromise and significant dysrhythmias are rarely associated with lithium poisoning, but can also occur in this setting as a result of excessive gastrointestinal and urinary fluid losses.

Gastrointestinal Decontamination In a patient with an early presentation of an acute overdose, or of an acute overdose superimposed on a chronic overdose of lithium, orogastric lavage may remove pills remaining in the stomach if spontaneous emesis has not already occurred. However, immediate-release preparations are absorbed quickly and extended-release preparations may not pass through even the largest tube. Syrup of ipecac–induced emesis should be considered when the history and clinical presentation are consistent with very recent ingestion and a lack of coingestants. Because lithium is not significantly adsorbed to activated charcoal, its only utility is for the treatment of known or potential coingestants.36,64 The use of a cathartic such as sorbitol has limited benefits and has the potential for complications because most consequential ingestions have spontaneous diarrhea.55 Enhanced gastrointestinal clearance may be accomplished by initiating whole-bowel irrigation with a balanced polyethylene glycol-electrolyte solution (PEG-ELS). If the patient has ingested a sustained-release lithium preparation, such as Lithobid or Escalith CR, then whole-bowel irrigation is even more important.62 When used, PEG-ELS should be administered at 2 L/h in the adult, or at 500 mL/h in a child. The endpoint of this therapy is a rectal effluent that has the same appearance as the instilled fluid (Antidotes in Depth: Whole-Bowel Irrigation). Sodium polystyrene sulfonate (SPS) is a cation ionic exchange agent that is frequently used to treat severe hyperkalemia. Its ability to effectively bind potassium in exchange for sodium so that excessive potassium can be excreted in the stool has made SPS a very valuable agent. One reason that SPS is so effective for hyperkalemia is that the actual amount of potassium to be bound and excreted is small. Because of the similarities between lithium and potassium, a possible role for SPS in the treatment of lithium toxicity has been considered. Studies in dogs show that orally administered lithium is cleared more rapidly when SPS is administered.45 Subsequent animal studies demonstrate the beneficial effects of SPS in reducing blood levels of intravenously administered lithium.44 In fact, a human case report describes success in using SPS to treat lithium poisoning.27 There are substantial concerns with the use of SPS, however. In the rodent studies, extremely large doses (10 g/kg) of SPS were necessary to reduce significant amounts of lithium. Even the lower doses of SPS now under study are much larger than those usually

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given to patients with renal failure. Another major concern is the effect of SPS on potassium. In mice, the hypokalemia induced can be significant; if extrapolated to humans, this electrolyte shift would contraindicate the use of SPS.43 Thus far, studies in humans receiving single doses of SPS demonstrate conflicting effects in causing hypokalemia11,69 and studies including multiple doses of SPS demonstrate the need for replacement potassium.56 In summary, SPS in doses comparable to those effectively used to treat experimental lithium toxicity in animals will almost certainly induce hypokalemia in humans. Thus, the complications of hypokalemia, such as dysrhythmias, hypernatremia, and fluid overload, must be anticipated, as well as the substantial amount of SPS that will be needed to achieve success. These concerns make SPS less appealing.

Fluid and Electrolytes During the evaluation of the patient it is prudent to begin hydration with 0.9% saline in order to promote good urine output to maximize the excretion of lithium. In managing a patient with a lithium overdose, it is essential that the patient’s fluid and electrolyte status be closely monitored and maintained. This approach may be obvious in the acutely poisoned patient who presents with nausea, vomiting, and diarrhea, but in the chronically overdosed patient, dehydration or an electrolyte disturbance may be the precipitating event for hospitalization. In all instances, collaboration and consultation with a nephrologist should be initiated early in the course of management if suspicion for toxicity is substantial. In patients with normal renal function, osmotic and saline diuresis have limited roles and have not been shown to increase lithium clearance significantly.37 When glomerular filtration is impaired, volume repletion with 0.9% sodium chloride solution followed by infusion at 1.5–2 times maintenance should be sufficient to maximize renal lithium clearance. Urinary alkalinization may have a limited beneficial effect on lithium excretion and clearance because sodium bicarbonate decreases lithium reabsorption in the proximal tubules. The use of sodium bicarbonate, however, is not recommended because of its potential to cause hypokalemia, alkalemia, and fluid overload, and because sodium bicarbonate does not significantly enhance elimination over that which can be accomplished by administering a balanced salt solution IV. Diuretics that act on the ascending limb of the loop of Henle or the distal tubule (eg, furosemide, ethacrynic acid, and the thiazides) have limited effects on lithium reabsorption, which maximally occurs in the proximal tubule.51 Indeed, they may worsen lithium poisoning, particularly if the patient becomes salt- or water-depleted. Three classes of agents shown to cause an initial increase in lithium excretion are osmotic agents (mannitol),67 carbonic anhydrase inhibitors, and phosphodiesterase inhibitors (aminophylline). In each case, although the agent may initially produce a small increase in lithium excreted, these agents may result in dehydration resulting in sodium and lithium retention. Therefore, their use is not recommended for the treatment of lithium toxicity. As noted, because chronic lithium therapy can induce diabetes insipidus, it can exacerbate its own toxicity. Amiloride has been shown to decrease the polyuria that is associated with lithium and therefore may help correct the fluid and electrolyte abnormalities as well as increase the excretion of lithium when nephrogenic diabetes insipidus is present. As with any potassium-sparing diuretic,

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dehydration must be prevented so as not to increase lithium reabsorption proximally, while simultaneously avoiding hyperkalemia. These are both rare events and patients are rarely given amiloride in the treatment of acute lithium toxicity.10

Extracorporeal Drug Removal Peritoneal dialysis (PD), which had been used in the past, is no more efficacious than the endogenous lithium clearance by the kidneys;15,77 thus, peritoneal dialysis is not indicated in the management of lithium overdoses in patients with functioning kidneys. The clearance of lithium by PD is between 10 and 15 mL/min, less than a normally functioning kidney.76 Because of PD’s potential to cause complications such as bowel perforation, peritonitis, or sepsis, PD’s only benefit may be for a patient who has renal failure who is already receiving chronic PD and for the patient who has a working PD catheter in place. In this circumstance, PD could be started until more definitive therapy, such as hemodialysis, becomes available. Definitive therapy for patients who manifest lithium toxicity and/or who cannot excrete lithium is extracorporeal removal by hemodialysis (HD). Because lithium is a small ion, has no protein binding, and has a relatively small volume of distribution, it is readily dialyzable.15 Clearance of lithium by hemodialysis is solely dependent on blood flow, and ranges from 70 mL/min to 170 mL/min, which is far greater than that of the kidney.20,24,35 Unfortunately, determining when to institute therapy is not always simple. Patients who are initially poisoned and have high lithium levels but no signs or symptoms may benefit the most from HD because lithium has not yet fully distributed to tissue compartments that are cleared less well than the plasma. Many of these patients will probably do well without HD, and the risks of the procedure must be considered before subjecting the patient to this invasive therapy. Conversely, after lithium has been distributed to the tissues, it is more difficult to remove by HD, and permanent sequelae may occur.34 Determining the need for HD should be based on a consideration of the probability that the patient may become toxic if elimination is not enhanced. Because lithium is not metabolized and is only renally excreted, all patients with potentially toxic lithium exposures and renal failure should undergo hemodialysis as soon as possible. These patients cannot clear lithium and may suffer long-term complications of toxicity. All patients with neurologic dysfunction, including altered mental status, should undergo hemodialysis.61 Patients who are stable, but who may not be able to tolerate sodium repletion, such as those with congestive heart failure, pulmonary edema, or anasarca, should also be considered for early hemodialysis. A patient who has only a mild tremor may not warrant HD, but must be monitored closely for further neurologic dysfunction. The most difficult decision regarding the initiation of HD relies on the interpretation of lithium levels. The definition of a “high” lithium level is arbitrary as well as dependent on the nature of the ingestion. After an acute ingestion, with no previous body burden of lithium, a level of ≥4.0 mEq/L should be considered an indication for HD regardless of the patient’s clinical status.34 At this level, as equilibration begins, some lithium will be excreted, and some will cross the cellular membrane, but it is unlikely that the patient will be able to excrete the lithium rapidly enough to prevent a significant amount from entering the central nervous system and causing

severe and potentially permanent neurologic toxicity.6,33 However, a patient with an acute on chronic overdose or chronic overdose already has a body burden of lithium, and therefore may develop toxicity at a lower level than 4.0 mEq/L.34 For these patients, a lithium level of ≥2.5 mEq/L and moderate to severe neurologic toxicity are reasonable indications for HD.32 A “rebound lithium level” is typically measured after hemodialysis because dialysis clears only the plasma; a significant amount of lithium is in the intracellular space and redistributes slowly into the plasma following treatment.20,34 Lithium levels should therefore be drawn immediately after hemodialysis, and repeated 6 hours postdialysis. If either level is high, or if the patient continues to show signs of neurologic toxicity, a second course of hemodialysis may be needed. For this reason, the dialysis catheter should not be removed until a significant rebound effect can be excluded. Recent studies indicate that continuous arteriovenous hemofiltration (CAVH) may serve as an alternate therapy to hemodialysis.8,71 CAVH and continuous venovenous hemofiltration (CVVH) use essentially the same mechanism to remove toxins from the body, except that in CVVH, the patient has a pump connected to the circuit because of the lack of a gradient across the vessels. In CAVH, the difference in arterial and venous pressure serves as the pump that moves the blood around the circuit. Continuous arteriovenous hemofiltration works on the principle that as blood is constantly being filtered, any toxin that is present will be removed gradually from the body (Chap. 6). The benefits of CAVH over hemodialysis are that CAVH is a continuous process and although filtering takes place in a monitored setting, there is no need for specialized personnel, as there is for HD, and there may be fewer complications. In an effort to increase the efficiency in toxin removal, several studies now suggest continuous venous or arterial hemodiafiltration (CAVHDF) as the primary form of extracorporeal therapy. These forms of therapy are CAVH or CVVH with dialysis inserted into the circuit.12,41 In a recent study,41 seven patients with severe lithium toxicity were evaluated, four with acute and three with chronic overdoses. The acutely overdosed patients underwent CAVHDF, whereas the chronically overdosed were treated with CVVHDF. Clearances of 20–62 mL/min were achieved. Because the clearance is far less than that of HD, the total duration of the procedure must be longer to achieve similar total drug elimination. The authors found that CAVHDF and CVVHDF were both able to remove a significant amount of total body lithium burden and that all patients improved. In only one of their patients was there a rebound rise in the lithium level.34,35 The authors concluded that either CAVHDF or CVVHDF may be excellent methods for removing lithium while preventing a rebound elevation of lithium following the procedure. A disadvantage of CAVHDF is the need to have the patient in a monitored setting for the entirety of the process. HD remains a better modality in terms of speed of toxin removal, and therefore may be better at preventing the gravest of complications, namely permanent neurologic deficits. Although more controlled studies must be performed, hemodiafiltration (HDF) may play an important role in treating patients with lithium toxicity, especially when HD is not available. In addition, HDF may be useful to attenuate the rebound effect in patients who have completed HD. Currently, CAVH and CVVH cannot be recommended as the sole extracorporeal therapeutic intervention for lithium removal if HD is available.

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SUMMARY Lithium plays an essential role in the psychopharmacologic armamentarium. Its use is extensive in diverse psychiatric and nonpsychiatric disorders. Lithium is available in various salt forms in controlled- and immediate-release preparations. Because of the profile of the patients using this drug, the diverse reasons for adverse drug effects, and the ease for developing toxicity (acute and/or chronic), the care for patients poisoned with lithium is complicated. Early recognition of poisoning and rapid use of hemodialysis are essential to decrease patient morbidity and mortality.

REFERENCES 1. Aita JF, Aita JA, Aita VA: 7-Up anti-acid lithiated lemon soda or early medicinal use of lithium. Nebr Med J 1990;75:277–279. 2. Alessi N, Naylor MW, Mohammad G, et al: Update on lithium carbonate therapy in children and adolescents. J Am Acad Child Psychiatry 1994;33:291–303. 3. Allison JH, Stewart MA: Reduced brain inositol in lithium treated rats. Nat New Biol 1971;233:267–268. 4. Amdisen A: Clinical features and management of lithium poisoning. Med Toxicol Adv Drug Exper 1988;3:18–32. 5. Anath J: Side effects in the neonate from psychotropic agents excreted through breast-feeding. Am J Psychiatry 1978;135:801–804. 6. Apte SN, Langston WJ: Permanent neurological deficits due to lithium toxicity. Ann Neurol 1983;13:452–455. 7. Atherton JC, Doyle A, Gee A, et al: Lithium clearance: Modification by the loop of Henle in man. J Physiol 1990;437:377–391. 8. Ayuso Gatell A, Leon Regidor MA, Mestre Saura J, et al: Acute lithium poisoning: Treatment with continuous arteriovenous hemofiltration. Rev Clin Exp 1989;185:195–197. 9. Baraban JM, Worley PF, Snyder SH: Second messenger and psychoactive drug action. Focus on the phosphoinositide system and lithium. Am J Psychiatry 1989;146:1251–1260. 10. Battle DC, Von Riote AB, Gaviaria M, et al: Amelioration of polyuria by amiloride in patient receiving long-term lithium therapy. N Engl J Med 1985;313:409–414. 11. Belanger DR, Tierne MG, Dickerson G: Effect of sodium polystyrene sulfonate on lithium availability. Ann Emerg Med 1992;21: 1312–1315. 12. Bellomo R, Kearly Y, Parkin G: Treatment of life-threatening lithium toxicity with continuous arteriovenous hemodiafiltration. Crit Care Med 1991;19:836–837. 13. Berridge MJ, Downes CD, Hanley RR: Neurological and development action of lithium. A unifying hypothesis. Cell 1989;59:411–419. 14. Berridge MJ, Downes CP, Hanley RR: Lithium amplifies agonistdependent phosphatidylinositol response in brain and salivary gland. Biochem J 1982;206:587–595. 15. Blye E, Lorch J, Cartell S: Extracorporeal therapy in the treatment of intoxication. Am J Kidney Dis 1984;3:321–338. 16. Boer WH, Koomans HA, Dorhout Mees EJ: Lithium clearances in healthy humans suggesting reabsorption beyond the proximal tubules. Kidney Int 1990;37:S39–S44. 17. Brust JC, Hammer JS, Challenor Y, et al: Acute generalized polyneuropathy accompanying lithium poisoning. Ann Neurol 1979;6: 360–362. 18. Christensen EM, Kusano E, Yusufi ANK, et al: Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. J Clin Invest 1985;75:1969–1979. 19. Chuang DM: Neurotransmitter receptors and phosphoinositide turnover. Annu Rev Pharmacol Toxicol 1989;29:71–110.

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20. Clendeninn NJ, Pond SM, Kaysen G, et al: Potential pitfalls in the evaluation of the usefulness of hemodialysis for the removal of lithium. Clin Toxicol 1982;19:341–352. 21. Demers R, Lukesh R, Prichard J: Convulsions during lithium therapy. Lancet 1970;2:315–316. 22. Demers RG, Heninger G: Electrocardiographic changes during lithium therapy. Dis Nerv Syst 1970;31:674–677. 23. Emerson GH, Dyson WL, Utiger RD: Serum thyrotropin and thyroxin concentrations in patients receiving lithium carbonate. J Clin Endocrinol Metab 1973;36:338–346. 24. Feneves AZ, Emmett M, White MG: Lithium toxicity associated with acute renal failure. South Med J 1984;77:1472–1474. 25. Forrest JN, Cohen AD, Torretti J, et al: On the mechanism of lithium induced diabetes insipidus in man and the rat. J Clin Invest 1974; 53:1115–1123. 26. Frazer A, Mendel J, Secunda SK, et al: The prediction of brain lithium concentration from plasma or erythrocyte measure. J Psychiatr Res 1973;10:1–7. 27. Gehrke JC, Watling SM, Gehrke CW, et al: In-vivo binding of lithium using the cation exchange resin sodium polystyrene sulfonate. Am J Med 1996;14:37–38. 28. Gitten M: Lithium and the kidney. An updated review. Drug Saf 1999;3:231–243. 29. Goddard J, Bloom SR, Frackowiak RS, et al: Lithium intoxication. BMJ 1991;302:1267–1269. 30. Goodnick PJ, Fieve RR, Meltzer HC, et al: Lithium elimination halflife and duration of therapy. Clin Pharmacol Ther 1981;29:47–50. 31. Groth U, Prellwitz W, Jahnchen E: Estimation of pharmacokinetic parameter of lithium from saliva and urine. Clin Pharmacol Ther 1974; 16:490–498. 32. Hansen HE, Amdisen A: Lithium intoxication. Q J Med 1978;14: 123–144. 33. Hartitzch BV, Hoenich NA, Leigh RJ, et al: Permanent neurological sequelae despite hemodialysis. Br Med J 1972;4:757–759. 34. Jaeger A, Sauder P, Kopeferschmitt J, et al: When should dialysis be performed in lithium poisoning? A kinetic study in 14 cases of lithium poisoning. J Toxicol Clin Toxicol 1993;31:429–447. 35. Jaeger A, Sauder P, Kopeferschmitt J, et al: Toxicokinetics of lithium intoxication treated by hemodialysis. J Toxicol Clin Toxicol 1985;23: 501–517. 36. Jones J, Mullen MJ, Dougherty J, et al: Repetitive doses of activated charcoal in the treatment of poisoning. Am J Emerg Med 1987;5: 305–311. 37. Kirchner K: Lithium as a marker for proximal tubule delivery during low salt intake and diuretic infusion. Am J Physiol 1987;253: F188–F196. 38. Kofman O, Belmaker RH: Biochemical, behavior and clinical studies of the rate of inositol in lithium treatment and depression. Biol Psychiatry 1989;34:839–852. 39. Kudrow L: Lithium prophylaxis for cluster headache. Headache 1977; 17:15–18. 40. Lapierre G, Stewart RB: Lithium carbonate and leukocytosis. Am J Hosp Pharm 1980;37:1525–1528. 41. LeBlanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 1996;27:365–372. 42. Lewis DA: Unrecognized chronic lithium neurotoxic reactions. JAMA 1983;250:2029–2030. 43. Linakis JG, Hull KM, Lacouture PG, et al: Sodium polystyrene sulfonate treatment for lithium toxicity. Effects on serum potassium concentration. Acad Emerg Med 1996;3:333–337. 44. Linakis JG, Hull KM, Lee C, et al: Effects of delayed treatment with sodium polystyrene sulfate on serum lithium concentrations in mice. Acad Emerg Med 1995;2:681–685. 45. Linakis JG, Lacouture PG, Eisenberg MS, et al: Administration of activated charcoal or sodium polystyrene sulfonate (Kayexalate) as gas-

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49.

50. 51. 52. 53. 54.

55. 56. 57.

58. 59. 60. 61.

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tric decontamination for lithium intoxication: An animal model. Pharmacol Toxicol 1989;65:387–389. Manji HK, Hsaio JK, Risby ED, et al: The mechanism of action of lithium: Effects on serotonergic and noradrenergic systems in normal subjects. Arch Gen Psychiatry 1991;48:505–512. Manji HK, Potter WZ, Lenox RH: Signal transduction pathways. Molecular targets for lithium’s action. Arch Gen Psychiatry 1995; 52:531–543. Mork A, Geiser A: Mode of action of lithium on the catalytic unit of adenylate cyclase from rat brain. Pharmacol Toxicol 1981;60: 241–248. Odagaki Y, Koyama R, Matsubara S, et al: Effects of chronic lithium treatment on serotonin binding sites in rat brain. J Psychiatr Res 1990;24:271–277. Okusa MD, Jovita L, Crystal T: Clinical manifestations and management of acute lithium intoxication. Am J Med 1994;97;383–389. Petersen V, Hvidt S, Thomsen K, et al: Effect of prolonged thiazide treatment on renal lithium clearance. Br Med J 1974;3:143–145. Prakash R: A review of the hematological side effects of lithium. Hosp Commun Psychiatry 1971:36:127–128. Rana RS, Hokin LE: Role of phosphoinositides in transmembrane signaling. Physiol Rev 1990;70:115–164. Richman CM, Makki MM, Weiser PA, et al: Effect of lithium carbonate on chemotherapy induced neutropenia and thrombocytopenia. Am J Hematol 1984;16:313–323. Riegel JM, Becker CE: Use of cathartics in toxic ingestions. Ann Emerg Med 1981;10:254–258. Roberge RJ, Martin TG, Schneider SM: Use of sodium polystyrene sulfonate in a lithium overdose. Ann Emerg Med 1993;22:1911–1915. Sachs GS, Renshaw PF, Lafer B, et al: Variability of brain lithium levels during maintenance treatment: A magnetic resonance spectroscopy study. Biol Psychiatry 1995;38:422–428. Salta R, Klein I: Effects of lithium on the endocrine system: A review. J Lab Clin Med 198;110:130–136. Sansone MEG, Ziegler DK: Lithium toxicity: A review of neurologic complications. Clin Neuropharmacol 1985;8:242–248. Saul RF, Hamburger HA, Selhorst JD: Pseudotumor cerebri secondary to lithium carbonate. JAMA 1985;253:2869–2870. Schou M: Long-lasting neurological sequelae after lithium intoxication. Acta Psychiatr Scand 1984;70:594–602.

62. Smith SW, Ling LJ, Halstenson C: Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991;20:536–539. 63. Sproule BA, Hardy BG, Schulman KI: Differential pharmacokinetics of lithium in elderly patients. Drugs Aging 2000;16:165–177. 64. Spyker DA: Activated charcoal reborn: Progress in poison management. Arch Intern Med 1985;145:43–44. 65. Strayhorn JM, Nash JL: Severe neurotoxicity despite “therapeutic” serum lithium levels. Dis Nerv Syst 1977;38:107–111. 66. Thomsen K, Bak M, Shirley DG: Chronic lithium treatment inhibits amiloride-sensitive sodium transport in the rat distal nephron. J Pharmacol Exp Ther 1999;289:443–447. 67. Thomsen K, Schou M: Renal lithium excretion in man. Am J Physiol 1968;215:823–827. 68. Tilkian AG, Schroeder JS, Kao JJ: Cardiovascular effects of lithium in man: A review of the literature. Am J Med 1976;61:665–670. 69. Tomaszewski C, Musso C, Pearson JR, et al: Lithium absorption prevented by sodium polystyrene sulfonate in volunteers. Ann Emerg Med 1992;21:1308–1311. 70. Vacaflor L, Lehmann HE, Ban TA: Side effects and teratogenicity of lithium carbonate treatment. J Clin Pharmacol J New Drugs 1970;10: 387–389. 71. Van Bommel EF, Kalmeijer MD, Possen HH: Treatment of high lithium toxicity with high-volume continuous venovenous hemofiltration. Am J Nephrol 2000;20:408–411. 72. Vestergaard L, Amdisen A, Schou M: Clinically significant side effects of lithium treatment. A survey of 237 patients in long term treatment. Acta Psychiatric Scand 1980:62:193–200. 73. Weinstein MR, Goldfield MD: Cardiovascular malformations with lithium use during pregnancy. Am J Psychiatry 1975;132:529–531. 74. White K, Cohen J, Nelson R, et al: Relationship between plasma, RBC and CSF lithium concentrations in human subjects. Int Pharmacopsychiatry 1979;14:185–189. 75. Whitworth P, Kendall DA: Effects of lithium on inositol phospholipid hydrolysis and inhibition of dopamine D1 receptors mediated cyclic AMP formation by carbachol in rat brain slices. J Neurochem 1989; 53:536–541. 76. Wilson JH, Donker AJ, van der Helm GK, et al: Peritoneal dialysis for lithium poisoning. Br Med J 1971;2:749–750. 77. Winchester JF: Evaluation of artificial organs: Extracorporeal removal of drugs. Artif Organs 1986;10:316–323.

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OPIOIDS Lewis S. Nelson

been exploited in two distinct manners: they have been used clinically to produce profound analgesia and nonmedicinally for their psychoactive effects. To this day, opioids find their widest clinical application in the relief of acute or chronic suffering. Opioids are available in various formulations which allow administration by virtually any route: oral, parenteral (ie, SC/IV/IM), transdermal, transmucosal, epidural, intrathecal, rectal, and intranasal, as well as inhalational. Patients may also benefit from several of the nonanalgesic effects engendered by certain opioids. For example, codeine finds widespread use as an antitussive agent and diphenoxylate as an antidiarrheal drug. Unfortunately, the history of opium and its derivatives is marred by mankind’s endless quest for drugs that produce pleasurable effects. Opium smoking was so problematic in China by the 1830s that the government attempted to prohibit its importation by the British East India Company. This act led to the Opium Wars with Britain. China eventually conceded and, in addition to allowing importation and sale of the drug, was forced to turn over Hong Kong to British rule. The euphoric and addictive potential of the opioids are immortalized in the works of several famous writers, such as Thomas de Quincey (Confessions of an English Opium Eater, 1821), Samuel Coleridge (The Rime of the Ancient Mariner, 1798), and Elizabeth Barrett Browning (Aroura Leigh, 1856).11 Because of mounting concerns of addiction and toxicity in the United States, the Harrison Narcotic Act was enacted in 1914, making the nonmedicinal use of opioids illegal. Since that time, the recreational and habitual use of heroin and other opioids remains at epidemic levels in the United States and worldwide despite massive attempts to curb their availability. Morphine was isolated from opium by Armand Séquin in 1804,140 and Charles Alder Wright synthesized heroin from it in 1874.225 Ironically, heroin was developed and marketed in 1898 as an antitussive agent by Bayer, the German pharmaceutical company, which legitimized its medicinal role.224 Subsequently, various agents with opioidlike effects have been marketed, each promoted for presumed advantages over morphine. In certain cases, such as fentanyl because of its pharmacokinetic profile, this assertion was realized, but generally, particularly with reference to

Emergency Medical Services (EMS) was called to provide assistance for a comatose 23-year-old man. EMS found the patient hypoventilating (2 breaths/min), cyanotic, and with prominent miosis. Earlier the same day the patient was evaluated in another hospital for a similar condition, and after supposedly having a dramatic response to naloxone, he was discharged. In the current Emergency Department (ED), the patient was ventilated by bag-valve mask while preparations were made to perform endotracheal intubation. Naloxone, 0.4 mg, was administered intravenously and the patient became alert with a respiratory rate of 24. At that point the patient looked uncomfortable, he developed diaphoresis, and his pupils dilated. Physical examination revealed piloerection, hyperactive bowel sounds, and bilateral pulmonary rales with a normal cardiac examination. An electrocardiogram (ECG) demonstrated sinus tachycardia, and an arterial blood gas was reported as pH, 7.38; PCO2, 28 mm Hg; and PO2 (on 40% Venti-mask), 140 mm Hg. A portable chest radiograph showed diffuse patchy infiltrates. The patient received continuous low-flow oxygen therapy for 24 hours in the intensive care unit (ICU), at all times maintaining his oxygen saturation in the normal range. Over the observation period his lungs cleared, and he was discharged after an additional day of observation with a referral back to his methadone maintenance treatment program.

HISTORY AND EPIDEMIOLOGY The medicinal value of opium, the dried extract of the poppy plant (Papaver somniferum) is recorded around 1500 BC in the Ebers papyrus.140 Raw opium is typically composed of at least 10% morphine, but extensive variability exists by growing region.109 Although reformulated as laudanum (deodorized tincture of opium; 10 mg morphine/mL) by Paracelsus, as well as paregoric (camphorated tincture of opium; 0.4 mg/mL),127 Dover’s powder (pulvis Doveri), and Godfrey’s cordial in later centuries,140 their contents remained largely the same: phenanthrene poppy derivatives, such as morphine and codeine. Over the intervening centuries since the Ebers papyrus, opium and its components have

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abuse potential, the advantages have not been realized and fall short of expectations. The terminology used in this chapter recognizes the broad range of agents commonly considered to be opiumlike. The term opiate specifically refers to the relevant alkaloids that are derived directly from the opium poppy: morphine and codeine, and, to some extent, thebaine and noscapine. Opioids are a much broader class of agents that are capable of producing opiumlike effects or of binding to opioid receptors (detailed below). Opioids include the naturally occurring peptides such as endorphin. A semisynthetic opioid, such as heroin or oxycodone, may by created by the modification of an opiate. Alternatively, synthetic opioids are newly synthesized chemical compounds that bear little overt structural similarity to the opiates yet are capable of producing opioid effects experimentally or clinically. Methadone and meperidine are examples of synthetic opioids. The term narcotic refers to a sleep-inducing agent and was initially used to connote the opioids. In its current use, however, law enforcement and the public use the term to indicate any illicit psychoactive substance. Consequently, the term opioid is used hereafter to encompass the opioids and the opiates.

PHARMACOLOGY Opioid Receptor Subtypes Despite nearly a century of studying opioids, the existence of specific opioid receptors was not proposed until the mid-20th century.8 Beckett and Casy, synthetic chemists, noted a pronounced stereospecificity of existing opioids (only the l-isomer is active), and postulated the need for the drug to “fit” into a receptor. In 1963, after the study of the clinical interactions of nalorphine and morphine, the theory of receptor dualism was proposed,144 which postulated the existence of two classes of opioid receptors. However, it was not until 1973 that such opioid binding sites were demonstrated experimentally.183 Intensive experimental scrutiny using selective agonists and antagonists continues to permit refinement of receptor classification. The current, widely accepted schema postulates the coexistence of three major classes of opioid receptors, each with multiple subtypes, as well as several poorly defined minor classes. Initially, it was unclear why such an elaborate system of receptors existed, because no endogenous ligand could be identified. However, evidence for the existence of just such endogenous ligands was uncovered in 1975 with the discovery of met- and leuenkephalins,99 and the subsequent identification of
-endorphin and dynorphin. As a group, these endogenous ligands for the opioid receptors are called endorphins (endogenous morphine). Each is a 5-amino acid peptide, cleaved from a larger precursor peptide: proenkephalin, proopiomelanocortin, and prodynorphin, respectively. All three major opioid receptors have been cloned and sequenced.24 Each consists of seven transmembrane segments, along with an amino and a carboxy terminus. Significant sequence homology exists between the transmembrane regions of opioid receptors, and those of other members of the G-protein-binding receptor superfamily. However, the extracellular and intracellular segments differ from one another. These nonhomologous segments probably represent the ligand binding and signal transduction regions, respectively, which would be expected to differ

among the three classes of receptors. The individual receptors have distinct distribution patterns within the central nervous system and peripherally, and as described below, mediate unique, but not entirely understood, clinical effects. Until recently, researchers have used varying combinations of agonists and antagonists to pharmacologically distinguish the different receptor subtypes. However, molecular cloning technology, in which mutant mice lacking the genes for an individual opioid receptor (“knockout mice”) are bred, promises new insights into this complex subject. Because there are multiple opioid receptors and each elicits a different effect, determining which receptor an opioid agent binds to preferentially should allow prediction of a drug’s clinical effects. However, the binding of a drug typically is not limited to one receptor type, and it is the relative affinity of a drug for differing receptors that accounts for its clinical effects (Table 62–1). Even the endogenous opioid peptides exhibit substantial crossover among the receptors. Although the familiar pharmacologic nomenclature derived from the Greek alphabet is used throughout this textbook, the International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature has recommended a nomenclature change to make opioid receptor names more consistent with those of other neurotransmitter systems.51 In this new schema, the receptors are denoted by their endogenous ligand (opiates peptides) with a subscript identifying their chronologic order of discovery. The  receptor is therefore renamed as OP1, κ is renamed as OP2, and µ is renamed as OP3. Interestingly, the IUPHAR has not incorporated subtype nomenclature into their scheme, but recommends using a subscripted letter for such distinctions (eg, OP3A for µ1).

TABLE 62–1.

Clinical Effects Related to Opioid Receptors

Conventional Name

IUPHAR Name*

Important Clinical Effects of Receptor Agonists

µ1

OP3a

Supraspinal analgesia Peripheral analgesia Sedation Euphoria Prolactin release

µ2

OP3b

Spinal analgesia Respiratory depression Physical dependence Gastrointestinal dysmotility Pruritis Bradycardia Growth hormone release

κ1

OP2a

Spinal analgesia Miosis Diuresis

κ2

OP2b

Psychotomimesis Dysphoria

κ3

OP2c

Supraspinal analgesia

δ

OP1

Spinal and supraspinal analgesia Modulation of µ-receptor function Inhibit release of dopamine

*International Union of Pharmacology, Committee on Receptor Nomenclature with recommended subtype additions.

CHAPTER 62

Mu Receptor (
or OP3). The early identification of the µ receptor as the morphine binding site gave this receptor its designation.143 Although many exogenous agents produce supraspinal analgesia via µ receptors, an endogenous ligand has remained elusive. Although the likely candidate is
endorphin, the discovery of morphine and other morphinans in mammalian brain55 raises the possibility of a role for these nonpeptide opioids. Although it is unclear whether the mammalian morphine is a dietary component86 or is truly endogenous, a tentative biosynthetic pathway in the rat liver is described.260 Additionally, and equally unexplainable, opioid peptides, such as morphicetin and casomorphin, may be found in cow’s milk.14 Experimentally, there are two well-defined subtypes (µ1 and µ2), although there are currently no agents with sufficient selectivity to make this dichotomy clinically relevant. Experiments with knockout mice suggest that both subtypes derive from the same gene and that either posttranslational changes or local cellular effects subsequently differentiate them.115 It is the µ1 subtype that appears to be responsible for supraspinal (brain) analgesia, as well as for the pleasurable euphoria sometimes engendered by these agents. Although stimulation at the µ2 subtype produces spinallevel analgesia, it also produces respiratory depression. All currently available µ agonists have some activity at the µ2 receptor, and therefore produce some degree of respiratory compromise. It is not unexpected that µ receptors are localized to the regions of the brain involved in analgesia (periaqueductal gray, nucleus raphe magnus, medial thalamus75), euphoria and reward (mesolimbic system), and respiratory function (medulla).157 Predictably, µ receptors are found in the medullary cough center, peripherally in the gastrointestinal tract, and on various sensory nerve endings including the articular surfaces (see the discussion of analgesia under “Clinical Manifestations” below). Kappa Receptor ( or OP2). Although it is now known that dynorphins are the endogenous ligands for κ receptors, these receptors were originally identified by their ability to bind ketocyclazocine; thus, the label κ.143 Kappa receptors exist predominantly in the spinal cord of higher animals, although they are also found both in the antinociceptive regions of the brain154 and in the substantia nigra.262 Stimulation is responsible for spinal analgesia, miosis, and diuresis (via inhibition of antidiuretic hormone (ADH) release). Unlike µ, however, κ-receptor stimulation is not associated with significant respiratory depression or constipation. The κ receptor is currently subclassified into three subtypes. The κ1 receptor subtype is responsible for spinal analgesia;188 this analgesia is not reversed by µ selective antagonists,154 supporting the role of κ receptors as independent mediators of analgesia. Although the function of the κ2 receptor is largely unknown, stimulation of cerebral κ2 receptors by agents such as pentazocine produces psychotomimesis in distinction to the euphoria evoked by µ agonists.185 The κ3 receptor is found throughout the brain and appears to participate in supraspinal analgesia. This receptor is primarily responsible for the action of nalorphine, an agonist-antagonist opioid.181 Nalbuphine, another agonist-antagonist, exerts its analgesic effect via both κ1 and κ3 agonism, although both drugs are antagonists to morphine at the µ receptor.187 Delta Receptor ( or OP1). Little is known about  receptors, although the enkephalins are their endogenous ligands. Opioid peptides identified in the skin and brain of Phyllomedusa frogs,

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termed dermorphin and deltorphin, respectively, are potent agonists at the  receptor.125 Delta receptors may be important in spinal and supraspinal analgesia, probably via a noncompetitive interaction with the µ receptor.205,243 Delta receptors may also mediate dopamine release from the nigrostriatal pathway, where they modulate the motor activity associated with amphetamine.104 Delta receptors do not modulate dopamine in the mesolimbic tracts and have little behavioral reinforcing role. Subpopulations, specifically 1 and 2, have been postulated based on in vitro studies, but are not presently confirmed in vivo.243 Nociceptin/Orphanin FQ Receptor (ORL1 or OP4). The ORL1 receptor was identified in 1994, based on sequence homology during screening for opioid receptor genes with DNA libraries.19 It has a similar distribution pattern in the brain and uses similar transduction mechanisms as the other opioid receptor subtypes, and it binds many different opioid agonists and antagonists. However, its insensitivity to antagonism by naloxone, often considered the sine qua non of opioid character, delayed its acceptance as a valid opioid receptor subtype. Simultaneous identification of an endogenous ligand, called nociceptin by the French discoverers and orphanin FQ by the Swiss, allowed the designation OP4.19 A clinical role has yet to be defined, but anxiolytic and analgesic properties are described.19 Sigma Receptor (). Although originally conceived as an opioid subtype,143 the σ receptor is no longer considered to be opioid in character, and has not been given an IUPHAR OP designation. Investigation of this receptor revealed that it is insensitive to antagonism by naloxone, prefers ligands with a dextrorotatory stereochemistry, and has no endogenous ligand, all in contradistinction to the other opioid receptors. The effects of the σ receptor are nonetheless relevant to opioid pharmacology because certain opioids, such as dextromethorphan and pentazocine, are σ-receptor agonists. σ-Receptor stimulation is implicated in psychotomimesis and movement disorders, effects that are reported with both dextromethorphan and pentazocine independently.161 Antipsychotic agents, such as haloperidol, are σ-receptor antagonists, which effect may account for at least part of their antipsychotic effects.46,47 Other Receptors (Epsilon (ε), Zeta ()). The current scheme of opioid receptors, although clinically useful, has some pharmacologic shortcomings. Two other opioid receptor subtypes, although largely uncharacterized in humans, may ultimately prove to be important. The ε receptor is postulated on the basis of in vivo binding assays and has no known clinical role.167 The ζ receptor has been proposed, and may serve as an opioid growth factor receptor.274

Opioid Receptor Signal Transduction Mechanisms Figure 62–1 illustrates opioid receptor signal transduction mechanisms. Continuing research into the mechanisms by which an opioid receptor induces an effect on the receptor-bearing cell has produced confusing, and often contradictory, results. Despite the initial theory that each receptor subtype was linked to a specific transduction mechanism, individual receptor subtypes may use one or more mechanisms, depending on several factors, including receptor localization (eg, presynaptic vs postsynaptic). As noted, all opioid receptor subtypes are members of a superfamily of membrane-bound receptors, which are coupled to GTP binding

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α2

+ K K+

-

NT

[B]

[C]

Gz

-

[D]

Gi/o

Ca 2+ Ca 2+

Gi [C]

Go

-

[B] K++

-

Gi [A]

α2 -

Gz Adenylate cyclase

-

[D] ATP

cAMP

Figure 62–1. Opioid receptor signal transduction mechanisms. Upon binding of an opioid agonist to an opioid receptor, the respective G protein is activated. G proteins may (A) reduce the capacity of adenylate cyclase to produce cAMP; (B) close Ca2+ ion channels that reduce the signal to release neurotransmitters; (C) open K+ channels and hyperpolarize the cell, which indirectly reduces cell activity. Each mechanism has been found coupled to each receptor subtype depending on location of the receptor (pre/postsynaptic) as well as of the neuron within the brain (see text). Note that α2 receptors (D) mediate similar effects, using a different G protein (Gz). NT=neurotransmitter. Adenylate cyclase/cAMP (A) Inhibition of adenylate cyclase activity by Gi or Go is the classic mechanism for postsynaptic signal transduction invoked by the inhibitory µ receptors.245 However, this same mechanism has also been identified in cells bearing either δ or κ receptors.27,269 Activation of cAMP production by adenylate cyclase, with subsequent activation of protein kinase A, occurs following exposure to very-low-dose opioid agonists and produces excitatory, antianalgesic effects.37 Calcium channels (B) Presynaptic µ receptors inhibit norepinephrine release from the nerve terminals of cells of the rat cerebral cortex. Adenylate cyclase does not appear to be the modulator for these receptors because the inhibition of norepinephrine release is not enhanced by raising intracellular cAMP levels by various methods.212 Opioid-induced blockade is, however, prevented by increased intracellular calcium levels that are induced either by calcium ionophores, which increase membrane permeability to calcium, or by raising the extracellular calcium concentration.212 This implies a role for opioid-induced closure of N-type calcium channels, presumably via a Go protein.90 Reduced intraterminal concentrations of calcium prevent the neurotransmitter-laden vesicles from binding to the terminal membrane and releasing their contents. Nerve terminals containing dopamine appear to have an analogous relationship with inhibitory κ receptors, as do acetylcholinebearing neurons with δ opioid receptors.212 Potassium channels (C) Increased conductance through a potassium channel, generally mediated by Gi or Go, results in membrane hyperpolarization with reduced neuronal excitability.79,169 Alternatively, protein kinase A–mediated reduction in membrane potassium conductance enhances neuronal excitability.37

proteins, or G proteins.157 The G protein is responsible for signaling the cell that the receptor has been activated and for the initiation of the desired cellular effects. The G proteins are generally of the pertussis-toxin-sensitive, inhibitory subtype known as Gi or Go, although coupling to a cholera-toxin-sensitive, excitatory Gs subtype was recently described.37 Regardless of subsequent effect, the G proteins consist of three conjoined subunits, ,
, and γ, from which the
γ subunit is liberated upon the binding of GTP to the  subunit. Upon dissociation from the
γ subunit, the  subunit modifies specific effector systems, such as phospholipase C or adenylate cyclase, or it may directly affect a channel or transport protein. The GTP is subsequently hydrolyzed by a GTPase intrinsic to the  subunit, which prompts its reassociation with the
γ subunit and termination of the receptor-mediated effect.204

CLINICAL MANIFESTATIONS Table 62–2 outlines the clinical effects of opioids.

Therapeutic Effects Analgesia. Although classical teaching attributes opioid analgesia solely to the brain, opioids actually appear to modulate cerebral cortical pain perception at supraspinal, spinal, and peripheral levels. The regional distribution of the opioid receptors confirms that µ receptors are responsible for most of the analgesic effects of morphine within the brain. They are found in highest concentration within areas of the brain classically associated with analgesia—the periaqueductal gray, nucleus raphe magnus, locus

CHAPTER 62

TABLE 62–2. Cardiovascular Dermatologic Endocrinologic Gastrointestinal

Neurologic

Ophthalmic Pulmonary

Clinical Effects of Opioids Peripheral vasodilation Orthostatic hypotension Flushing (histamine) Pruritis Reduced ADH release Reduced gonadotrophin release Reduced motility Reduced gastric acid secretion Increased biliary tract pressure Increased anal sphincter tone Sedation, coma Seizures (meperidine, propoxyphene) Antitussive Miosis Respiratory depression Bronchospasm (histamine) Pulmonary edema

ceruleus, and medial thalamus.180 Microelectrode-induced electrical stimulation of these areas,199 or iontophoretic application of agonists into these regions, results in profound analgesia.12 Specifically, enhancement of inhibitory outflow from these supraspinal areas to the sensory nuclei of the spinal cord (dorsal roots) dampens nociceptive neurotransmission. Additionally, inactivation of the µ-opioid receptor gene in embryonic mouse cells results in offspring that are insensitive to morphine analgesia.145 These mice maintain normal concentrations of other opioid receptor subtypes, which are able to bind ligands. Interestingly, blockade of the N-methyl-D-aspartate (NMDA) receptor, a mediator of excitatory neurotransmission, enhances the analgesic effects of µ opioid agonists and may reduce the development of tolerance (see “Dextromethorphan” later in this chapter).194 Even more intriguing is the finding that low-dose naloxone (0.25 µg/kg/h) actually improves the efficacy of morphine analgesia.67 Administration of higher-dose, but still low-dose, naloxone (1 µg/kg/h) obliterated its opioid-sparing effect. Although undefined, the mechanism may relate to selective inhibition of Gs-coupled excitatory opioid receptors by extremely low concentrations of opioid receptor antagonist.38 Delta and κ receptors are responsible for mediation of analgesia as well, but they exert their analgesic effect predominantly in the spinal cord. Conceptually, these receptors modulate nociceptive impulses in transit to the thalamus via the spinothalamic tract to reduce the brain’s perception of the pain. Agents with strong binding affinity for  receptors in humans produce significantly more analgesia than morphine when both are individually administered intrathecally.158 Indeed, the utility of spinal and epidural opioid analgesia is predicated on the direct administration of opioid near the κ and  receptors in the spinal cord. Agonist-antagonist agents, with agonist affinity for the κ receptor and antagonist effects at the µ receptor, maintain analgesic efficacy. Interestingly, communication between the immune system and the peripheral sensory nerves occurs in areas of tissue inflammation. In response to inflammatory mediators (eg, interleukin-1210), immune cells locally release opioid peptides, which bind and activate peripheral opioid receptors on sensory nerve terminals. Agonism at these receptors reduces afferent pain neurotransmission and may inhibit the release of other proinflammatory compounds such as substance P.228 Of note, intra-articular morphine (1 mg)

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administered to patients after arthroscopic knee surgery produces significant, long-lasting analgesia that can be prevented with intraarticular naloxone.227 The clinical analgesic effect of 5 mg of intra-articular morphine is equivalent to 5 mg of morphine given intramuscularly.29 Intra-articular analgesia is locally mediated by µ receptors. Despite their well-defined analgesic properties and their recommendation by many clinical practice guidelines, opioids continue to be underprescribed for patients with acute and chronic pain. Reluctance often stems from the fear that patients may develop addiction or abuse. However, despite extensive investigation, this concern remains unfounded.103,105 Furthermore, opioid analgesics are often better tolerated, safer, and less expensive than the alternatives. Euphoria. The pleasurable effects of many of the drugs abused by humans appear to be mediated by the release of dopamine in the mesolimbic system.9,52 This final common pathway is shared by all opioids that activate the µ/ receptor complex in the ventral tegmental area, which, in turn, indirectly promotes the release of dopamine in the mesolimbic region.163 Opioids may also have a direct reinforcing effect on their self-administration through µ receptors within the mesolimbic system.89 The sense of well-being and euphoria associated with strenuous exercise appears to be mediated by endogenous opioid peptides and µ receptors. This so-called “runners’ high” is acutely reversible with naloxone,44 and naloxone may also produce dysphoria in nonexercising, highly trained athletes. Even in normal individuals, high-dose naloxone (up to 4 mg/kg) may produce dysphoric symptoms.32 Exogenous opioids do not induce uniform psychological effects. Some, particularly the highly lipophilic agents such as heroin, result in euphoria and a sense of well-being, whereas morphine is largely devoid of such pleasurable effects.221 Morphine, however, is analgesic, anxiolytic, and sedating. Because heroin has little affinity for opioid receptors and must be deacetylated to morphine for effect, it is likely that these seemingly incompatible properties relate to pharmacokinetic differences in blood-brain barrier penetration. Fentanyl produces effects that are noted to be subjectively similar to heroin by chronic users.122 These pleasurable effects are suggested by the ascent of fentanyl abuse among anesthesiologists studied in the 1970s.254 In distinction, certain opioids, such as pentazocine, produce dysphoria, an effect, as noted earlier, that relates to their affinity for κ or σ receptors.185 Antitussive. Codeine and dextromethorphan are two opioid agents with cough-suppressant activity. However, it is unlikely that cough suppression is mediated via the µ1 opioid receptor because the ability of other opioids to suppress the medullary cough centers is not correlated with their analgesic effect. Various models suggest the possible involvement of the µ2 or κ opioid receptor, the 5-HT1A serotonin receptor, or perhaps the σ or NMDA receptors.110

Toxic Effects When used correctly for medical purposes, opioids are remarkably safe and effective agents.7,131 However, excessive dosing for any reason may result in serious toxicity. Most adverse or toxic effects are predictable based on the “opioid” pharmacodynamics (eg, respiratory depression), although several agents produce unexpected

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

“nonopioid” or agent-specific responses. These drugs and effects are specifically addressed below. Determining that a patient is suffering from opioid toxicity is generally more important than identifying the specific agent involved. Notwithstanding some minor variations, patients poisoned by all available opioids predictably develop a constellation of signs known as the opioid toxidrome (Chap. 17); mental status depression, hypoventilation, miosis, and reduced bowel motility are the classical elements. Respiratory Depression. Experimentally, using various opioid agonists and antagonists, µ2 receptors are consistently implicated in the respiratory depressant effects of morphine.132 Through these receptors, opioid agonists reduce ventilation by diminishing the sensitivity of the medullary chemoreceptors to hypercapnea.257 In addition to the loss of hypercarbic stimulation, opioids also depress the ventilatory response to hypoxia.257 The combined loss of hypercarbic and hypoxic drive leaves virtually no stimulus to breathe and apnea follows. Among the available opioid agonists, equianalgesic doses of all agents produce approximately the same degree of respiratory depression.57,218 Patients chronically exposed to opioid agonists, such as those on methadone maintenance, experience chronic hypoventilation, although tolerance to the loss of hypercarbic drive may develop over several months.141 However, such patients never develop complete tolerance to the loss of hypoxic stimulation.209 Although some opioids, notably the agonistantagonists, demonstrate a ceiling effect on respiratory depression, such sparing is generally at the expense of analgesic potency.66 The different profiles of activity are likely a result of differential activities at the opioid receptor subtypes; that is, agonist-antagonists are predominantly κ-receptor agonists, and either partial agonists or antagonists at µ sites. It is important to recognize that ventilatory depression may be secondary to either a reduction in respiratory rate or in tidal volume. Thus, although more accessible for clinical measurement, the respiratory rate is not an ideal index of ventilatory depression. In fact, in humans morphine-induced respiratory depression initially relates more closely with changes in tidal volume.218 Escalating doses of opioids result in a reduction of respiratory rate as well. Pulmonary Edema. Reports linking opioids with the development of pulmonary edema began to accumulate in the 1960s, although the first report was made by William Osler in 1880.176 Virtually all opioids are implicated, and opioid-related pulmonary edema is reported in diverse clinical situations. Pulmonary edema may be an isolated finding or may occur in the setting of multisystem organ damage. Typically, the patient awakens from opioid coma, either spontaneously or following an opioid antagonist, and over the subsequent several minutes to hours develops hypoxemia and pulmonary rales. Occasionally, classic frothy, pink sputum is present in the patient’s airway, or in the endotracheal tube of an intubated patient. Pulmonary edema was described in 71 out of 149 (48%) of 149 hospitalized heroin overdose patients in New York City,56 and the outcome is generally dependent on comorbid conditions and delay to care. No single mechanism can be consistently invoked in the genesis of opioid-associated pulmonary edema, and several prominent theories are each well supported by experimental data. Although several authors ascribe pulmonary edema to the administration of naloxone, the majority of affected patients had already suffered respiratory arrest and these patients were given naloxone to reestablish spontaneous breathing. In these patients it is likely that

naloxone merely “uncovered” the clinical findings of acute lung injury that were not evident because of the inability to perform an adequate examination. Other evidentiary cases involve surgical patients given naloxone postoperatively who subsequently awoke with pulmonary edema. In addition to presumably receiving the naloxone for ventilatory compromise or hypoxia, these patients also received multiple intraoperative medications, further obscuring the etiology.195,238 However, although naloxone is ordinarily safe when administered to nonopioid-tolerant individuals, the production of acute opioid withdrawal may be responsible for “naloxone-induced” pulmonary edema. In this situation, as in patients with “neurogenic” pulmonary edema, massive sympathetic discharge from the central nervous system occurs and produces pulmonary edema from the acute effects of catecholamines on the myocardium. Indeed, in an interesting series of experiments, precipitated opioid withdrawal in nontolerant dogs was associated with dramatic cardiovascular changes and abrupt elevation of serum catecholamine levels.155,156 The effect was more dramatic in dogs with an elevated PCO2 than in those with a normal or low PCO2, suggesting the need to adequately ventilate patients prior to reversal with naloxone. However, even though abrupt precipitation of withdrawal by naloxone may contribute to the development of pulmonary edema, it cannot be the sole effect. Pulmonary edema was noted in 50–90% of the postmortem examinations performed on heroin overdose patients,88,93 many of whom were declared dead before arrival to medical care and thus never received naloxone. In addition, neither naloxone nor any other opioid antagonist was available when Osler and others described their initial cases of pulmonary edema. Alternatively, the negative intrathoracic pressure generated by attempted inspiration against a closed glottis creates a large pressure gradient across the alveolar membrane and draws fluid into the alveolar space.118 This mechanical effect, also known as the Müller maneuver, was invoked as the etiology of ventilator-associated pulmonary edema prior to the advent of demand ventilators and neuromuscular blockers. In the setting of opioid poisoning, glottic laxity may prevent adequate air entry during inspiration. This effect may be especially prominent at the time of naloxone administration, in which case breathing may be reinstituted before the return of adequate upper airway function. Cardiovascular. Arteriolar and venous dilation secondary to opioid use may result in mild reduction in blood pressure.255 This effect is clinically useful for the treatment of acute pulmonary edema. However, while patients do not typically develop significant supine hypotension, orthostatic changes in blood pressure and pulse routinely occur.276 Bradycardia is unusual, although a reduction in heart rate is common as a result of the associated reduction in central nervous system stimulation. Opioid-induced hypotension appears to be mediated by histamine release,63 although induction of histamine release does not appear to occur through interaction with an opioid receptor. It may be related to the nonspecific ability of certain compounds to activate mast cell G proteins,6 which induce degranulation of histamine-containing vesicles. Many agents share this ability, which seems to be conferred by the presence of a positive charge on a hydrophobic molecule.6 Accordingly, not all opioids are equivalent in their ability to release histamine.6 After administration of one of four different opioids to 60 healthy patients, meperidine was noted to produce the most, and fentanyl the least, hypotension and elevation of plasma histamine levels.65 The combination of H1 and H2 antago-

CHAPTER 62

nists is effective in ameliorating the hemodynamic effects of opioids in humans.186 Notwithstanding claims of efficacy, a beneficial role for naloxone may only occur with extremely high doses. Prominent cardiovascular toxicity may occur with the use of propoxyphene, which causes wide-complex dysrhythmias and negative contractility through sodium channel antagonism similar to that of type IA antidysrhythmic agents (see “Propoxyphene” later in this chapter). Adulterants or coingestants may also produce significant cardiovascular toxicity. For example, quinine-adulterated heroin is associated with dysrhythmias;137,217 cocaine, surreptitiously added to heroin, may cause significant myocardial ischemia or infarction.97 Similarly, concern that naloxone administration may “unmask” cocaine toxicity in patients simultaneously using cocaine and heroin (“speedball”) is probably warranted, although rarely reliably reported.152 Miosis. The mechanism by which opioids induce miosis remains controversial and support for each of several mechanisms may be found in the literature. Stimulation of parasympathetic pupilloconstrictor neurons in the Edinger-Westphal nucleus of the oculomotor nerve by morphine produces miosis. Additionally, morphine increases firing of pupilloconstrictor neurons to light,126 which increases the sensitivity of the light reflex (central reinforcement of light reflex).259 Although sectioning of the optic nerve may blunt morphine-induced miosis, the consensual reflex in the denervated eye is enhanced by morphine.148 Because opioids classically mediate inhibitory neurotransmission, hyperpolarization of sympathetic nerves, or hyperpolarization of inhibitory neurons to the parasympathetic neurons (removal of inhibition), may ultimately be found to mediate the classic “pinpoint pupil” associated with opioid use. Not all opioid-using patients present with miosis. Patients receiving meperidine69 and propoxyphene regularly maintain normal pupillary size. Those using agents with predominantly κ-agonist effects (eg, pentazocine) may not develop miosis. Mydriasis may occur in severely poisoned patients secondary to hypoxic/anoxic brain insult. Additionally, concomitant drug use or the presence of adulterants may alter pupillary findings. For example, the combination of heroin and cocaine (“speedball”) may produce virtually any size pupil, depending on the relative contribution by each drug. Similarly, patients ingesting Lomotil, or those patients using scopolamine-adulterated heroin,182 routinely develop large, “anticholinergic” pupils. Seizures. Seizures are a rare complication of the therapeutic use of most opioids. In patients with acute opioid overdose, they are most likely to be caused by hypoxia. However, experimental models in which morphine is microinjected into various brain regions of animals demonstrate a proconvulsant effect.175 This effect is not inhibited by naloxone, suggesting that a mechanism other than opioid receptor binding is involved. In humans, morphine-induced seizures are only reported in neonates and may be related to incomplete formation of their blood-brain barrier.119 However, seizures should be anticipated in patients with meperidine, propoxyphene, or tramadol toxicity. These agents are discussed below. Naloxone antagonizes the convulsant effects of propoxyphene in mice, although it is not nearly as effective in preventing seizures from meperidine or its metabolite normeperidine.70 Interestingly, naloxone potentiates the anticonvulsant effects of benzodiazepines and barbiturates, although in a single study it antagonized the effects of phenytoin.101 The ability of fentanyl to induce seizures remains controversial. After several

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reported cases of fentanyl-induced seizures,198 electroencephalograms (EEGs) and electromyelograms (EMGs) were performed on 127 patients undergoing fentanyl anesthesia.223 When assessed clinically and with EMG studies about one-third were considered to have seized. However, in no case did the corresponding EEG reveal epileptiform activity. It appears likely that the rigidity and myoclonus associated with fentanyl are readily misinterpreted as a seizure. Movement Disorders. With rapid intravenous injection of certain high-potency opioids, especially fentanyl, patients may experience acute muscular rigidity. This rigidity primarily involves the trunk, and may impair chest wall movement and exacerbate hypoventilation. Although the mechanism is currently unclear, it may be related to blockade of dopamine receptors in the basal ganglia.60 Indeed dopamine,253 but not amantadine,249 alleviates the rigidity. Additional experimental data suggest that the 2-adrenergic receptor is also involved.258 Chest wall rigidity is common in patients undergoing operative anesthesia and may necessitate administration of neuromuscular blocking agents to allow mechanical ventilation. Similar effects contribute to lethality during epidemics of fentanyl-adulterated heroin.120 Opioid antagonists are generally therapeutic,162 but may produce adverse hemodynamic effects, withdrawal phenomenon, or uncontrollable pain depending on the situation. Interestingly, rapid escalation of methadone doses may produce choreoathetoid movements as a result of enhanced striatal dopamine release.13 This may relate to the opposing effects on GABAergic interneurons produced by µ and κ receptors. Methadone, a µ agonist, inhibits the release of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter, within the striatum and mesolimbic system, the ultimate effect of which is to enhance dopamine release. This possibility is intriguing given the developing concept that many forms of addiction result from the final common pathway of enhanced mesolimbic dopamine neurotransmission.9 Gastrointestinal Effects. Historically, the morphine analogue apomorphine was used as a rapidly acting emetic whose clinical utility was limited by its tendency to depress the patient’s level of consciousness. Emesis induced by apomorphine is mediated through agonism at dopamine-2 receptor subtypes within the chemoreceptor trigger zone of the medulla. Many opioids, morphine in particular, produce significant nausea and vomiting when used therapeutically.22 It is not clearly established whether these effects are inhibited by naloxone, but it is likely that they are not. Although diphenoxylate and loperamide are widely used therapeutically to manage diarrhea, opioid-induced constipation is most frequently a bothersome side effect of both the therapeutic and recreational use of opioids. Mediated by µ2 receptors within the smooth muscle of the intestinal wall, constipation is ameliorated by oral naloxone. Provided that the hepatic glucuronidative capacity is not exceeded (at doses of approximately 6 mg), enteral naloxone is poorly bioavailable and thus induces few, if any, opioid withdrawal symptoms.149 A recently introduced quaternary ammonium agent, methylnaltrexone, is a bioavailable opioid that antagonizes the effects of opioids on the gastrointestinal tract, yet is unable to cross the blood-brain barrier.272 Thus, the opioid withdrawal syndrome does not occur. This agent is not yet available in this country.

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY tromethorphan and the phencyclidine (PCP) component of the fluorescence polarization immunoassay (Abbott TDx),151,256 a widely used drug-of-abuse screening test (Chap. 7).

DIAGNOSTIC TESTING Laboratory Considerations Although it is always tempting to seek laboratory confirmation of an ingested substance in acutely poisoned patients, current laboratory methodology suffers from several important limitations and confounding variables. In general, the most apparent impediment to the use of laboratory testing in the acute care setting is the lack of timely reporting of results. Patients may suffer grave consequences if therapy is withheld pending test results. Opioid-poisoned patients, in particular, are amenable to rapid clinical diagnosis because of the uniqueness of the opioid toxidrome. Additionally, the availability of several distinct classes of agents capable of producing similar opioid effects limits the utility of laboratory tests, such as immunoassays, that rely on structural features to identify drugs. Furthermore, because there are remarkable differences in test availability, and because the accuracy and sensitivity of each test differ, interpretation of the test results may be difficult. Because opioids may be chemically detectable long after their clinical effects have resolved, assay results cannot be considered in isolation, and must be viewed in a clinical context. Several well-described problems with laboratory testing of opioids are described below and in Chapter 7. Cross-Reactivity. Many opioids share remarkable structural similarities. Interestingly, structurally similar agents, such as methadone and propoxyphene, do not necessarily share the same clinical characteristics (Fig. 62–2). Because most assays depend on structural features to identify a drug, structurally similar agents may be detected in lieu of the desired drug. Whether a similar drug is noted by the assay depends on the sensitivity and specificity of the assay used, as well as the serum concentration of the agent. Some cross-reactivities are predictable, such as that of codeine with morphine on a variety of screening tests.34 Other cross-reactivities are less predictable, as with the cross-reaction of dex-

Congeners and Adulterants. Commercial opioid assays, which are specific for morphine, are unlikely to detect most of the semisynthetic and synthetic opioids. In some cases, epidemic fatalities involving fentanyl derivatives remained unexplained despite what appeared to be obvious opioid toxicity, until the ultrapotent fentanyl derivative, -methylfentanyl, was specifically sought and identified by more sophisticated testing.120 Oxycodone, hydrocodone, and other common morphine derivatives have variable detectability by different opioid screens.223 Adulterants, such as scopolamine or quinine, are not detectable on an opioid screen. Drug Metabolism. A fascinating dilemma may arise in patients who ingest moderate to large amounts of poppy seeds.61,116 These seeds, which are widely used for culinary purposes, are derived from poppy plants similar to P. somniferum, and contain both morphine and codeine. Patients may develop dramatically elevated serum morphine and codeine concentrations,61,214 and test positive for morphine. Because the presence of morphine on a drugs-of-abuse screen may suggest illicit heroin use, the implications are substantial. Federal workplace testing regulations thus require corroboration of a positive morphine assay with assessment of another heroin metabolite, 6-monoacetylmorphine, prior to reporting a positive result.159 Humans cannot acetylate morphine and therefore cannot synthesize monoacetylmorphine, but readily deacetylate heroin, which is diacetylmorphine. A similar problem may occur in patients taking therapeutic doses of codeine. Because codeine is demethylated to morphine, a morphine screen may be positive independently of the structural cross-reactivity described earlier. Thus, determination of the serum codeine or monoacetylmorphine level is necessary in these patients. Determination of the serum codeine is not foolproof,

Methadone Propoxyphene

Phencyclidine Dextromethorphan

Figure 62–2. Structural similarity between methadone and propoxyphene and between phencyclidine and dextromethorphan.

CHAPTER 62

however, because codeine is present in the opium preparation used to synthesize heroin.

MANAGEMENT The consequential effects of acute opioid poisoning are central nervous system and respiratory depression. Although early support of ventilation and oxygenation is generally sufficient to prevent death, prolonged use of bag-valve mask ventilation and endotracheal intubation may be avoided by cautious administration of an opioid antagonist. Opioid antagonists, such as naloxone, competitively inhibit the binding of opioid agonists to the opioid receptors, allowing the patient to resume spontaneous respiration. Naloxone competes at all receptor subtypes, although not equally, and is effective at reversing almost all adverse effects mediated through opioid receptors. “Antidotes in Depth: Opioid Antagonists” has a complete discussion of naloxone and other opioid antagonists. However, because most clinical findings associated with opioid poisoning are nonspecific, the diagnosis requires clinical acumen. Differentiating acute opioid poisoning from other etiologies with similar clinical presentations may be challenging. Patients manifesting the opioid toxidrome, those found in an appropriate environment, or those with characteristic physical clues such as fresh needle marks require little corroborating evidence. However, subtle presentations of opioid poisoning may be encountered and other entities superficially resembling opioid poisoning may occur. Hypoglycemia, hypoxia, and hypothermia are common, readily treatable clinical presentations that share features with opioid poisoning. Each may be rapidly diagnosed with routinely available, real-time testing. Other drugs responsible for similar clinical presentations include clonidine, PCP, phenothiazines, and sedative-hypnotic agents, primarily benzodiazepines. In such patients, however, clinical evidence is usually available to assist in diagnosis. For example, nystagmus is nearly always noted in PCPintoxicated patients, hypotension or electrocardiographic abnormalities in phenothiazine-poisoned patients, and coma with virtually normal vital signs in those patients poisoned by benzodiazepines. Most difficult to differentiate on clinical grounds may be toxicity produced by the centrally acting antihypertensive agents such as clonidine (see “Clonidine” later in this chapter and Chap. 51). Additionally, a myriad of traumatic, metabolic, and infectious etiologies must always be considered and evaluated appropriately, and may occur simultaneously.

Antidote Administration The goal of naloxone therapy is not necessarily complete arousal; rather, the goal is reinstitution of adequate spontaneous ventilation. Because precipitation of withdrawal is potentially detrimental and often unpredictable, the lowest practical naloxone dose should be administered initially with rapid escalation as warranted by the clinical situation. Most patients respond to 0.05 mg of naloxone administered intravenously, although, because the onset may be slower than with larger doses, the requirement for ventilatory assistance may be slightly prolonged. Administration in this fashion will effectively avert endotracheal intubation and allow timely identification of patients with nonopioid causes for their clinical condition, yet diminish the precipitation of acute opioid withdrawal. Subcutaneous administration may allow for smoother

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arousal than the high-dose intravenous route,250 but is unpredictable in onset and likely prolonged in offset. This can be a considerable disadvantage if the therapeutic goal is exceeded and the withdrawal syndrome develops. In the absence of a confirmatory history or diagnostic clinical findings, the cautious empiric administration of naloxone may be both diagnostic and therapeutic. Naloxone, even at extremely high doses, has an excellent safety profile in patients with non-opioidrelated indications, such as those with spinal cord injury15 and acute ischemic stroke. Thus, administration in an empiric fashion to most non-opioid-poisoned patients is unlikely to be harmful. However, administration of naloxone to opioid-dependent patients may result in adverse effects; obviously, precipitation of an acute withdrawal syndrome should be anticipated. The obligatory agitation, hypertension, and tachycardia, while rarely life-threatening, may produce significant distress to both the patient and the clinical staff. Additionally, emesis, a common feature of acute opioid withdrawal, may be particularly hazardous in patients who do not rapidly regain consciousness after naloxone administration. For example, patients with concomitant ethanol or sedative-hypnotic exposure, or those with head trauma, are at substantial risk for the pulmonary aspiration of their vomitus if their airway is unprotected. Identification of patients likely to respond to naloxone would conceivably reduce the unnecessary and potentially dangerous precipitation of withdrawal in opioid-dependent patients. Routine prehospital administration of naloxone to all patients with subjectively assessed altered mental status or respiratory depression was not beneficial in 92% of patients.270 Alternatively, although not perfectly sensitive, a respiratory rate less than or equal to 12 breaths per minute in an unconscious patient presenting via EMS best predicted a response to naloxone.94 Interestingly, in hospitalized patients, neither respiratory rate less than 8 per minute nor coma was able to predict a response to naloxone.262 Whether the discrepancy between the latter two studies is a result of the demographics of the patient groups or whether patients with prehospital opioid overdose present differently than those patients with therapeutic misadventures is unclear. Regardless, relying on the respiratory rate to assess the need for ventilatory support or naloxone administration is not ideal because hypoventilation secondary to hypopnea may precede that caused by bradypnea.201,218 The decision to discharge a patient who awakens appropriately following naloxone administration is based on practical considerations. Patients presenting with profound hypoventilation or hypoxia are at risk for the development of acute lung injury or posthypoxic encephalopathy. Thus, it seems prudent to observe these patients for at least 24 hours in a medical setting. Those patients manifesting only moderate signs of poisoning who remain normal for at least several hours following parenteral naloxone are likely safe to discharge. However, the need for pyschosocial intervention in patients with uncontrolled drug use, or following a suicide attempt, may prevent discharge from an ED. Patients with recurrent or profound poisoning by long-acting opioids, such as methadone, or patients with large gastrointestinal burdens (eg, “body packers” or sustained-release preparations) may require continuous infusion of naloxone to ensure continued adequate ventilation (Table 62–3). An hourly infusion rate of twothirds of the initial reversal dose of naloxone is sufficient to prevent recurrence.73 Titration of the dose may be necessary as the clinical situation indicates. Although repetitive bolus dosing of naloxone may be effective, it is labor intensive and subject to error.

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TABLE 62–3.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

How to Use a Naloxone Infusion

1. If a naloxone bolus is successful, administer two-thirds of the effective bolus dose per hour by IV infusion; frequently reassess the patient’s respiratory status. 2. If respiratory depression is not reversed following the bolus dose: Intubate the patient, as clinically indicated, or Administer up to 10 mg of naloxone as an intravenous bolus. If the patient does not respond, do not initiate an infusion. 3. If the patient develops withdrawal following the bolus dose: Allow the effects of the bolus to abate. If respiratory depression recurs, administer one-half of the initial bolus dose, and begin an intravenous infusion at two-thirds of the initial bolus dose per hour. Frequently reassess the patient’s respiratory status. 4. If the patient develops withdrawal signs or symptoms during the infusion: Stop the infusion until the withdrawal symptoms abate. Restart the infusion at one-half the initial rate; frequently reassess the patient’s respiratory status. Exclude withdrawal from other substances. 5. If the patient develops respiratory depression during the infusion: Readminister one-half of the initial bolus and repeat until reversal occurs. Increase the infusion by one-half the initial rate; frequently reassess the patient’s respiratory status. Exclude continued absorption, readministration of an opioid, or other etiologies for the respiratory depression.

Despite the availability of long-acting opioid antagonists, such as naltrexone and nalmefene,111 that theoretically may permit single-dose reversal of methadone poisoning, the attendant risk of precipitating an unrelenting withdrawal syndrome hinders their use as agents for initial opioid reversal. However, these agents may have a clinical role in the maintenance of consciousness and ventilation in opioid-poisoned patients already awakened by naloxone. Expectedly, prolonged observation and perhaps antidote readministration may be required in order to match the pharmacokinetic parameters of the two agents. Otherwise well children who ingest short-acting opioids may be given a long-acting opioid antagonist initially, because they are not expected to develop a prolonged, potentially hazardous withdrawal. However, the same caveats remain regarding the need for extended observation periods if ingestion of methadone or other long-acting opioids is suspected.

Rapid and Ultrarapid Opioid Detoxification Although not an emergent therapy of opioid poisoning or dependence, the concept of antagonist-precipitated opioid withdrawal has been promoted extensively as a “cure” for opioid (particularly heroin and oxycodone) addiction. Rather than slow, deliberate withdrawal, or detoxification, from opioids over several weeks, antagonist-precipitated withdrawal occurs over several hours or days.192 The purported advantage of this technique is a reduced risk of relapse to opioid use because the duration of discomfort is reduced and a more rapid transition to naltrexone maintenance can be achieved. Mechanistic explanations include withdrawal-induced catecholamine depletion, rapid normalization of receptor regulation, and enhanced endogenous opioid release,219 but each is based largely on circumstantial evidence.

Rapid opioid detoxification (ROD) techniques are usually offered by outpatient clinics and typically consist of naloxone- or naltrexone-precipitated opioid withdrawal tempered with varying amounts of clonidine, benzodiazepines, antiemetics, or other drugs. Ultrarapid opioid detoxification (UROD) uses a similar concept but involves the use of deep sedation or general anesthesia for greater patient control and comfort. Both techniques are costly; UROD under anesthesia commonly costs upward of $5000. Whether the reduced cost of short-term hospitalization for detoxification offsets this cost remains to be proven. Although most observational studies find excellent short-term results, relapse to drug use is very common following either technique. This may suggest a need for improved aftercare or may reflect a fundamental flaw in the mechanistic rationalization of the therapy. The reported risks of these techniques are anecdotal and remain largely undefined but are of substantial conceptual concern. In one study, 10% of all patients who received UROD returned to the same hospital’s ED for opioid withdrawal symptoms.64 Transient pulmonary edema, renal insufficiency, and thyroid hormone suppression are reported following UROD, and many patients still manifest the opioid withdrawal 48 hours after the procedure.81,184 Furthermore, the medical license of a physician performing UROD in New Jersey was suspended by state health authorities after their investigation into six deaths related to the procedure. In addition, selection bias, the lack of randomization, control groups, or blinding, and variations in treatment protocols and endpoints hinder the external applicability of much of the available research on antagonist-precipitated opioid withdrawal.171

OTHER OPIOIDS Although the vast majority of opioid-poisoned patients will follow predictable clinical courses, certain opioids taken in overdose may produce atypical manifestations. Some of these effects can be anticipated, such as fentanyl-induced muscle rigidity, whereas others cannot. Therefore, careful clinical assessment and institution of empiric therapy is usually necessary to ensure proper management (Table 62–4).

Agonist-Antagonists The opioid agonists in common clinical use tend to have specific binding affinity toward one class of opioid receptor, usually the µ class. The agonist-antagonist agents differ in that they interact with multiple receptor types at clinically relevant doses and may have different effects at each receptor. Thus, while most opioids typically produce either agonist or antagonist effects, these agents may have agonist effects at one receptor subtype and antagonistic effects at another receptor subtype. Pentazocine, for example, may elicit a withdrawal syndrome in a µ-opioid-tolerant individual because of antagonist or partial agonist effects at the µ receptor. This effect forms the basis of the claim offered by many methadone-dependent patients that they are “allergic to Talwin.” However, this same drug can induce substantial analgesia in nontolerant patients through its agonist effects at κ1 receptors. Although the clinical effects following overdose resemble the other opioid agents, they are significantly less likely to produce severe morbidity or mortality because of a ceiling effect on respiratory depression (see “Respiratory Depression” earlier in this chapter).

CHAPTER 62

TABLE 62–4.

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911

Classification, Potency, and Characteristics of Opioid Agents

Agent (Representative trade name)

Typea

Derivation

Analgesic dose (mg) (via route, equivalent to 10 mg morphine SCb)

Buprenorphine (Buprenex) Butorphanol (Stadol) Codeine Dextromethorphan (Robitussin DM)

P/AA AA Ag NEC

Semisynthetic Semisynthetic Natural Semisynthetic

0.4 IM 2 IM 120 PO Nonanalgesic (10–30 PO)

Diphenoxylate (Lomotil)

Ag

Synthetic

Nonanalgesic (2.5 PO)

Fentanyl (Sublimaze) Heroin (Diamorph)

Ag Ag

Synthetic Semisynthetic

0.125 IM 5 SC

Hydrocodone (Hycodan, Vicodin) Hydromorphone (Dilaudid) LAAM (Orlaam)

Ag Ag Ag

Semisynthetic Semisynthetic Synthetic

10 PO 1.3 SC (Flexible oral dosingd)

Levorphanol (Levodromoran) Loperamide (Imodium) Meperidine, Pethidine (Demerol)

Ag Ag Ag

Semisynthetic Synthetic Synthetic

2 SC/IM Nonanalgesic (2 PO) 75 SC/IM

Methadone (Dolophine) Morphine Nalbuphine (Nubain) Nalmefene (Revex) Nalorphine Naloxone (Narcan) Naltrexone (Trexan) Oxycodone (Percocet, Oxycontin) Oxymorphone (Numorphan) Paregoric (Parapectolin) Pentazocine (Talwin) Propoxyphene (Darvon)

Ag Ag AA Ant AA Ant Ant Ag Ag Ag AA Ag

Synthetic Natural Semisynthetic Semisynthetic Semisynthetic Semisynthetic Semisynthetic Semisynthetic Semisynthetic Natural Semisynthetic Synthetic

10 IM 10 SC/IM 10 IM Nonanalgesic (0.1 IM) 15 IM Nonanalgesic (0.1–0.4 IV/IM) Nonanalgesic (50 PO) 10 PO 1 SC 25 mL PO 50 SC 65 PO

Tramadol ( Ultram)

Ag

Synthetic

50–100 PO

Commentsa,c Opioid substitution therapy Often combined with acetaminophen Antitussive; psychotomimetic via σ/NMDA receptor Antidiarrheal agent, combined with atropine; difenoxin is potent metabolite Very-short-acting (10 years) heroin users in Australia had self-overdosed on heroin,40 while among recent-onset heroin users, 23% had overdosed on heroin and 48% had been present when someone else overdosed.76 Risk factors for fatality following heroin use include the concomitant use of other drugs, particularly ethanol,42,128,208 recent abstinence, as occurs during incarceration,213 and perhaps unanticipated fluctuations in the purity of the available heroin.43,203 Because most overdoses occur in seasoned heroin users, and as many as 85% occur in the company of other users,40 a trial distribution of naloxone to heroin users was recently initiated.235 Although earlier administration of antidote would certainly be beneficial, certain issues make this approach controversial. For example, despite the acknowledged injection skills of the other users in the “shooting gallery,” their judgment is likely to be impaired. In one survey, summoning an ambulance was the initial response to overdose of a companion in only 14% of cases.41 Furthermore, the short duration of action of naloxone makes recrudescence likely and, without appropriate observation, potentially lethal. Compounding this problem is the precipitation of acute opioid withdrawal and the inevitable attempt to try to overcome the effects of naloxone with massive doses of heroin. This is likely to result in significantly more profound adverse effects after the short-lived effects of naloxone wane. Recently, the increased recognition of the efficacy of intranasal administration, or snorting, has fostered a resurgence of heroin use, particularly in suburban communities.80 The reasons for this trend are unclear, although it is widely suggested that the rising purity and falling price of available heroin have rendered it more suitable for intranasal use.3 However, because intranasal administration of a 3% heroin in lactose mixture produces clinical and pharmacokinetic effects that are similar to an equivalent dose administered intramuscularly,35 the causal relationship between rising heroin purity and increased intranasal use is uncertain.203 Smoking has also increased in popularity in the United States, albeit not to the extent that has occurred in other countries (see “Chasing the Dragon” later in this chapter). Use among celebrities and musicians has legitimized intranasal heroin use as a “safe” alternative to intravenous use. This usage is occurring despite a concomitantly reported rise in heroin deaths in regions of the country in which its use is now prevalent.177 Although intranasal use may be less dangerous than intravenous use from an infectious disease perspective, it is clear that both fatal overdose and drug dependency remain common. Adulterants, Contaminants, and “Heroin” Substitutes. The history of heroin adulteration and contamination alone could fill a

textbook chapter. Street-level heroin almost always contains adulterants or contaminants. What differentiates the two is the intent of their admixture. Adulterants are typically benign because it would be unwise to inflict harm on the consumer, although they are occasionally responsible for epidemic death. Interestingly, most heroin overdose fatalities do not have serum morphine levels that are substantially different from those of current users, raising the possibility that their death is related to an adulterant or contaminant.42,273 Historically, alkaloids, such as quinine and strychnine, were used to adulterate heroin in order to mimic the bitter taste of heroin and to mislead clients. Quinine may have first been added to quell an epidemic of malaria among intravenous heroin users in New York City in the 1930s.88 That quinine adulteration was common is demonstrated by the common practice of urine screening for quinine as a surrogate marker for heroin use.265 However, excessive quinine admixture is implicated as a causative factor in an epidemic of heroin-related deaths in the District of Columbia between 1979 and 1982.135 Toxicity attributed to quinine in heroin users includes cardiac dysrhythmias137 (Chap. 21), amblyopia,18 and thrombocytopenia.30 Quinine adulteration is currently much less important than it was in the past. Trend analysis of illicit wholesale and retail (street-level) heroin adulteration over a 12year period in Denmark revealed that while caffeine, acetaminophen, methaqualone, and phenobarbital were all prevalent adulterants, quinine was not found.106 In Spain during the period 1985–1987, retail heroin did not contain quinine. A British analysis of wholesale samples from the late 1980s did not report any with quinine adulteration.173 Data on adulteration in the United States are unavailable. Other reported adulterants include thallium,196 lead,178 cocaine,97 amphetamines,28 chloroquine,172 and strychnine.96 Poisoning by scopolamine-tainted heroin reached epidemic levels in the northeastern United States in 1995.182 Exposed patients presented with acute psychosis and unmistakable anticholinergic signs. Several patients were treated with physostigmine with excellent therapeutic results. Fentanyl Analogues. Fentanyl (Sublimaze) is a short-acting, highly potent opioid agonist that is widely used in clinical medicine. Whereas fentanyl has approximately 50–100 times the potency of morphine, sufentanil, another available anesthetic opioid, has 5–10 times the potency of fentanyl. In some regions of the country, fentanyl and illicit fentanyl analogues (such as 3-methyl fentanyl or para-fluorofentanyl) are common drugs of abuse.277 Seasoned heroin users could not easily differentiate fentanyl from heroin, although in one study, the heroin was noted to provide a more intense “rush.”122 Regional epidemics of heroin substitutes with “superpotent” activity occasionally produce a dramatic rise in “heroin-related” fatalities. Epidemic death among heroin users first appeared in Orange County, California, in 1979 and was traced to -methylfentanyl sold under the brand name China White.120 Similar epidemics of China White poisoning occurred in Pittsburgh in 1988 and in Philadelphia in 1992, although the adulterant in these cases was 3-methylfentanyl, another potent analogue.91,142 A more recent epidemic in New York City marked the reappearance of 3methylfentanyl under the brand names Tango and Cash. Typically, the patients present comatose and apneic, with no opioids detected on blood and urine analysis.16 In such cases, unsuspecting users administer their usual “dose” of heroin, measured in 25-mg “bags,” which surreptitiously contain variable amounts of an illicit

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fentanyl analogue. Because of the exceptional potency of this fentanyl analogue—as much as 6000 times greater than morphine— higher-than-usual doses of naloxone may be needed to successfully compete for the opioid receptor. Oxycodone. In some regions of the United States, particularly where heroin is difficult to obtain, abuse of pharmaceutical sustained-release oxycodone (Ocycontin) for its psychoactive effects is at epidemic levels. Users typically crush the tablet, which destroys the sustained-release matrix and liberates large amounts of insufflatable or injectable oxycodone. Oxycodone, which is commonly available in 5-mg immediate-release doses in combination with acetaminophen (Percocet), may be obtained in a controlledrelease form containing as much as 80 mg (a 160-mg tablet was removed from the market).190 Opioid dependence requiring detoxification and death are a common sequelae of this practice. Clostridial Infections. Despite the ubiquity of Clostridium sp. in soil, heroin-related clostridial infections, whether caused by C. botulinum, C. tetani, or other species, are rare. This may relate to the harsh conditions that occur during the opium refinement process or as a result of the need for strict anaerobic conditions for clostridial growth. When they occur, the clinical syndromes are similar to those of conventional botulism or tetanus (Chaps. 75 and 109). The common link among the patients who develop clinical botulism or tetanus is subcutaneous administration of the drug, whether following extravasation or by intent, as in “skin popping” or intramuscular injection. Interestingly, during the 1950s and early 1960s, users of quinine-adulterated heroin in New York City26 and Chicago130 were substantially more likely to develop tetanus than users of non-quinine-adulterated heroin. This is likely a result of the extensive tissue destruction caused by subcutaneous quinine administration. Tetanus also occurs in patients receiving intramuscular quinine for therapeutic reasons.271 More recently, subcutaneous injection of an impure form of heroin known as “black tar heroin” was implicated in 26 cases of botulism in California.179 It is not yet known whether the minimally processed heroin was contaminated with C. botulinum or whether it lead to improved anaerobic growing conditions for the spores. In 2000, more than 35 injection drug users in the United Kingdom and Ireland developed a syndrome of sustained hypotension, markedly elevated peripheral white blood cell count, and soft tissue infection at an injection site.1 Nearly half of the victims died of the disease. Although initial concerns focused on cutaneous anthrax infection, C. novyi was ultimately recovered from most of the patients. The exact cause and source of the organism remain undefined. “Chasing the Dragon.” Although intravenous injection is the preferred means of heroin self-administration in the United States, in other countries, including the Netherlands,84 the United Kingdom,78 and Spain,48 the prevalent method is “chasing the dragon.” When chasing the dragon, users inhale a thick, white pyrolysate that is generated by heating heroin base on aluminum foil using a hand-held flame. Although some of the heroin effluvium is dissipated into the surroundings, this means of administration produces heroin pharmacokinetics that are similar to those observed following intravenous administration.102 Chasing the dragon is not a new phenomenon, but it has gained acceptance recently among both intravenous heroin users and drug-naïve individuals.234 The reasons for this shift are diverse, but probably relate to the avoidance of in-

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jection drug use with its concomitant risks.78 The increasing availability of the smokable base form of heroin is clearly associated,49 but whether it is a cause or an effect of this trend is unknown. In the early 1980s, an unexplainable cluster of spongiform leukoencephalopathy was identified in the Netherlands that occurred solely in individuals involved in chasing the dragon.267 Other causes of this unique clinicopathologic entity include various viral infections (eg, bovine spongiform leukoencephalopathy, or “mad cow” disease), hexachlorophene, pentachlorophenol, and metal poisoning, although none appeared responsible for this phenomena. Since the initial report, similar cases have appeared in other parts of Europe215 as well as in the United States.121 Initial findings may occur after as little as 2 weeks of use and include bradykinesia, ataxia, and speech abnormalities. Although symptoms may arrest at this stage, progression to spasticity or hypotonia may occur over several weeks. Death occurs in approximately 25% of reported cases. The prominent symmetric cerebellar and cerebral white matter destruction noted on brain imaging with CT and MRI239 correspond with those noted at necropsy.267 The syndrome has the characteristics of a point-source toxic exposure, but no culpable contaminants have been identified. Although initially postulated to be related to excessive exposure to aluminum fumes, neither the dose inhaled nor the serum levels support this hypothesis. Furthermore, the widespread administration of heroin by this route in some regions argues against the involvement of aluminum. Treatment is largely supportive, with slow resolution possible. Based on the finding of regional mitochondrial dysfunction on functional brain imaging, coenzyme Q supplementation, 300 mg qid, has purported benefit,121 but has not undergone controlled study. Body-Packers. In an attempt to transport illicit drugs from one country to another, “mules,” or body-packers, ingest large numbers of multiple-wrapped packages of concentrated cocaine or heroin. After arrival at their destination, cathartics are administered so that the packets may be passed and delivered. When the authorities discover such mules, they may be brought to a nearby hospital for evaluation and management. Although generally asymptomatic on arrival, these patients are at risk for delayed, prolonged, or lethal poisoning as a consequence of packet rupture.248 An abdominal radiograph is usually sufficient for confirmation of gastrointestinal smuggling,92 but occasional false-negative radiographs occur, even in patients with enormous packet counts.147 Patients in whom body-packing is suspected should be observed, even in the absence of packets on plain abdominal radiograph. Computed tomography is able to identify packets,153 but should be considered only in suspicious cases with negative radiographs, or potentially to document packet clearance from the gastrointestinal tract. Computed tomography may potentially provide information about the contents of the packets. However, although heroin, cocaine, and hashish can be differentiated by their Hounsfield unit values in vitro, there is no evidence that such measurements are accurate in a clinical setting. Magnetic resonance imaging may also identify packets, but is unable to differentiate their contents. Ultrasonography does not offer any advantage over radiography and is both user dependent and more difficult to perform.92 Rapid urine testing for drugs of abuse may assist in determining the packet content,25 but the same information is usually obtained more rapidly by simply asking the patient or by identifying clinical toxidromes. In the past, determining the country of origin of the current journey was nearly diagnostic of packet content. How-

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ever, because most of the heroin imported into the United States now originates in South America, which is also the major source of imported cocaine, and no longer from Asia, the discernment from cocaine on this basis is impossible. In fact, given the common source of both drugs, body-packers may be “double-breasting” or carrying both heroin and cocaine packets simultaneously. Regardless of the content, appropriate treatment for asymptomatic patients should include whole-bowel irrigation with polyethylene glycol solution (Chap. 5). Subsequent management differs based on the presumed packet content. Patients body-packing cocaine who develop symptoms require immediate surgical packet removal (Chap. 67), whereas those with heroin packets can often be managed nonoperatively with continuous infusion of naloxone,48 oral activated charcoal, and whole-bowel irrigation. Intestinal perforation or obstruction by the packets requires surgical intervention. Packets that do not progress beyond the stomach should probably be removed surgically, although endoscopic removal of one or a few packets may be carefully performed. The need to remove multiple packets would require repeated insertions of the endoscope, increasing the likelihood of packet rupture by the endoscope.

Agents Used in Opioid Substitution Therapy: Methadone, LAAM, Buprenorphine, and Clonidine Two contrasting approaches to the management of patients with chronic opioid use exist: detoxification or maintenance therapy. Detoxification is probably most appropriate for patients motivated or compelled to discontinue opioid use and may be performed either by slow withdrawal of an opioid agonist or with the assistance of opioid antagonists (see above). Maintenance therapy may include the use of a long-acting opioid antagonist such as naltrexone to pharmacologically proscribe opioid use. Alternatively, and more commonly, maintenance therapy involves opioid substitution therapy. Methadone is a synthetic µ opioid receptor agonist used in the treatment of chronic pain but currently is in widespread use as a maintenance substitute for heroin dependence. Available for this latter use for more than 35 years through methadone maintenance treatment programs (MMTP),53 methadone replaces the illicit heroin with a legal, oral, and long-acting agent. This agent allows patients to abstain from activities associated with procurement and administration of heroin and should eliminate much of the morbidity and mortality associated with drug addiction. While often successful, some methadone users continue to use heroin or other illicit substances.112 Although therapeutic methadone is generally safe, rapid dose escalation during induction by the treatment program may unintentionally produce toxicity and, rarely, fatal respiratory depression.20,55,268 Similarly, acute overdose results in clinical findings typical of opioid poisoning of a duration substantially longer than expected following overdose of prototypical therapeutic opioids. Intentional, nonsuicidal methadone overdosage is common and may ironically relate to the manner in which MMTPs dispense the drug. That is, most patients attending MMTPs are given supratherapeutic doses to prevent surreptitious heroin use.3,231,232 Additionally, many MMTPs supply their established patients with sufficient methadone to last through a weekend or holiday without need to revisit the program. Taken together, such dosing regimens may allow diversion of portions of the dose without the attendant

risk of opioid withdrawal. Furthermore, home storage of this surplus drug in inappropriate containers, such as baby bottles,85 is a frequent cause of unintentional methadone ingestion by children.10 Such events can be anticipated, however, because methadone is frequently formulated as a palatable liquid and may not be distributed in child-resistant containers. An increasing number of childhood poisonings with methadone are reported in England and is probably related to increased prescribing of the drug.10 Death is, unfortunately, frequent in these children.10 A relatively new agent, levo--acetylmethadol (LAAM; Orlaam), also known as levomethadyl acetate, is used in heroin substitution programs in a manner analogous to methadone.58 LAAM is a long-acting synthetic opioid agonist, an effect attributable in part to its metabolism to two separate active metabolites, norLAAM and dinor-LAAM. Its duration of effect approaches 4 days,98 allowing thrice weekly dosing. This increased dosing interval, as compared to daily methadone, is associated with an improved quality of life and reduced cost of therapy.191 However, until LAAM is more widely accepted, there are significant limitations to its use such as the inability to easily obtain the medication while traveling. The inability to dispense “take-home” doses, as is done with compliant methadone maintenance patients, is one significant limitation that was recently abolished. This previously tight control over LAAM’s availability has made diversion difficult and may account for the relative paucity of human overdose data. In the one documented case of LAAM overdose, the clinical course, including the duration of effect, was nearly identical to that expected following methadone overdose.95 One consequential adverse effect of therapeutic LAAM use is QTc interval prolongation, an effect that is associated with ventricular dysrhythmias. Because prescription of methadone or LAAM is restricted to certain practitioners at federally licensed programs, many patients are unable to obtain such therapy. However, as occurs in other countries, the primary care setting provides an alternative means by which to administer opioid substitution therapy, albeit not methadone. Buprenorphine, a partial µ-opioid agonist, is effective in doses of 6–16 mg/d133 at suppressing both opioid withdrawal symptoms and the covert use of illicit drugs.150,170 Its restricted µ receptor agonist effects also offer effective analgesia in opioidnaïve patients with fewer side effects than the conventional opioids. In opioid-dependent patients, however, buprenorphine competes with the extant opioid for the µ receptor and may produce the opioid withdrawal syndrome. A ceiling effect on respiratory depression may occur particularly at lower doses, but respiratory depression may prove fatal following overdose.242 Interestingly, naloxone may prevent the clinical effects of buprenorphine, but is relatively ineffective at reversing the effects once they manifest. This likely relates to the very slow dissociation of buprenorphine from the µ receptor. Furthermore, it is consistent with buprenorphine’s long duration of clinical effect (allowing thrice weekly dosing) despite its elimination half-life of 3 hours. Buprenorphine is administered by the sublingual route because of its poor oral bioavailability. Although it is not currently FDA approved for this indication, its relative freedom from federal restriction makes this therapy particularly promising. Methadone poisoning is qualitatively identical to that produced by morphine with a dramatically prolonged duration of effect. Although the pharmacokinetics of LAAM suggest that the clinical effects of overdose may be even more complex than those of methadone overdose, including a delayed onset of effect due to the need for metabolism,251 limited clinical experience suggests that

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they are quantitatively similar.95,191,240 Interestingly, intravenous LAAM produces characteristic opioid effects nearly instantly that are due to the parent compound, although the peak effect, due to the metabolites, is achieved in several hours.251 The opioid effects of LAAM may be more resistant to reversal by naloxone than are those caused by methadone,59 but they will probably respond to escalating antagonist dosing. Regardless, following an appropriate response to the administration of naloxone symptom, recurrence should be expected because naloxone’s duration of effect is only about 1 hour. In many cases, continuous infusion of naloxone or possibly administration of a long-acting opioid antagonist is indicated to maintain adequate ventilation. Although patients with uncomplicated heroin overdoses may typically be discharged from the ED if asymptomatic without an opioid antagonist after an appropriate observation period,220 those who overdose on methadone or LAAM almost always require hospital admission. Following sustained-release morphine overdose, naloxone, to enhance gastrointestinal motility, and whole-bowel irrigation with polyethylene glycol may be indicated. Clonidine is widely used by both clinicians and patients to reduce the disturbing autonomic effects of opioid withdrawal. Although clonidine is not related to any opioid in structure, clonidine-poisoned patients may present with clinical syndromes identical to those poisoned by morphine or other µ-active opioids. In fact, other imidazoline agents, such as tetrahydrozoline, as well as other centrally acting 2 agonists, such as guanabenz, produce similar toxicity. Patients present with lethargy, miosis, bradycardia, and respiratory depression, although hypotension is generally more pronounced than with opioid poisoning. Children, in particular, may develop periodic apnea. Because there is functional overlap between 2 and µ receptors within the brain (Fig. 62–1), naloxone occasionally improves the level of consciousness and ventilatory status in children with clonidine poisoning5,264 (Chap. 51).

Specific or Unique Agents Meperidine. Meperidine, also called pethidine, is widely used for the treatment of chronic and acute pain syndromes. Although not typically problematic as an illicit drug, at least one catastrophic epidemic resulted from its attempted clandestine synthesis (see “MPTP” below). Acute overdose of meperidine produces clinical manifestations typical of the other opioids, although pupillary constriction is less pronounced, and, if it occurs, is less persistent than that associated with morphine.69 However, normeperidine, a toxic, renally eliminated hepatic metabolite, accumulates in patients on chronic high-dose meperidine therapy, such as those with sickle-cell disease or cancer.108,237 A similar accumulation occurs in patients with renal insufficiency,237 in whom the elimination half-life increases from a normal of 14–21 hours to 35 hours. Normeperidine causes excitatory neurotoxicity, which manifests as delirium, tremor, myoclonus, or seizures. On the basis of animal studies, the seizures should not be expected to respond to naloxone.70 In fact, experimental evidence suggests that naloxone may potentiate normeperidine-induced seizures, presumably by inhibiting an anticonvulsant effect of meperidine.36 Hemodialysis using a high-efficiency membrane may be an option for patients already receiving this therapy or for those in significant distress, but clearances are limited and the toxicity generally self-limited. Although primarily an opioid, meperidine is capable of exerting effects at other types of receptors. The most consequential

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non-opioid-receptor effects occur through the serotonin receptor. Particularly in patients using monoamine oxidase inhibitors (MAOIs), blockade of the presynaptic reuptake of released serotonin may produce the serotonin syndrome,17 characterized by muscle rigidity, hyperthermia, and altered mental status (Chap. 58). It should be noted that dextromethorphan, discussed below, also may produce this syndrome. Conversely, the simultaneous use of MAOIs and morphine, fentanyl, or methadone is not expected to produce the serotonin syndrome based on the currently appreciated pharmacology of these drugs. MPTP. In 1982, several cases of acute, severe parkinsonian symptoms were identified in intravenous drug users.124 Because of the severe bradykinesia the patients were labeled “frozen addicts” and extensive investigations into the etiology of the problem ensued. This ultimately led to the discovery of MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine), an inadvertent product of the attempted synthesis of the illicit meperidine analogue MPPP (1methyl-4-phenyl-4-propionoxy-piperidine). MPTP was introduced by incorrect heating of the synthetic mixture at a clandestine drug laboratory. MPTP is metabolized to MPP+ by monoamine oxidase-B in glial cells. MPP+ is a paraquatlike agent capable of selectively destroying the dopamine-containing cells of the substantia nigra by inhibiting mitochondrial oxidative phosphorylation.165,246 Pretreatment with deprenyl, a monoamine oxidase-B inhibitor, can prevent toxicity.87 The index cases initially responded to standard antiparkinsonian therapy, but none improved substantially and the effects of the medications waned.4 Although calamitous for those patients exposed, MPTP has proven to be invaluable in the development of experimental models for the study of Parkinson disease.82 Several of the original “frozen” patients subsequently underwent stereotactic implantation of fetal adrenal tissue grafts into their basal ganglia with encouraging results.62 Dextromethorphan. Dextromethorphan is devoid of analgesic properties altogether, even though it is the optical isomer of levorphanol, a potent opioid analgesic. Based on this structural relationship, dextromethorphan is commonly considered an opioid, although its receptor pharmacology is actually extremely complex. At high doses, dextromethorphan does bind to opioid receptors to produce miosis and central nervous system depression. Reversal of these opioid effects by naloxone is reported in both children216 and adults.211 Binding to the phencyclidine site on the NMDA receptor, and subsequent inhibition of calcium influx through this receptor-linked ion channel, causes sedation. This same activity may account for its antiepileptic properties and also for its neuroprotectant effects in ischemic brain injury.31,229 Because NMDA receptor blockade also enhances the analgesic effects of µ-opioid agonists, combination therapy with morphine and dextromethorphan (MorphiDex) was recently introduced (see “Analgesia” earlier in this chapter).72 Blockade of presynaptic serotonin reuptake by dextromethorphan may elicit the serotonin syndrome in patients on monoamine oxidase inhibitors.225 Movement disorders, described as choreoathetoid- or dystonialike,77 occasionally occur and are likely a result of alteration of dopaminergic neurotransmission. Interaction of dextrorphan, the active O-demethylation metabolite of dextromethorphan, with the σ receptor produces a phencyclidinelike dysphoria.117,236 This metabolite is produced by CYP2D6, an enzyme with a well-described genetic polymorphism. Patients with the extensive metabolizer polymorphism appear to experience

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more drug-related psychoactive effects, whereas patients with poor metabolizers suffer more adverse effects related to the parent compound.275 Dextromethorphan is available without prescription in cold preparations, primarily because of its presumed lack of significant addictive potential. However, the recreational abuse of dextromethorphan is increasing, particularly among high school students.168 This increase in use likely relates to its easy availability and to its presumed lack of toxicity. There is abundant promotional information on the Internet and pure, powdered dextromethorphan is available without substantial regulatory oversight. Common street names include “DXM,” “dex,” or “roboshots,” and users often have expectations of euphoria and hallucinations, not the phencyclidinelike dysphoria that commonly occurs.160,266 Reports of substantial Robitussin or Coricidin consumption raise several considerations, including acetaminophen poisoning, opioid dependency, and bromide toxicity. This last concern relates to the common formulation of dextromethorphan as the hydrobromide salt and is most easily recognized as a dramatically elevated serum chloride when measured on an autoanalyzer164(Chaps. 24 and 63).

Tramadol. Tramadol (Ultram) is a novel synthetic analgesic agent with both opioid and nonopioid mechanisms responsible for its clinical effects. Although it binds only weakly to µ opioid receptors,197 tramadol exhibits cross-tolerance with morphine in rats,114 suggesting an opioid-mediated mechanism of analgesia. The demethylated metabolite M1 exhibits higher-affinity binding to µ receptors in vitro and may be important in patients chronically using tramadol. However, the role of M1 in the acute analgesic effect is not well defined. Naloxone only partially reverses tramadol-induced analgesia in mice197 and in humans,33 suggesting that an independent, nonopioid mechanism is also involved in mediating the clinical effects of tramadol. This appears to be inhibition of reuptake of biogenic amines, specifically serotonin and norepinephrine.197 This mechanism is supported by the nearly complete reversal of analgesic efficacy by yohimbine, an 2adrenergic antagonist that inhibits release of these neurotransmitters.50 Accordingly, patients using monoamine oxidase inhibitors may be at risk for development of the serotonin syndrome. A large number of spontaneous reports to the FDA suggest that the therapeutic use of tramadol may cause seizures, particularly in the first day after initiating therapy.107 However, epidemiologic studies have been unable to confirm this association.68 Overdose experience is limited to 71 patients collected in a prospective, poison center–based series,226 although several fatal multidrug overdoses, including tramadol, are reported.71 Tramadol-related seizures are not responsive to naloxone, but are suppressed with benzodiazepines. In fact, the package insert cautions against the use of naloxone in tramadol overdose because, in animals treated with naloxone, the risk of seizure is increased and the outcome not improved.247 Correspondingly, one patient in the prospective series had a seizure that was temporally related to naloxone administration.226 Tramadol abuse is reported but its extent is undefined. Opioid users recognized tramadol as an opioid only when given in an amount that was 6 times the therapeutic dose, but at this dose the users did not develop opioidlike clinical effects such as miosis.193 Following large overdose, patients may develop the typical opioid toxidrome. However, significant respiratory depression is uncommon,226 and it should respond to naloxone.200,,226 Urinary drug

screening is generally negative for opioids in tramadol-exposed patients.226 Propoxyphene. Like its structural analogue methadone, propoxyphene binds µ opioid receptors to produce the expected opioid clinical findings. However, following overdose, unanticipated properties of propoxyphene manifest. Propoxyphene and its hepatic metabolite, norpropoxyphene, produce myocardial sodium channel blockade identical to the type IA antidysrhythmic agents.136 This results in QRS complex widening and negative inotropy; QRS prolongation was identified in 42 (19%) of 222 propoxyphene-overdosed patients.139 These symptoms may be corrected with the parenteral administration of hypertonic sodium bicarbonate230 or with lidocaine.263 As in patients with tricyclic antidepressant overdose, the sodium ion component of the sodium bicarbonate enhances sodium influx through a partially occluded sodium channel by augmenting the extracellular to intracellular sodium concentration gradient. The paradoxical effect of lidocaine, another sodium channel blocker, may be explained by the very different dissociation constants of these two agents with the sodium channel. Lidocaine, a class IB agent, may competitively displace propoxyphene and norpropoxyphene, both more highly toxic sodium channel blockers (Chap. 52). Naloxone has never been shown to be effective therapy for the cardiotoxic effects of propoxyphene, although in one reported case, hemodynamic improvement was probably related to naloxone-induced propoxyphene withdrawal.83 Propoxyphene overdose may also produce acute central nervous system toxicity, which usually manifests as seizures. In one study of propoxyphene-overdosed patients, 10% of the subjects developed seizures.139 Although the exact mechanism is unclear, experimental models demonstrate that only propoxyphene, and not norpropoxyphene, is capable of inducing seizures.136 Therapy for seizures should follow standard management strategies, including benzodiazepines or barbiturates. Phenytoin has not been studied, but is not expected to be beneficial. High-dose naloxone (60 mg/kg IP) prevents experimental propoxyphene-induced seizures,70 but its role in seizure termination is undefined. Propoxyphene is often formulated with acetaminophen (Darvocet-N) or salicylates (Darvon compound) for additive analgesic effects. Patients who overdose on the combinations may suffer toxicity from either of these two nonopioid analgesics. Because patients may be consequently acetaminophen-poisoned yet be asymptomatic or manifest only opioid toxicity, empiric quantitative serum analysis for acetaminophen is indicated. Delayed peak serum acetaminophen concentrations after ingestion of combination opioid products may occur.2,241 The precise clinical implication of this delay is unclear (Chap. 32). Furthermore, propoxyphene’s respiratory-depressant effects may hinder the ability to detect salicylate poisoning by clinical examination, suggesting a situation in which empiric laboratory testing for salicylates may be indicated. Diphenoxylate and Loperamide. Although diphenoxylate is structurally similar to meperidine, its extreme insolubility limits absorption from the gastrointestinal tract. This factor may enhance its utility as an antidiarrheal agent, which presumably occurs via a local opioid effect at the gastrointestinal µ receptor. However, the standard adult formulation may result in significant systemic absorption and toxicity in children, and all such ingestions should be deemed consequential. Diphenoxylate is formulated with a small

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dose (0.025 mg) of atropine (as Lomotil), both to enhance its antidiarrheal effect and to discourage illicit use. Because both components of Lomotil may be absorbed and because their pharmacokinetic profiles differ somewhat, a biphasic clinical syndrome is occasionally noted.146 Patients may manifest atropine poisoning (anticholinergic toxidrome) either independently or concomitantly with the opioid effects of diphenoxylate. Delayed, prolonged, or recurrent toxicity is common,207 and is classically related to the delayed gastric emptying effects inherent to both opioids and anticholinergics. However, these effects are more likely explained by the accumulation of the hepatic metabolite difenoxin, which is a significantly more potent opioid than diphenoxylate206 and which possesses a longer serum half-life.113 Still, the relevance of gastroparesis is highlighted by the retrieval of Lomotil pills by gastric lavage as late as 27 hours postingestion.207 A recent review of 36 pediatric reports of Lomotil overdoses found that although naloxone was effective in reversing the opioid toxicity, recurrence of central nervous system and respiratory depression was common.146 This series included a patient with an asymptomatic presentation 8 hours postingestion who was observed for several hours and discharged. This patient returned to the ED 18 hours postingestion with marked signs of atropinism.146 In this same series, children with delayed onset of respiratory depression and other opioid effects were reported,146 and others describe cardiopulmonary arrest 12 hours postingestion.39 Naloxone infusion may be appropriate for patients with recurrent signs of opioid toxicity. Because of the delayed and possibly severe consequences, all children, and adult patients with potentially significant ingestions, should be admitted for monitored observation in the hospital. Loperamide (Imodium) is another insoluble meperidine analogue that is used to treat diarrhea. This agent is available without a prescription and the paucity of adverse patient outcomes thus far reported in the medical literature suggests that the safety profile of this agent is extremely high.134

SUMMARY For many reasons, opioid use is widespread. Overdose and toxicity, both intentional and innocent, remain a major cause of drugrelated morbidity and mortality. Acute lethality related to opioids is primarily caused by respiratory depression. Thus, mechanical ventilation, or the administration of a short-acting opioid antagonist, should be adequate initial therapy. An appreciation of the pharmacologic differences between the various opioids allows identification and appropriate management of patients poisoned by these agents.

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ANTIDOTES IN DEPTH

Opioid Antagonists Mary Ann Howland

Morphine

Naloxone, nalmefene, and naltrexone are pure competitive opioid antagonists at the mu (µ), kappa (κ), and delta (
) receptors. Naloxone is used to reverse respiratory depression for patients manifesting opioid toxicity. The parenteral dose should be enough to maintain adequate airway reflexes and ventilation.19 Dose titration, beginning with 0.05 mg and increasing as indicated to 0.4 mg, to 2 mg, and finally to 10 mg, will prevent abrupt opioid withdrawal and limit withdrawal-induced adverse effects such as vomiting and the potential for aspiration pneumonia. Naltrexone is used orally for patients following opioid detoxification to maintain opioid abstinence and also as an adjunct to achieve ethanol abstinence. Nalmefene is a parenteral agent whose duration of action falls between naloxone and naltrexone.

HISTORY Naloxone

Naltrexone

The effects of opium were recognized as early as the 3rd century 55 BC. By the 19th century, morphine (named for Morpheus, the god of dreams) was isolated from opium. In the 20th century, the presence of endogenous opioid peptides and families of opioid receptors including µ,
, and κ were elucidated. The 20th century also witnessed an ever-evolving series of complications of opioid addiction and abuse. Awareness of these social problems resulting from opioid abuse and the ability to understand structure-activity relationships led to the synthesis of many new drugs in the hope of producing potent opioid agonists free of abuse potential. Although this has not been achieved, opioid antagonists and partial agonists were developed. N-allylnorcodeine was the first opioid antagonist synthesized, in 1915 by J. Pohl, and in the 1940s the pharmacology of N-allylnormorphine (nalorphine) was characterized.35,63 In 1954, Lasagna and Beecher reported that nalorphine, a derivative of morphine, had both agonist and antagonist effects.55 This eventually led to the development of levallorphan, naloxone, naltrexone, and nalmefene. Lewenstein and Fishman synthesized naloxone in 1960, and Matossian synthesized naltrexone in 1963.7

CHEMISTRY Nalmefene

Minor alterations can convert an agonist into an antagonist.34 The substitution of the N-methyl group on morphine by a larger group led to nalorphine and also converted an agonist, levorphanol, to an antagonist, levallorphan.55 Naloxone, naltrexone, and nalmefene are derivatives of oxymorphone.

PHARMACOLOGY Naloxone, naltrexone, and nalmefene are pure competitive opioid antagonists at the µ (responsible for analgesia, miosis, euphoria, respiratory depression, and decreased GI motility), κ (responsible

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for weaker analgesia, miosis, respiratory depression, dysphoria, anxiety, nightmares, and hallucinations), and
receptors. These antagonists are most potent at the µ receptor, often necessitating higher doses for effects at the κ and
receptors. These agents bind to the opioid receptor in a competitive fashion, preventing the binding of agonists, partial agonists, or mixed agonist-antagonists without producing any action of their own. Naloxone, naltrexone, and nalmefene are similar in their potencies, but differ primarily in their pharmacokinetics, with both nalmefene and naltrexone having longer durations of action than naloxone. Naltrexone can be administered orally. Selective antagonists for µ, κ, and
are available experimentally and are undergoing investigation.38 Both nalorphine and levallorphan are weak competitive antagonists at the µ receptor and agonists at the κ receptor. Nalorphine and levallorphan are no longer marketed because of undesirable κ agonist properties. In the proper doses, pure opioid antagonists reverse all of the effects of endogenous and exogenous opioid agonists at the µ, κ, and
receptors, except for those of buprenorphine, which has a very high affinity for and slow rate of dissociation from µ receptor.53,55 Effects on other receptors and receptor subtypes are under investigation.38 Effects reversed include CNS depression, respiratory depression, analgesia, miosis, inhibition of baroreceptor reflexes, some vasodilation, muscular rigidity, and laryngospasm (commonly seen with fentanyl use), and slowed gastrointestinal motility, all manifestations of opioid receptor effects.23,55 Actions of opioid agonists that are not mediated by interaction with opioid receptors, such as direct mast-cell liberation of histamine or the sodium channel blocking effects of propoxyphene, are not reversed.4 Opioid-induced seizures in animals tend to be antagonized by opioid antagonists with the exception of those caused by meperidine and tramadol.8,29,55,62 A report of two newborns who developed seizures associated with a fentanyl and a morphine infusion demonstrated abrupt resolution following the administration of naloxone.13 Both patients had electroencephalogram (EEG) monitoring during the seizures and the documented burst-suppression pattern was apparently terminated after naloxone administration. It was recently discovered that opioids operate bimodally on opioid receptors.11 At low concentrations, stimulation is excitatory and actually antianalgesic. This antianalgesic effect is modulated through a Gs protein and is usually less important clinically than the well-known inhibitory actions that result from coupling to a Go protein at usual analgesic doses. Extremely low doses of opioid antagonists (ie, 0.25 µg/kg/h of naloxone) enhance the analgesic potency of the opioid and attenuate or prevent the development of tolerance and dependence.11,28 Coadministration of these very low doses of antagonists or derivatives (ie, methylnaltrexone) with the opioid also limit opioid-induced adverse effects such as nausea, vomiting, constipation, and pruritus.11,28,73 It is hypothesized that these beneficial effects result from modulating the opposing excitatory effects of opioids.

ADVERSE REACTIONS Opioid antagonists prevent the actions of opioid agonists if administered as pretreatment, reverse the effects of endogenous and exogenous opioids, and unmask the manifestations of opioid withdrawal in opioid-dependent patients. Pure opioid antagonists produce very few effects in the non-opioid-dependent patient,

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even when administered in high doses.16,17,41,67 Adverse effects excluding withdrawal and resedation are rare. Patients tolerant to opioid agonists such as morphine exhibit opioid withdrawal reactions (yawning, lacrimation, diaphoresis, rhinorrhea, piloerection, mydriasis, vomiting, diarrhea, myalgias, mild elevations in heart rate and blood pressure, and insomnia) when exposed to opioid antagonists or agonist-antagonists such as pentazocine. Although ultrarapid heroin detoxification is associated with fatalities occurring in the postoperative period, opioid withdrawal ordinarily is not life-threatening. Opioid withdrawal is usually physically and psychologically disabling for the patient. In addition, if vomiting occurs because of withdrawal while the patient’s airway is unprotected, aspiration pneumonia may complicate the patient’s recovery. Resedation is a function of the relative duration of action of the opioid antagonist and the opioid agonist. Most opioid agonists have a duration of action longer than that of naloxone and shorter than that of naltrexone, whereas the relationship is variable with nalmefene. A long duration of action is advantageous when the antagonist is used to promote abstinence, but is unwanted when an inappropriately large dose is administered to an opioid-dependent patient. Rare case reports describe acute lung injury (previously termed noncardiogenic pulmonary edema), hypertension, and cardiac dysrhythmias in association with naloxone administration.3,12,25,45,54,57,59 However, acute lung injury clearly occurs following heroin overdose in the absence of naloxone. Because naloxone is administered to patients who have apparent opioid intoxication, it may be that naloxone is unmasking the acute lung injury previously induced by the opioid, but which is covert because of the patient’s respiratory depression.14 Hypertension and cardiac dysrhythmias are most frequently reported following anesthesia and opioid reversal in patients with underlying cardiac or pulmonary disorders. The clinical complexities of the setting and case reports make it difficult to analyze and attribute these adverse effects solely to naloxone.10 Unmasking an underlying clinical condition may also be a logical cause of cardiac dysrhythmias developing after naloxone-induced heroin reversal in a patient simultaneously abusing cocaine.43 In view of the large number of naloxone doses administered, naloxone has a remarkably safe profile.

USE FOR OPIOID AND ETHANOL ABSTINENCE Opioid dependence is managed by detoxification and prolonged opioid abstinence, or substitution with either methadone or naltrexone.42 Any pure opioid antagonist could be substituted, but naltrexone is chosen because of its oral absorption and long duration of action as compared to that of naloxone or nalmefene.36,41,56 One milligram of naloxone intravenously blocks 25 mg of intravenous heroin for an hour, whereas 50 mg of oral naltrexone blocks this dose of heroin for 24 hours; 100 mg has a blocking effect of 48 hours, and 150 mg is effective for 72 hours. Nalmefene blocks the actions of 2 µg/kg of intravenous fentanyl with a duration of action that is also dose dependent; 0.5 mg IV, 2 mg IV, and 50 mg orally last 4, 8, and 50 hours, respectively.26,27 Before naltrexone can be administered, the patient must be detoxified from the opioid of dependence, and then naloxone is usually administered intravenously to confirm that the patient is no longer physi-

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cally dependent. Should opioid withdrawal occur, it will be shortlived following naloxone, whereas it would be prolonged following naltrexone or nalmefene. Naltrexone does not produce tolerance, although prolonged treatment with naltrexone produces up-regulation of opioid receptors.72 Naltrexone is also used as adjunctive therapy in ethanol dependence based on the theory that the endogenous opioid system modulates the intake of ethanol.51 Naltrexone reduces ethanol craving, the number of drinking days, and relapse rates.51,69 Naltrexone induces moderate to severe nausea in 15% of these patients, possibly as a result of alterations in endogenous opioid tone induced by prolonged ethanol ingestion.52

MISCELLANEOUS USES Endogenous opioids, including endorphins, dynorphins, and enkephalins, are involved in the regulation of many bodily functions, and opioid receptors are found not only in the central nervous system (CNS), but also throughout the body. Often these receptors and endogenous opioids work in concert with other neurotransmitter systems to modulate many effects.20,22,65,67 For instance, during shock, the release of circulating endorphins produces an inhibition of central sympathetic tone by stimulating κ receptors within the locus ceruleus, resulting in vasodilation. Also, by stimulating the nucleus ambiguus, vagal tone is enhanced. However, the benefits from treatment of patients in septic shock with naloxone are variable.15,61 Naloxone may have a temporizing effect through elevation of mean arterial pressure.33 Although promising in animal models of spinal cord injury, a human investigation of naloxone at doses about 100 times that used in the management of overdoses failed to demonstrate improvement in neurologic recovery.9 Opioid antagonists have been used in the management of overdoses with nonopioids such as ethanol,5,18,48,58 clonidine,71 captopril,66 and valproic acid.1,46 In none of these instances was improvement as dramatic or consistent as in the reversal of the toxic effects of an opioid.

PHARMACOKINETICS AND PHARMACODYNAMICS Oral naloxone is poorly bioavailable because of extensive firstpass effect.20 Naloxone is well absorbed by the intramuscular, subcutaneous, and endotracheal routes of administration. The onset of action after intravenous administration is extremely fast and occurs within 1–2 minutes. The distribution half-life of about 5 minutes is rapid because of its high lipid solubility, and the volume of distribution is 0.8–2.64 L/kg.30,31,50 The elimination half-life is 60–90 minutes in adults, and approximately 2–3 times longer in neonates.10,50 Naloxone is metabolized by the liver to several compounds, including a glucuronide.10 The duration of action of naloxone is approximately 20–90 minutes6,21 and depends on the dose of the agonist, the dose and route of administration of the naloxone, and the rate of elimination of the agonist and naloxone. Naltrexone is rapidly absorbed, with peak plasma concentrations occurring at 1 hour and an oral bioavailability of 5–60%.32,44,68,70 Distribution is rapid, with a volume of distribution of about 15 L/kg and low plasma-protein binding.37,40 Naltrexone is metabolized in the liver to -naltrexol (with 2–8% activity) and

2-hydroxy,3-methoxy--naltrexol.67 Naltrexone has an enterohepatic cycle.27,70 The plasma elimination half-life is 10 hours for naltrexone and 13 hours for -naltrexol.44,68,70 The terminal phase of elimination is 96 hours for naltrexone and 18 hours for -naltrexol.2 Nalmefene is a derivative of naltrexone, with an oral bioavailability of 40%. After oral administration, peak plasma concentrations are usually reached within 1–2 hours.16 Protein binding is approximately 45%.16 Following oral administration, its half-life is 8–9 hours and demonstrates first-order kinetics up to 300-mg doses.16 Although one study showed the half-life to be 108 ± 38 minutes after intravenous dosing, the study design may have been inadequate to determine the half-life.30 Another study demonstrated a terminal half-life of 10.8 ± 5 hours after a 1-mg intravenous dose.49 The apparent volume of distribution (Vd) is 3.9 L/kg for the central compartment and 8.6 L/kg at steady state. Nalmefene is metabolized in the liver to an inactive glucuronide conjugate that then probably undergoes enterohepatic recycling accounting for about 17% of the drug’s reappearance in the feces. Less than 5% is excreted unchanged in the urine.

DOSING The initial dose of antagonist is dependent on the dose of the agonist and the relative binding affinity of the agonist to the various opioid receptors in comparison to the antagonist. The presently available antagonists have a greater affinity for the µ receptor than for the κ or
receptors. Therefore, the presence of an opioid with a greater affinity for the κ or
receptor (eg, pentazocine, propoxyphene) requires a larger-than-ordinary dose of antagonist to cause reversal.47 The dose of antagonist necessary for a child may equal the adult dose because antagonists are competitive and dependent on the size of the ingested dose of agonist. The duration of action of the antagonist depends on many drug and patient variables, such as the dose and clearance of both antagonist and agonist. Evaluation of the return of respiratory depression should be monitored continuously and resedation should be treated with either repeated rebolusing of the antagonist or, if necessary, with another bolus followed by a continuous infusion. What constitutes an observation period is dependent on many factors. Following the use of naloxone, observation for 4 hours should be adequate to determine whether respiratory depression will return. The experience with nalmefene is too limited to estimate an adequate observation time, although 24 hours seems prudent. An oral dose of 150 mg of naltrexone generally lasts 72 hours and this should be adequate for the majority of ingestions with the exception of those opioids, such as levo--acetylmethadol (LAAM), that have extremely long durations of action. Naltrexone should never be administered to a patient who is opioid dependent.60 A challenge dose of naloxone to verify the lack of opioid dependency is strongly recommended before initiation of naltrexone. A dose of naloxone of 0.4 mg IV will reverse the respiratorydepressant effects of most opioids and is an appropriate starting dose in the non-opioid-dependent patient. However, this dose in an opioid-dependent patient will usually produce withdrawal. Therefore, 0.05 mg is a practical starting dose in most patients, increasing to 0.4 mg, then to 2 mg, and finally to 10 mg. If there is no response to 10 mg, then an opioid is unlikely to be responsible for the respiratory depression. Return of respiratory depression requires repeated bolus doses or a continuous infusion.39 Two-thirds

CHAPTER 62

of the bolus dose of naloxone that resulted in reversal, when given hourly, will usually maintain the desired effect.58 This dose can be prepared for an adult by multiplying the effective bolus dose by 6.6, adding that quantity to 1000 mL, and administering the solution at a 100-mL/h IV infusion rate. Titration upward or downward is easily accomplished as necessary to maintain adequate ventilation and avoid withdrawal. A continuous infusion of naloxone is not a substitute for continued vigilance. An arbitrary length of time of 12–24 hours is often chosen for observation based on the presumed opioid, the route of administration, and the dosage form. The patient must be observed for about 2 hours after discontinuance of the naloxone to assure that respiratory depression will not recur. Body-packers are a unique subset of patients who must have special individualized management strategies (Chap. 62). Naltrexone is administered orally in a variety of dosage schedules for the treatment of opioid dependence. Fifty milligrams daily, Monday through Friday, and 100 mg on Saturdays is a common dosing regimen. Alternatively, 100 mg every other day or 150 mg every third day can be administered. The initial intravenous dose of nalmefene is 0.1 mg in a 70-kg person in whom opioid dependency is suspected. If withdrawal does not ensue, 0.5 mg can be given, followed by 1 mg in 2–5 minutes as necessary. If intravenous access is unavailable, the intramuscular or subcutaneous route may be used, but the onset of action is delayed by 5–15 minutes after a 1-mg dose. For the reversal of postoperative opioid depression, a starting dose of 0.25 µg/kg is used, followed by incremental doses of 0.25 µg/kg every 2–5 minutes to the desired effect or to a total of 1 µg/kg.

AVAILABILITY Naloxone (Narcan) for intravenous, intramuscular, or subcutaneous administration is available in concentrations of 0.02 mg/mL, 0.4 mg/mL, and 1 mg/mL, with and without parabens, and in 1-mL and 2-mL ampules and in 10-mL multidose vials. Naloxone may be diluted in normal saline or 5% dextrose to facilitate continuous intravenous infusion. Any prepared solution should be used within 24 hours. Nalmefene (Revex) is available in a blue-labeled 1-mL ampule containing 100 µg/mL and in a green-labeled 2-mL ampule containing 1 mg/mL. Naltrexone is available as 50-mg pale yellow capsule-shaped tablets, scored and imprinted with DuPont on one side and the number 11 on the other side.

ACKNOWLEDGMENT Richard S. Weisman, PharmD, contributed to this section in a previous edition.

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3. Andree RA: Sudden death following naloxone administration. Anesth Analg 1980;59:782–784. 4. Barke KE, Lindsay BH: Opiates, mast cells and histamine release. Life Sci 1993;18:1391–1399. 5. Barros S, Rodriguez G: Naloxone as an antagonist in alcohol intoxication [letter]. Anesthesiology 1981;54:174. 6. Berkowitz BA: The relationship of pharmacokinetics to pharmacologic activity: Morphine, methadone and naloxone. Clin Pharmacokinet 1976;1:219–230. 7. Blumberg H, Dayton HB: Naloxone, naltrexone, and related noroxymorphones. In: Costa E, Greengard P, Braude MC, et al, eds: Narcotic Antagonists: Advances in Biochemical Psychopharmacology, vol. 8. New York, Raven Press, 1973, pp. 33–44. 8. Bonfiglio MF: Naloxone in the treatment of meperidine induced seizures. Drug Intell Clin Pharm 1987;21:174–175. 9. Bracken MB, Shepard MJ, Collins WF, et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury. N Engl J Med 1990;322:1405–1411. 10. Chamberlain JM, Klein BL: A comprehensive review of naloxone for the emergency physician. Am J Emerg Med 1994;6:650–656. 11. Crain S, Shen K: Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain 2000;84:121–131. 12. Cuss FM, Colaco CB, Baron JH: Cardiac arrest after reversal of effects of opiates with naloxone. Br Med J 1984;288:363–364. 13. Da Silva O, Alexandrou D, Knoppert D, Yound GB: Seizure and electroencephalographic changes in the newborn period induced by opiates and corrected by naloxone infusion. J Perinatol 1999;19:120–123. 14. Dauberstein JL, Kaufman DM: A clinical study of an epidemic of heroin intoxication and heroin induced pulmonary edema. Am J Med 1971;51:704–714. 15. DeMaria A, Craven DE, Heffernan JJ, et al: Naloxone versus placebo in treatment of septic shock. Lancet 1985;1:1363–1365. 16. Dixon R, Gentile J, Hsu HB, et al: Nalmefene: Safety and kinetics after single and multiple oral doses of a new opioid antagonist. J Clin Pharmacol 1987;27:233–239. 17. Dixon R, Howes J, Gentile J, et al: Nalmefene: Intravenous safety and kinetics of a new opioid antagonist. Clin Pharmacol Ther 1986; 39:49–52. 18. Dole VP, Fishman J, Goldfrank L, et al: Arousal of ethanol-intoxicated comatose patients with naloxone. Alcohol Clin Exp Res 1982; 6:275–279. 19. Emergency Cardiovascular Care Guidelines. Part 8: Advanced challenges in resuscitation. Toxicology in ECC. Circulation 2000;102: 1–223. 20. Evans CJ, Hammond DL, Frederickson RCA: The opioid peptides. In: Pasternak GW, ed: The Opiate Receptors. Clifton Park, NJ: Humana Press, 1988, pp. 23–71. 21. Evans JM, Hogg MJ, Lunn JN, Rosen M: Degree and duration of reversal by naloxone of effects of morphine in conscious subjects. Br Med J 1974;2:589–591. 22. Faden AI, Jacobs TP, Monsey E, et al: Endorphins in experimental spinal injury: Therapeutic effect of naloxone. Ann Neurol 1981;10: 326–332. 23. Fahnenstich H, Steffan J, Kau N, Bartmenn P: Fentanyl-induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med 2000;28:836–839. 24. Fishman J, Roffwarg H, Hellman L: Disposition of naloxone-7,83H in normal and narcotic-dependent men. J Pharmacol Exp Ther 1973; 183:575–580. 25. Flacke JW, Flacke WE, Williams GD: Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977;47:376–378. 26. Gal TJ, DiFazio CA: Prolonged antagonism of opioid action with intravenous nalmefene in man. Anethesiology 1986;64:175–180. 27. Gal TJ, DiFazio CA, Dixon R: Prolonged blockade of opioid effect with oral nalmefene. Clin Pharmacol Ther 1986;40:537–542.

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28. Gan T, Ginsberg B, Glass P, et al: Opioid-sparing effects of a lowdose infusion of naloxone in patient administered morphine sulfate. Anesthesiology 1997;87:1075–1081. 29. Gilbert PE, Martin WR: Antagonism of the convulsant effects of heroin, d-propoxyphene, meperidine, normeperidine and thebaine by naloxone in mice. J Pharmacol Exp Ther 1975;192:538–541. 30. Glass PS, Jhaveri RM, Smith LR: Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg 1994;78: 536–541. 31. Goldfrank LR, Weisman RS, Errick JK, Lo MW: A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med 1986; 15:566–570. 32. Gonzalez JP, Brogden RN: Naltrexone: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 1988;35:192–213. 33. Hackshaw KV, Parker GA, Roberts JW: Naloxone in septic shock. Crit Care Med 1990;18:47–51. 34. Harris LS: Narcotic antagonists—Structure-activity relationships. In: Costa E, Greengard P, Braude MC, et al, eds: Narcotic Antagonists: Advances in Biochemical Psychopharmacology, vol. 8. New York, Raven Press, 1973, pp. 13–20. 35. Hart ER, McCawley EL: The pharmacology of n-allylnormorphine as compared with morphine. J Pharmacol Exp Ther 1944;82:339–348. 36. Kleber HD, Kosten TR, Gaspari J, Topazian M: Nontolerance to the opioid antagonism of naltrexone. Biol Psychiatry 1985;20:66–72. 37. Kogan MJ, Verebey K, Mule SJ: Estimation of the systemic availability and other pharmacokinetic parameters of naltrexone in man after acute and chronic oral administration. Res Commun Chem Pathol Pharmacol 1977;18:29–34. 38. Kramer TH, Shook JE, Kazmierski W, et al: Novel peptidic mu opioid antagonists: Pharmacologic characterization in vitro and in vivo. J Pharmacol Exp Ther 1989;249:544–551. 39. Lewis JM, Klein-Schwartz W, Benson BE, et al: Continuous naloxone infusion in pediatric narcotic overdose. Am J Dis Child 1984;138: 944–946. 40. Ludden TM, Malspeis L, Baggot JD, et al: Tritiated naltrexone binding in plasma from several species and tissue distribution in mice. J Pharm Sci 1976;65:712–716. 41. Martin WR: Naloxone: Diagnosis and treatment; Drugs five years later. Ann Intern Med 1976;85:765–768. 42. Martin WR, Jasinski DR, Mansky PA: Naltrexone, an antagonist for the treatment of heroin dependence: Effects in man. Arch Gen Psychiatry 1973;28:784–790. 43. Merigian KS: Cocaine-induced ventricular arrhythmias and rapid atrial fibrillation temporally related to naloxone administration. Am J Emerg Med 1993;1:96–97. 44. Meyer MC, Straughn AB, Lo MW, et al: Bioequivalence, dose-proportionality and pharmacokinetics of naltrexone after oral administration. J Clin Psychiatry 1984;45:15–19. 45. Michaelis LL, Hickey PR, Clark TA, et al: Ventricular irritability associated with the use of naloxone hydrochloride. Ann Thorac Surg 1984;18:608–624. 46. Montero FJ: Naloxone in the reversal of coma induced by sodium valproate. Ann Emerg Med 1999;33:357–358. 47. Moore RA, Rumack BH: Naloxone: Underdosage after narcotic poisoning. Am J Dis Child 1980;134:156–158. 48. Moss LM: Naloxone reversal of nonnarcotic-induced apnea. JACEP 1973;2:46–48. 49. Nalmefene. Physician’s Desk Reference. Montvale, NJ, Medical Economics, 1997, p. 1863. 50. Ngai SH, Berkowitz BA, Yang JC, et al: Pharmacokinetics of naloxone in rats and man: Basis for its potency and short duration of action. Anesthesiology 1976;44:398–401. 51. O’Malley SS, Jeffe AJ, Chang G, et al: Naltrexone and coping skills therapy for alcohol dependence. Arch Gen Psychiatry 1992;49: 881–887.

52. O’Malley S, Krishinan-Sarin S, Farren C, O’Connor P: Naltrexoneinduced nausea in patients treated for alcohol dependence: Clinical predictors and evidence for opioid mediated effects. J Clin Psychopharmacol 2000;20:69–76. 53. Pasternak GW: Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 1993;16:1–18. 54. Prough DS, Roy R, Bumgarner J: Acute pulmonary edema in healthy teenagers following conservative doses of intravenous naloxone. Anesthesiology 1984;60:485–486. 55. Reisine T, Pasternak G: Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al, eds: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996, pp. 521–549. 56. Renault PF: Treatment of heroin dependent persons with antagonists: Current status. In: Willette RE, Barnett G, eds: Naltrexone: Research Monograph. Rockville, MD, National Institute on Drug Abuse, 1980;28:11–22. 57. Schwartz JA, Koenigsberg MD: Naloxone-induced pulmonary edema. Ann Emerg Med 1987;16:1294–1296. 58. Sorenson SC, Mattison K: Naloxone as an antagonist in severe alcohol intoxication [letter]. Lancet 1978;2:688–689. 59. Tanaka GY: Hypertensive reaction to naloxone. JAMA 1974;228: 25–26. 60. Tornabene VW: Narcotic withdrawal syndrome caused by naltrexone. Ann Intern Med 1974;81:785–787. 61. Tuggle DW, Horton JW: Effects of naloxone on splanchnic perfusion in hemorrhagic shock. J Trauma 1989;29:1341–1345. 62. Umans JG, Inturrisi CE: Antinociceptive activity and toxicity of meperidine and normeperidine in mice. J Pharmacol Exp Ther 1982; 223:203–223. 63. Unna K: Antagonistic effect of n-allyl-normorphine upon morphine. J Pharmacol Exp Ther 1943;79:27–31. 64. Van den Berg MH, Van-Giersbergen PL, Cox-Van-Put J, et al: Endogenous opioid peptides and blood pressure regulation during controlled stepwise hemorrhagic hypotension. Circ Shock 1991;35: 102–108. 65. Van Giersbergen PL, Cox-Van-Put J, de-Jong W: Central and peripheral opiate receptors appear to be activated during controlled hemorrhagic hypotension. J Hypertens 1989;7(Suppl):2–27. 66. Varon J, Duncan SR: Naloxone reversal of hypotension due to captopril overdose. Ann Emerg Med 1991;20:1125–1127. 67. Verebey K, DePace A, Jukofsky D, et al: Quantitative determination of 2-hydroxy-3-methoxy-6-naltrexol (HMN), naltrexone, and 6naltrexol in human plasma, red blood cells, saliva and urine by gas liquid chromatography. J Anal Toxicol 1980;4:33–37. 68. Verebey K, Volavka J, Mule SJ, Resnick RB: Naltrexone: Disposition, metabolism, and effects after acute and chronic dosing. Clin Pharmacol Ther 1976;20:315–328. 69. Volpicelli JR, Clay KL, Watson NT, O’Brien CP: Naltrexone in the treatment of alcoholism: Predicting response to naltrexone. J Clin Psychol 1995;56(Suppl 7):39–44. 70. Wall ME, Brine DR, Perez-Reyes M: Metabolism and disposition of naltrexone in man after oral and intravenous administration. Drug Metab Disposition 1981;9:369–375. 71. Wedin GP, Edwards LJ: Clonidine poisoning treated with naloxone. Am J Emerg Med 1989;7:343–344. 72. Yoburn BC, Markham CL, Pasternak GW, Inturrisi CE: Upregulation of opioid receptor subtypes correlates with potency changes of morphine and DADLE. Life Sci 1988;43:1319–1324. 73. Yuan C, Foss JF, O’Connor M, et al: Methylnaltrexone for reversal of constipation due to chronic methadone use. JAMA 2000;283: 367–372.

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SEDATIVE-HYPNOTICS AGENTS David C. Lee

zodiazepines, other pharmaceutical drugs, and nonpharmaceutical agents (Table 63–1).

Ambulance personnel brought a 23-year-old male into the Emergency Department (ED). He was found outside a bar lying on the street. He initially ambulated into the ambulance with help from the paramedics. He was lethargic and answered questions and followed commands intermittently. Initial vital signs included a heart rate of 55 beats/min, a blood pressure of 138/90 mm Hg, a respiratory rate of 12 breaths/min, an oral temperature of 36.8°C (98.3°F), and a room air pulse oximetry reading of 96%. His pupils were 2 mm and there were no signs of trauma. He had a good gag reflex and his exam was otherwise unremarkable. His bedside glucose test was normal. His electrocardiogram (ECG) revealed a sinus bradycardia at a rate of 53 beats/min. He was treated with 2 mg of intravenous naloxone and 100 mg of intravenous thiamine without response. He was placed on a stretcher in a hallway and was presumed to have alcohol intoxication. Thirty minutes later, he became cyanotic and he responded sluggishly to physical stimuli. His repeat vital signs were a heart rate of 50 beats/min, a blood pressure of 128/86 mm Hg, and a pulse oximetry reading of 88%. He was mechanically ventilated with a bag-valve mask. He became slightly more arousable. A decision was made to intubate him; however, the patient was very combative when attempts at intubation were made. When he was placed on 100% oxygen by mask, his pulse oximeter reading plummeted to 88% and he appeared apneic. Midazolam was given for sedation and intubation was performed successfully. Blood alcohol results returned with a level of 80 mg/dL. Urine toxicology screening for drugs-of-abuse was negative. Other routine laboratory screening was unremarkable. Two hours later, he rapidly regained consciousness and self-extubated himself. He demanded to leave and appeared lucid and coherent. He admited to drinking a mixture of “Blue Nitro” (α-butyrolactone) and vodka. Although he had done this before, he stated he “may have taken an extra spoonful.” He declined admission to a detoxification program and was released 6 hours later.

HISTORY AND EPIDEMIOLOGY Poisoning with sedative-hypnotic agents is one of the more common overdoses. According to data collected by the American Association of Poison Control Centers, sedative-hypnotics are consistently one of the top five agents associated with fatalities by overdose (p. 1752 and Chap. 116). With the ubiquitous worldwide use of sedative-hypnotics, this category of agents is probably involved in substantially more deaths than are reported. Several advocates of euthanasia favor suicide by sedative-hypnotic poisoning, specifically with barbiturates.79 Throughout history, sedative-hypnotic use and abuse have been commonplace. Mythology of ancient cultures is replete with stories of poisons or agents that cause sleep or a state of unconsciousness (Chap. 1). Overdoses of pharmaceutical sedative-hypnotics were reported soon after the commercial introduction of bromide in 1853. Other commercial agents that were subsequently developed include chloral hydrate, paraldehyde, sulfonyl, and urethane. In 1903, the barbiturates were introduced and quickly replaced the older agents. This class of drugs dominated the market for sedative-hypnotics for the first half of the 20th century. Unfortunately, because barbiturates have a relatively small therapeutic index and substantial potential for abuse, they quickly became a major health problem. By the 1950s and 1960s, barbiturates were frequently implicated in self-poisonings and overdoses and were responsible for the majority of all drug-related suicides. As fatalities from barbiturates increased, attention shifted to curbing their abuse and finding safer alternatives.26,147,157 These safer alternatives included methyprylon, glutethimide, ethchlorvynol, and methaqualone. Unfortunately, however, many of these agents also had significant undesirable effects. With the introduction of benzodiazepines in the early 1960s, barbiturates and the original alternatives were quickly supplanted. Presently, benzodiazepines are the most commonly prescribed sedatives. First synthesized by Hoffman-LaRoche in 1955 and marketed in 1960, there are now more than 50 differing types of benzodiazepines marketed and thousands developed. In the 1980s, benzodiazepines captured more than 80% of the anxiolytic market and more than 50% of the hypnotic market.80,162 As opposed to the barbiturates, the ingestion of a benzodiazepine alone accounts for relatively few deaths.57 Most deaths blamed on benzodiazepines

Sedative hypnotics refer to a loosely defined category of agents that are used to induce a calming effect and to limit excitability (sedative), or to induce drowsiness and sleep (hypnotic). Anxiolytics or tranquilizers are other medical terms that are used to describe these agents. Because many different types of drugs, botanicals, and foods are used for this effect, sedative-hypnotics actually encompass a wide range of agents. This chapter focuses on agents used solely for their sedative-hypnotic effects. Sedativehypnotics can be divided into four major groups: barbiturates, ben-

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PART D

TABLE 63–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Sedative-Hypnotics Pharmaceutical Antihistamines Diphenhydramine Doxylamine Benzodiazepines* Barbiturates* Bromides• Chloral Hydrate* Cyclic antidepressants Amitriptyline Imipramine Maprotiline Ethchlorvynol (Placidyl) Glutethimide (Doriden) Meprobamate (Miltown)* Methyprylon (Noludar)• Methaqualone (Quaalude)*• Paraldehyde• Propofol* Sulfonal• Urethane• Zaleplon Zolpidem* Nonpharmaceutical Ethanol* Dietary supplements Botanicals Cypripedium calceolus (nerveroot) Primula veris (cowslip) Piscida piscipula (Jamaican dogwood) Humulus lupulus (hops) Passiflora incarnata (passion flower) Valeriana officinalis (valerian)* γ-Hydroxy butryrate (GHB)*• γ-Butyrolactone (GBL)* Furanone* Melatonin Tryptophan

*Documented interactions with the GABA system. • Not marketed in the United States.

have occurred from mixed overdoses of benzodiazepines and other sedative-hypnotic agents.71 Although benzodiazepines represent most of the market for pharmaceutical sedatives by prescription, many nonprescription agents are used as hypnotics. There are also many “dietary supplements” and nonpharmaceutical agents that are promoted as sedative-hypnotics. With the exception of the antihistamines and γ-hydroxybutyrate (GHB) analogues, the majority of these are relatively nontoxic in the therapeutic or overdose settings.7

PHARMACOLOGY All of the sedative-hypnotics can produce central nervous system (CNS) depression. Most clinically effective sedative-hypnotic agents produce their physiologic effects by enhancing the function of GABA system. This has been well described for benzodiazepines and barbiturates. With increasing understanding of this

system, the mechanisms of action of many older agents have also been attributed to the GABA system (Table 63–1). GABAA receptors are the primary mediators of inhibitory neurotransmission in the brain. The GABAA receptor is a pentameric structure composed of varying polypeptide subunits associated with a chloride channel on the postsynaptic membrane (see Fig. 10–9). These subunits are classified into three families:
, , and γ. The most common GABAA receptor in the brain is composed of
12γ2 subunits.38 Sedative-hypnotics alter the function of the chloride channel by increasing either its frequency or duration of opening. Indirect-acting agonists, such as the benzodiazepines, require the presence of GABA to affect the channel. Other agents, such as barbiturates and propofol, can directly open the channel at high doses without the presence of GABA.136 This may explain the relatively high lethality seen with barbiturate overdoses as compared to benzodiazepine overdoses. Toxicity of many of the sedative-hypnotics can be explained by their action on the various GABA receptor configurations. Differing sedative-hypnotics have unique affinities for certain GABA receptors with specific subunits. Variations in the five subunits of the GABA receptor confers the potency of its sedative, anxiolytic, hypnotic, amnestic, and muscle-relaxing properties.119 Almost all sedative-hypnotics bind to GABAA receptors containing the
1 subunit. Low doses of benzodiazepines are only affective at GABAA receptors with the γ2 subunit.38 Even within classes of sedative-hypnotics, there are varying affinities for differing subunits. This model helps explain why flunitrazepam has greater amnestic properties than diazepam, and why clonazepam has a greater anxiolytic property than both flunitrazepam and diazepam.45 There are also GABAB and GABAC receptors. GABAB receptors are coupled to a G protein and are located pre- and postsynaptically. Like GABAA receptors, GABAC receptors are also associated with a chloride channel; however, they are insensitive to barbiturates and benzodiazepines (Chap. 10). As such their function has not been clearly elucidated.21,33,48 Many sedative-hypnotics have activity at multiple differing receptor sites. Not only do sedative-hypnotics increase the effects of GABA-mediated inhibitory neurotransmission, many sedativehypnotics decrease the affects of glutamate-mediated excitatory neurotransmission. Trichloroethanol, the active metabolite of chloral hydrate, decreases the effect of glutamate on N-methyl-Daspartate (NMDA) receptors.140 Barbiturates, etomidate, and propofol interact with NMDA and AMPA/kainate receptor function with barbiturates, markedly attenuating the excitatory effects of glutamate.28,138,184 GHB also has affinity for inhibitory presynoptic GABAB receptors, which may explain the resultant muscular activity such as twitching. In addition there is evidence to suggest that there are also specific GHB receptor sites.5,11,111 Certain sedative-hypnotics will have specific sites that are concentrated in varying areas of the CNS. For example, benzodiazepines associated with GABA receptors tend to bind at specific areas in the CNS. There are two structurally different “central” benzodiazepine receptors found in the brain: type I (ω1) and type II (ω2). Type I receptors tend to be located throughout the brain and to contain the GABAA
1 subunit.45 Therefore, they are hypothesized to affect anxiety, sleep, and amnesia. Type II receptors tend to be concentrated in the hippocampus, striatum, and spinal cord, and are hypothesized to affect muscle relaxation and dependence. Zolpidem and zaleplon have greater affinity for type I receptors (specifically the
1 subunit) and lower affinity for type II receptors

CHAPTER 63

than benzodiazepine hypnotics. For this reason, they are thought to have potent hypnotic affects and less addiction potential.45,74,77 Benzodiazepines also are active at certain types of benzodiazepine receptors that are not associated with the GABA receptor. These receptors differ structurally, pharmacologically, and physiologically from GABA-associated benzodiazepine receptors. Because the function and the structure of these receptors are not well defined, attempts to classify them are not satisfying. These sites have been labeled “peripheral” benzodiazepine receptors because of their predominant location on the outer membrane of the mitochondria, but they are also present in erythrocytes that lack mitochondria.135,139 These receptors are prevalent throughout the body, with the greatest concentrations located in steroid-producing cells in the adrenal gland, the anterior pituitary gland, and the reproductive organs. The exact endogenous ligands or proteins that bind to these receptors are not clearly elucidated. Several types of endogenous benzodiazepinelike substances, endozepines, anthralin, porphyrins, and diazepam-binding inhibitors are proposed to bind to these receptors.63 Although the exact role of these receptors remains unclear, it is postulated that benzodiazepines may influence basic cellular functions such as mitochondrial respiratory control, cell growth, and cell differentiation. Peripheral benzodiazepine receptors also appear to affect several biologic systems that are designed to cope with stress, such as the hypothalamic-pituitary system, the sympathetic nervous system, the renin-angiotensin system, and the neuroendocrine-immune system.63,183 These receptors may have a “neurosteroid” effect by modulating steroidogenesis. They are hypothesized to alleviate anxiety and stress without the presence of GABA by resulting in neurosteroid release in the adrenal glands.41,114,132 Peripheral benzodiazepine receptors may be of significance in modulating pathologic conditions such as hepatic encephalopathy, anxiety disorders, and abnormal immune function. Peripheral benzodiazepine receptors in the CNS are markedly decreased after neurotoxic insults caused by domoic acid, an excitatory amino acid, and the neurotoxins soman and 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP).77,91,92,97 These peripheral receptors are increased in the presence of encephalopathies caused by hepatic failure and thiamine deficiency.27,99,103 Cardiac benzodiazepine receptor sites are linked to calcium channels (specifically, dihydropyridine sites) in animal tissues.46,101,120–123 This mechanism may represent the theoretical support for the use of benzodiazepines in the treatment of the cardiac toxicity of agents such as chloroquine, cocaine, and sympathomimetics.12,83,109,130

PHARMACOKINETICS/TOXICOKINETICS Most sedative-hypnotics are rapidly absorbed in the GI tract with the rate-limiting step being dissolution and dispersion of the drug. Barbiturates and benzodiazepines are primarily absorbed in the small intestine. Clinical effects are determined by the relative ability of these drugs to penetrate the blood-brain barrier. Agents that are highly lipophilic penetrate most rapidly. The ultrashort-acting barbiturates are clinically active in the most vascular parts of the brain (gray matter first) within 30 seconds of administration, resulting in sleep shortly thereafter. After initial distribution, many of the sedative-hypnotics undergo a redistribution phase as they are dispersed to other body tis-

SEDATIVE-HYPNOTICS AGENTS

931

sues, specifically fat. Drugs that are redistributed, such as the lipophilic (ultrashort-acting) barbiturates and some of the benzodiazepines (diazepam, midazolam), may have a brief clinical effect as the early peak concentrations in the brain rapidly decline. The clinical activity of many of these drugs is determined by their rapid distribution and redistribution (
phase) and not by their elimination ( phase) (Chap. 11; Table 63–2). Many of the sedative-hypnotics are metabolized to pharmacologically active intermediates. This is particularly true for chloral hydrate and some of the benzodiazepines. The benzodiazepines can be hepatically demethylated, hydroxylated, or conjugated with glucuronide. Glucuronidation proceeds rapidly to the production of inactive metabolites. Benzodiazepines, such as diazepam, that undergo demethylation yield active intermediates that may possess more prolonged therapeutic half-lives than the parent compound. Because of the individual pharmacokinetics of sedative-hypnotics and the production of active metabolites, there is often no correlation between the therapeutic half-life and the biological half-life. The majority of sedative-hypnotics, such as the highly lipidsoluble barbiturates and the benzodiazepines, are highly proteinbound. The kidney poorly filters the agents and elimination occurs principally by hepatic metabolism. Notable exceptions include chloral hydrate and meprobamate. Drugs with a low lipid-to-water partition coefficient, such as meprobamate and the longer-acting barbiturates, are poorly protein-bound and more subject to renal excretion, which can be influenced. Elimination can be increased with manipulation of urinary pH and hemodialysis (Chap. 6). Another mechanism is the use of multiple doses of activated charcoal (Antidotes in Depth: Activated Charcoal). Phenobarbital is a classic example of an agent whose elimination can be manipulated with these techniques. However, because of the high protein binding and high lipid solubility of most other agents, any attempts at acutely increasing the rate of elimination of the majority of sedative-hypnotics would be unsuccessful.

PHARMACODYNAMICS Overdoses of multiple different types of sedative-hypnotics can be more lethal than an overdose of a single agent. These agents often act synergistically at the GABA site. For example, both barbiturates and benzodiazepines act on the GABA site, but barbiturates hold the ionophore open longer, while benzodiazepines increase the frequency of ionophore opening.161 Varying sedative-hypnotics may increase the affinity of another agent at their respective binding sites. For example, pentobarbital increases the affinity of γ-hydroxybutyrate for its non-GABA binding site.163 Propofol potentiates pentobarbital’s effect on the chloride influx at the GABA receptor.169 Propofol also increases the affinity and decreases the rate of dissociation of benzodiazepines to their site on the GABA receptor.25,149 These actions cause an increased effect of each agent and clinically may lead to a deeper CNS and respiratory depression. Another mechanism of increasing synergistic toxicity is the inhibition of elimination. The combination of ethanol and chloral hydrate, the infamous “Mickey Finn,” has additive CNS depressant effects. Both drugs alter each other’s metabolism. Chloral hydrate competes for alcohol dehydrogenase, thereby prolonging the half-life of ethanol. The metabolism of ethanol generates nicotinamide adenine dinucleotide (NADH), which is needed as a cofac-

932

PART D

TABLE 63–2.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Sedative-Hypnotic Agents Plasma Half-Life (hours)

Benzodiazepines Alprazolam Chlordiazepoxide Clorazepate Clonazepam Diazepam Estazolam Flunitrazepam Flurazepam Lorazepam Midazolam Oxazepam Temazepam Triazolam Barbiturates Ultrashort acting Methohexital Thiopental Short acting Pentobarbital Secobarbital Intermediate acting Amobarbital Aprobarbital Butabarbital Long acting Barbital Mephobarbital Phenobarbital Primidone Others Alcohols Chloral hydrate Ethchlorvynol Phenols Propofol Imidazolecarboxylate Etomidate Piperidinediones Glutethimide Methyprylon Propanediols Meprobamate Carisoprodol Quinazolines Methaqualone Imidazopyridine Zolpidem Pyrazolopyrimidine Zaleplon

10–14 5–15 18–50 20–70 8–31 16–35 2.3 9–19 3–8 5–15 10–16 1.5–5.5

Protein Binding (%)

80 96 97 85.4 98.7 93 80 97.2 90 95

Vd (L/kg)

0.8 0.3 0.9 3.2 1.0–1.5

Active Metabolites

None Desmethylchlordiazepoxide, desmethyldiazepam, oxazepam Desmethyldiazepam, oxazepam None Desmethyldiazepam, hydroxydiazepam, oxazepam None 7-Amino-flunitrazepam N-Hydroxymethyl-flurazepam, desalkylflurazepam None 1-Hydroxymethylmidazolam None None None

97 90

3.4 0.8–1.3 1.0–1.5 0.6 0.75–1.37 0.7–1.5

3–6 8–10

73 72–86

2.2 1.5–3.5

Unclear None

15–48 15–40

60–70 46–70

0.5–1.0

None None

8–42 14–34 35–50

20 26

6–12 10–70 48–144 3.3–22.4

25 40–60 20–45 19

0.5–0.6 0.6–0.8

4.0–9.5 10–25

35–40 30–40

0.6–1.6 4

0.5–1 (initial)

98

2–10

1.25

76

2.5–4.5

5–22 3–6

47–59 60

2.7 0.97

4-Hydroxy-glutethimide 5–Methylpyrithyldione

6–16 8

20

0.75

None Meprobamate

19

80–90

5.8–6.0

1.4–4.5

92

0.54

None

1.0

60

1.4

None

tor for the metabolism of choral hydrate to trichloroethanol, an active metabolite. Finally, ethanol inhibits the conjugation of trichloroethanol, and trichloroethanol, in turn, inhibits the oxidation of ethanol (Fig. 63–1).158,159 Because of the greater variety of drugs, there are multiple drug-drug interactions that occur predominantly in the hospital

None None None

Phenobarbital None Phenobarbital, phenylethylmalonamide

Trichloroethanol

4-Hydroxymethaqualone

setting that may also prolong the half-life of many sedative hypnotic agents. This may significantly increase their potency. For example, midazolam, which undergoes hepatic metabolism via CYP3A4, can have a dramatic increase in half-life in the presence of certain antifungal agents that have a similar metabolism.134 The midazolam half-life undergoes a 400-fold rise when combined

CHAPTER 63

SEDATIVE-HYPNOTICS AGENTS

933

Figure 63–1. Metabolism of chloral hydrate and ethanol, demonstrating the interactions between chloral hydrate and ethanol metabolism. In particular, note the inhibitory (---) effects of ethanol on trichloroethanol metabolism and the converse. (Adapted, with permission, from Sellers EM, Lang M, Koch-Weser J: Interaction of chloral hydrate and ethanol in man. I. Metabolism. Clin Pharmacol Ther 1972;13:40.)

with itraconazole.10 This finding is also related to the fact that intravenous administration of an agent bypasses the majority of enteric P450 cytochrome metabolism.

Tolerance Ingestions of relatively large doses may not have the predicted effects in patients who chronically use sedative-hypnotics. These patients have often developed tolerance, the progressive diminution of effect of a particular drug with repeated administrations, often resulting in a need for greater doses to achieve the same effect. Tolerance can be secondary to pharmacodynamic and/or pharmacokinetic factors. However, in the majority of cases, tolerance to sedative-hypnotics is caused by pharmacodynamic changes.162 Pharmacodynamic tolerance occurs when there are adaptive neural and receptor changes (“plasticity”) after repeated expo-

sures. These changes include a decrease in number of receptors (“down-regulation”), reduction of firing of receptors (“receptor desensitization”), structural changes in receptors (“receptor shift”), and reduction of coupling of sedative-hypnotics and their respective GABAA-related receptor site. In this setting, there is a decreased effect of a drug even though there are no significant changes in plasma or CNS drug levels. For example, benzodiazepine-dependent patients have decreased GABAA receptor density and sensitivity.59,144 Pharmacodynamic tolerance to sedative-hypnotics can appear very quickly, even during short-term use. In one study, using an IV infusion of thiopental with a variable rate and a specific electroencephalogram (EEG) pattern, rapidly increasing thiopental levels were needed to produce a constant state of anesthesia.13 The degree of acute tolerance can be directly proportional to the degree of CNS depression produced by the drug.87 Thus, tolerance is dose related and can occur rapidly.

934

PART D

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Pharmacokinetic tolerance occurs when metabolic changes cause a decreasing plasma and CNS level of a chronically administered drug. For example, chronic phenobarbital administration can result in pharmacokinetic tolerance. Repeated use of phenobarbital will induce hepatic microsomal enzyme function causing a decreasing half-life. Thus, increasing doses of phenobarbital may be required to achieve the same level. Following termination of therapy, tolerance can be lost as the previously desensitized target receptors return to their original level of function. The rate at which this process occurs is governed by the biologic half-life of the particular sedative-hypnotic and any biologically active intermediates produced. Cross-tolerance readily exists among the sedative-hypnotics. Chronic use of benzodiazepines will not only decrease the activity of benzodiazepine binding sites on the GABA receptor, but it will also decrease the binding affinity of the barbiturate sites.78

TABLE 63–3.

Dependence and Withdrawal

collapse can also be caused by direct depression of cardiac contractility, dilation of vascular smooth muscle, and medullary depression of cardiovascular regulation. Although the physical examination can rarely be used to identify a particular sedative-hypnotic, it can give clues to the class of sedative-hypnotics (Table 63–3). Barbiturates cause fixed drug eruptions, which often are bullous eruptions over pressure-point areas. However, this phenomenon is not specific to barbiturates and is documented with other drugs, including carbon monoxide, methadone, imipramine, glutethimide, and benzodiazepines (nitrazepam, diazepam, oxazepam, and temazepam). Occasionally, the offending agent can be found in the aspirated fluid of these vesicles. Benzodiazepine overdoses have unique characteristics in children. In a case series of benzodiazepine overdoses in children with a mean age of 36 months, the majority of patients presented with symptoms typical of a sedative-hypnotic overdose, such as lethargy and CNS depression. It was noteworthy that 17% solely manifested ataxia.180 The presentation of acute iatrogenic sedative-hypnotic toxicity in a hospital setting is identical to the nonhospital setting: CNS and respiratory depression. The main differences are related to the route of administration, the greater potency of agents used in the hospital setting, and their side effects. There are other situations that differ between overdoses that occur in the hospital and in the community. In the critical care settings, large doses of sedative-hypnotics given chronically are associated with toxicities that are independent of the characteristics of the sedative-hypnotic. The toxicity maybe associated with the diluent of certain sedative-hypnotics, specifically propylene glycol. Multiple case reports document the development of hyperosmolar states, metabolic acidosis, and cardiovascular compromise in patients with prolonged use of lorazepam and etomidate.96,104,148 Fatal reactions have also been attributed to the carrier base of intravenous propofol.145 An additional area of concern is the unrecognized development of dependence and the iatrogenic precipitation of withdrawal. In the critical care setting, potent, fast-acting, short-lived sedatives are commonly used. However, it is these same characteristics that increase the potential for dependence. Rapid weaning from these medications may precipitate withdrawal, often with a delayed presentation after extubation and cessation of sedation (Chap. 72).

Physical drug dependence refers to a condition in which a physiologic withdrawal state is induced when a drug is suddenly stopped. In animal models, dependence can be easily and rapidly achieved with the use of benzodiazepines.94,95 Biologic theories of dependence are based on two main theories. The first involves actual decreases in endogenous production of a similar substance. Thus, when chronic sedative-hypnotic use occurs, the body reduces the amount of a similar endogenous substance. Although endogenous ligands are postulated for benzodiazepines, there has yet to be convincing confirmation of these agents. Presently, there is no proof that there is actual reduction of GABA or GABAergic agents during dependency. The second theory postulates that there are changes in the characteristic of the receptor. Similar to theories concerning tolerance, dependence is thought to mainly result from the “plasticity” of the receptor and the CNS. A molecular model of this theory describes a change in the protein subunits of the GABAA receptor, specifically replacing the
1 and 1 subunits with less active subunits, thereby decreasing the potency of sedative-hypnotics.45 When benzodiazepine use is diminished or discontinued, approximately one-third of chronic benzodiazepine users experience withdrawal, which can be life-threatening.95 Similar to other withdrawal states, withdrawal from sedative-hypnotic agents is usually more severe and has a more rapid onset when the agent involved has a short half-life. Factors that contribute to the severity of withdrawal include shorter half-life of the agent, higher daily dosage, and underlying medical and psychologic illness (Chap. 72).

CLINICAL MANIFESTATIONS Almost all patients with significant sedative-hypnotic overdoses will manifest slurred speech, ataxia, and incoordination similar to that which occurs with ethanol intoxication. Those with moderate to severe toxicity are stuporous or comatose, and the most severe cases may lose all neurologic responses. With increasing CNS depression, increasing respiratory depression occurs. Low minute and tidal volumes occur, causing signs of acute respiratory acidosis. Increasing hypoventilation and impending respiratory compromise contribute to cardiovascular depression. Cardiovascular

Clinical Findings of Sedative-Hypnotic Overdose

Clinical Signs

Sedative-Hypnotics

Hypothermia Unique odors Cardiac dysrhythmias Bradycardia Tachydysrhythmias Muscular twitching Acneiform rash Fluctuating coma GI bleeding Discolored urine Anticholinergic signs

Barbiturates, bromides, ethchlorvynol Chloral hydrate, ethchlorvynol Meprobamate GHB Chloral hydrate GHB, methaqualone, propofol Bromides Glutethimide, meprobamate Chloral hydrate, methaqualone Propofol (green/pink) Glutethimide

CHAPTER 63

DIAGNOSTIC TESTING In the undifferentiated comatose patient without a clear history, when drug overdose is a primary concern, laboratory testing including electrolytes, renal profile (blood urea nitrogen (BUN) and creatinine), glucose, arterial blood gas analysis, and cerebrospinal fluid (CSF) analysis may be useful to exclude metabolic abnormalities. Diagnostic imaging studies such as a CT scan of the head to detect space-occupying lesions are often essential. Routine laboratory screens for drugs of abuse are not helpful in the management of the undifferentiated comatose adult patient. These tests will vary in type, sensitivity, and specificity in differing institutions. Although almost all institutions will use immunoassay technology to screen drugs of abuse, different techniques in these clinical settings limit the ability to adequately identify many agents. Most will detect phenobarbital and certain benzodiazepines while many other sedative-hypnotics go undetected (Chap. 7). Many benzodiazepines go undetected because they undergo significant metabolism that produces many differing active metabolites. The parent drug may not be found in urine specimens because of its presence in very low concentrations, while the patient may have significant symptoms due to the presence of multiple active metabolites. In addition, newer agents such as alprazolam and triazolam undergo minimal metabolism but are quite active at serum concentrations that may be too low to allow detection. Certain agents such as clonazepam and flunitrazepam that are 7-amino analogues may not be detected because most benzodiazepine screens only identify metabolites of 1,4-benzodiazepines such as oxazepam or desmethyldiazepam (Chap. 7).50 On the other hand, screening may be useful in pediatric populations, especially if there is concern for child abuse.13 Specific laboratory levels may be helpful (ie, levels of ethanol or phenobarbital) to confirm or disprove overdoses of an agent, particularly if the etiology of the clinical condition is uncertain. However, specific levels of sedative-hypnotics other than phenobarbital are not routinely performed in most hospitals. Therefore, specific levels of sedative-hypnotics other than phenobarbital are rarely helpful in guiding management. Abdominal radiographs may be helpful if chloral hydrate is suspected because chloral hydrate is radiopaque (Chap. 8). Although immediate identification of a particular sedative-hypnotic agent may be helpful in predicting the length of toxicity, it rarely affects the acute management of the patient. The exception may be for phenobarbital where urinary alkalization may alter management.

MANAGEMENT With increasing doses, sedative-hypnotics typically produce drowsiness, CNS depression, unconsciousness, respiratory depression, cardiovascular collapse, and finally death. Treatments have been targeted to limit this progression. Historically, analeptics and other arousal agents (Antidotes in Depth: Antiquated Antidotes) were used with limited success. Similar to the majority of poisoned patients who present with unstable vital signs, the vast majority of patients with severe overdoses of sedative-hypnotics who present with unstable vital signs respond well to supportive care. Deaths secondary to sedative-hypnotic overdoses are a result of

SEDATIVE-HYPNOTICS AGENTS

935

respiratory collapse and careful attention should be focused on monitoring and maintaining adequate airway and oxygenation. As in the case of all critically ill patients, the airway should be controlled and adequate ventilation should be maintained. Supplemental oxygen, respiratory support, and prevention of aspiration are the cornerstones of treatment because mortality of sedativehypnotic poisoning is secondary to respiratory failure. Hemodynamic instability is often a secondary or a delayed manifestation of sedative-hypnotic poisoning and typically follows respiratory collapse. Hypotensive patients should be resuscitated with volume expansion. Vasopressors should be used when patients do not respond to intravenous fluids or when there is evidence of pulmonary edema. There are significant concerns with regard to the development of lethal dysrhythmias from the use of -adrenergic agonists in the setting of chloral hydrate overdose, because chloral hydrate is metabolized to the active halogenated hydrocarbon, trichloroethanol. In the setting of cardiac dysrhythmias, judicious use of -adrenergic antagonists is proposed.22,68,179

Decontamination All patients with significant ingestions should receive activated charcoal. The use of multiple-dose activated charcoal (MDAC) may not be effective in all poisonings. The use of MDAC has been extensively studied for phenobarbital; MDAC increases elimination of phenobarbital by 50–80%.14,15,20,86,126,170 However, in the only controlled study, no difference could be demonstrated in outcome measures (time to extubation and length of hospitalization) in intubated patients with phenobarbital overdoses randomized to single-dose versus MDAC.143 Although inconclusive, after ensuring an adequately protected airway, multiple doses of activated charcoal have potential benefits and limited adverse risks or costs (Antidotes in Depth: Activated Charcoal). Although the efficacy of delayed orogastric lavage is controversial, orogastric lavage should be considered in patients who overdose with agents that may develop concretions, specifically, phenobarbital and meprobamate.88,156 There are no antidotes useful to counteract all sedative-hypnotic overdoses. Flumazenil, a competitive benzodiazepine antagonist, has been developed for benzodiazepines. However, the use of flumazenil has a poor risk/benefit ratio in patients who have an undifferentiated sedative-hypnotic overdose (Antidotes in Depth: Flumazenil). There are very few situations when a patient with a sedativehypnotic overdose will require extracorporeal methods of drug removal. The use of hemodialysis is exceptionally uncommon. Hemodialysis should be considered in patients with chloral hydrate overdoses who develop life-threatening cardiac manifestations and in patients with ingestions of extremely large quantities of phenobarbital and meprobamate who require prolonged intubation times. Because the lethality of sedative-hypnotics is associated with the agent’s ability to cause respiratory depression, asymptomatic patients can be downgraded to a lower level of care after a period of observation. Thus, patients who have been monitored in the intensive care unit (ICU) for a period of time (8–12 hours) without signs of respiratory depression can be transferred to a general medical floor. Long-acting agents, such as meprobamate and clonazepam, or agents that can have a significant enterohepatic cir-

936

PART D

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

culation, such as glutethimide, will necessitate 24 hours of observation (Chap. 104).

SPECIFIC AGENTS Barbiturates

X

O N

Y

N

Z

O O

steroids, doxycycline, estrogens, phenothiazines, quinidine, and theophylline. Agents such as valproic acid that compete for these hepatic cytochromes may also decrease phenobarbital metabolism. Toxicity is manifested initially by slurred speech, ataxia, lethargy, nystagmus, headache, and confusion. As toxicity becomes more severe, the depth of coma increases, and severely poisoned patients may become anesthetized with total loss of neurologic function. Shock may occur as a result of medullary depression, peripheral vasodilation, or impairment of myocardial contractility. Hypothermia and cutaneous bullae are often present.17,49 Early deaths caused by barbiturate ingestions are a result of respiratory arrest and cardiovascular collapse, while delayed deaths are a result of acute renal failure, pneumonia, pulmonary edema, cerebral edema, and multiorgan system failure.4,70

Benzodiazepines

R1 In 1903, barbital became the first commercially available barbiturate. Many other barbiturates have been developed since then. These agents are all derivatives of barbituric acid (2,4,6-trioxohexa-hydropyrimidine), which by itself has no CNS depressant properties. Various side chains at the X, Y, and Z sites influence the individual barbiturate’s lipophilicity, potency, and rate of elimination. Barbiturates with long side chains tend to have increased properties in all three areas. However, the observed clinical effects also depend on absorption, redistribution, and the presence or absence of active metabolites. For this reason, the durations of action of barbiturates (like those of benzodiazepines) do not correlate well with their biologic half-lives. This family of agents can be divided into four categories based on their elimination half-lives (Table 63–2). In contrast to the long-acting barbiturates, the ultrashort-, short-, and intermediateacting agents tend to be more lipid soluble and more protein bound; have a high pKa, a more rapid onset, and a shorter duration of action; and are almost completely metabolized in the liver. After ingestion, barbiturates are preferentially absorbed in the small intestine and are eliminated by hepatic and renal mechanisms. Typically, lipophilic barbiturates are protein bound and have less renal clearance. Renal excretion of unchanged drug can be significant for the long-acting barbiturates. Elimination of phenobarbital, a long-acting barbiturate with a relatively low pKa (7.24), can be influenced with urinary alkalinization. Alkalinization of the urine with sodium bicarbonate to maintain a urinary pH of 7.5–8.0 can increase the amount of phenobarbital excreted 5–10-fold. This procedure is ineffective for the short-acting barbiturates, as they have higher pKa values, are more protein bound, and are primarily metabolized by the liver with very little excretion by the kidneys (Chap. 6). Barbiturates (especially the shorter-acting barbiturates) can accelerate their hepatic inactivation by enzyme autoinduction. Barbiturate use results in a marked increase in the enzyme content of the hepatic smooth endoplasmic reticulum and an increased rate of metabolism for a number of drugs and endogenous substances. Phenobarbital induces various hepatic cytochromes in the P450 system with the greatest effects on CYP3A.90 A variety of drug interactions are reported following the use of barbiturates. As a result of enzyme induction, clinically significant interactions lead to increases in the metabolism of -adrenergic antagonists, cortico-

R2

N R7 N

R3

R4 R2 '

Since the initial introduction of chlordiazepoxide in 1961 for anxiety, and of diazepam for seizure control in 1963,50 benzodiazepines have become extremely popular. Benzodiazepines are used principally as anxiolytics and sedatives. Temazepam and triazolam are exceptions, and are used as hypnotics to produce sleep; clonazepam is the only benzodiazepine used as a chronic anticonvulsant agent and for the treatment of bipolar disorders. Benzodiazepines may rarely cause paradoxical psychological and CNS effects including nightmares, delirium, toxic psychosis, and transient global amnesia.18,19,52,118,129 The incidence and intensity of CNS adverse events increases with age.124 The benzodiazepines are structurally organic bases with a benzene and a seven-member diazepine moiety. Similar to barbiturates, various side chains at R1, R2, R2′, R3, R4, and R7 will influence potency, duration of action, metabolites, and rate of elimination. Benzodiazepines tend to be highly protein bound and lipophilic. They passively diffuse into the CNS, their main site of action. Because of their lipophilic nature, benzodiazepines are extensively metabolized via oxidation and conjugation in the liver prior to their renal elimination. Because they are mainly hepatically metabolized, the rate of elimination may not fluctuate in overdose.6 Many of the benzodiazepines have active metabolites that are produced in various parts of the body. For example, metabolites of chlorazepate are formed in the gastrointestinal (GI) tract, while metabolites of diazepam are formed primarily in the liver. A unique property of the benzodiazepine sedative-hypnotics is their relative safety even following substantial ingestion. The relatively safety of benzodiazepines is probably a result of their

CHAPTER 63

GABA-receptor properties.136 Unlike many other sedative-hypnotic agents, benzodiazepines do not open GABA channels independently at high tissue levels, and they do not result in “receptor desensitization,” in which receptors limit their rate of activity in the constant presence of an agonist. Most obtunded patients become arousable within 12–36 hours following a benzodiazepine overdose because of the development of acute tolerance.151 The duration of coma in elderly patients, however, may be prolonged. Benzodiazepines are not known to cause any specific systemic injury, and their long-term use has not been associated with specific organ toxicity. Deaths caused by benzodiazepine ingestions alone are extremely rare; deaths are usually secondary to combined overdoses.71,160 Supportive care is the mainstay of treatment. Tolerance to the sedative effects of the benzodiazepines occurs more rapidly than does tolerance to the antianxiety effects.110,150 Abrupt withdrawal following long-term use of benzodiazepines may precipitate a benzodiazepine withdrawal syndrome, which can be characterized by changes in perception, paraesthesias, headaches, tremors, and weight loss. Withdrawal from benzodiazepines is common and almost a third of long-term users manifest withdrawal.94 Alprazolam and lorazepam are associated with more severe withdrawal symptoms and more frequent recurrent symptoms as compared to chlordiazepoxide and diazepam.94,95 Withdrawal can also occur when a chronic user of a particular benzodiazepine is switched to another benzodiazepine with a different receptor activity.115 In acute overdoses, drugs-of-abuse screens are of very limited value as they can have difficulty in identifying benzodiazepines, leading to false-positive and false-negative results.43,50 Specific plasma concentrations of benzodiazepines also have no use in clinical management.44

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Chloral hydrate is currently used as a sedating agent for children prior to medical procedures in controlled situations.1,112 Several comprehensive studies of clinical and pharmacologic characteristics of chloral hydrate use in neonates and infants suggest that even single-dose administration may result in prolonged chloral hydrate, trichloroethanol, and trichloroacetic acid halflives.117,146 This latter metabolite was still detectable at 6 days postadministration. These factors may be of concern in neonates and those infants exposed to repetitive doses. Acute chloral hydrate poisoning causes other organ system toxicity atypical of the other sedative-hypnotics. Cardiac dysrhythmias appear to be the main cause of death.68 The compound reduces myocardial contractility, and increases myocardial sensitivity to catecholamines.23,29,167,179 Specifically, many halogenated hydrocarbons produce nonuniform changes in repolarization throughout the myocardium, predisposing to the development of reentrant circuits. A premature ventricular contraction, as occurs following release or injection of epinephrine, initiates this reentrant rhythm. Thus, persistent cardiac dysrhythmias (ventricular fibrillation, ventricular tachycardia, torsades de pointes) are common terminal events.68 Standard antidysrhythmic agents are often ineffective. -Adrenergic antagonists are currently considered the drug of choice for the treatment of most dysrhythmias secondary to chloral hydrate ingestions.22,23,181 Chloral hydrate can also cause GI toxicity and overdoses can produce nausea, vomiting, hemorrhagic gastritis, and, rarely, gastric and intestinal necrosis, leading to perforation and esophagitis with stricture formation.102,133,171 Chloral hydrate is radiopaque and can be detected on radiographs. Few hospital-based laboratories have the capability to rapidly detect chloral hydrate or its metabolites.

Ethchlorvynol Chloral Hydrate

Chloral hydrate (2,2,2,-trichloroethane-1,1-diol) belongs to the one of the oldest classes of pharmaceutical hypnotics, the chloral derivatives. This agent was introduced in 1832, and is still commonly used in the pediatric population. Chloral hydrate is well absorbed, although irritating to the GI tract. It has a wide tissue distribution, rapid onset of action, and rapid hepatic metabolism. Trichloroethanol, the first active metabolite, is lipid soluble and is responsible for the majority of chloral hydrate’s hypnotic effects. Chloral hydrate is metabolized by hepatic alcohol dehydrogenase (Fig. 63–1). Trichloroethanol has a plasma half-life of 4–12 hours and is metabolized to inactive trichloroacetic acid by alcohol and aldehyde dehydrogenases. It is then conjugated with glucuronide and excreted by the kidney as urochloralic acid. Less than 10% is excreted unchanged. This mechanism is inefficient in infants and neonates and the elimination half-lives of chloral hydrate and trichloroethanol are markedly increased in children younger than 2 years of age.

Ethchlorvynol (1-chloro-3-ethyl-penten-4-yl-3-ol) was introduced in 1955 as a substitute for barbiturates. It is rapidly absorbed and lipid soluble. It is primarily hepatically metabolized and has a half-life of 25 hours. However, because of its high lipophilicity, it is readily stored in adipose tissue. Thus, its half-life can exceed 100 hours in overdoses. It is unclear whether its major metabolite, ethynyl 3,4-diol, is active. Stomach contents often reveal a pinkish (500-mg capsules) or greenish (750-mg capsules) tinged content. In addition, because of its volatility, it produces a characteristic pungent plastic or vinyl-like odor on the breath. As a result of its formulation, extraction of the compound and intravenous injection is an alternative route of abuse. Acute pulmonary edema often rapidly occurred following intravenous injection.36Symptoms and signs of ethchlorvynol overdoses can resemble barbiturate overdoses. These include prolonged coma, hypothermia, and bullous lesions. These lesions may be scattered and not confined to pressure points, and ethchlorvynol may be found in blister fluid.58 Prolonged coma is a characteristic of ethchlorvynol poisoning.165 Although hemodialysis increases the rate of removal of the drug

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from the plasma, complete plasma clearance during a 4–6-hour hemodialysis has little impact on total body clearance because of the significant lipid solubility and volume of distribution (4 L/kg). Hemoperfusion has been suggested as a better choice than hemodialysis, but either approach is rarely, if ever, indicated.89

Glutethimide

rapidly and completely absorbed from the GI tract within 2–3 hours. It is highly protein bound (70–90%), and almost exclusively metabolized in the liver to 4-hydroxymethaqualone, as well as to numerous other hydroxy metabolites.24,81 Unlike many of the other sedative-hypnotics, hyperreflexia, clonus, and significant muscular hyperactivity can occur. Paresthesias and peripheral neuropathies can be a residual effect following overdose.2,3

Methyprylon

Glutethimide (3-ethyl-3-phenyl-2 l-2,6-piperidinedione) was introduced in 1954 as a substitute for barbiturates. It is poorly watersoluble and is slowly and erratically absorbed from the GI tract. Absorption may be significantly enhanced by coingestion of ethanol. Because of its lipophilic nature, it concentrates in fat-containing tissues. It is metabolized in the liver, and more than 14 metabolites have been identified, some of which are biologically active and may contribute to its toxicity.38 High lipid solubility and delayed absorption may explain the cyclic variation in CNS depression that occurs in acute overdoses. In addition, the enterohepatic circulation of metabolites, especially of 4-hydroxyglutethimide (4-HG), which is more potent than the parent compound, may explain the fluctuating clinical course that occurs in severely intoxicated patients. Other active metabolites include 2-phenylglutarimide and γ-butyrolactone (an analogue of GHB). Profound, prolonged coma with a fluctuating mental status is the hallmark of glutethimide overdose. Unlike many of the other sedative-hypnotic agents, glutethimide can result in diverse anticholinergic symptoms such as dilated pupils.69 It is also reported to produce thick and tenacious bronchial secretions with impairment of ventilation.32 Toxic psychosis, seizures, cerebellar ataxia, and peripheral neuropathy are associated with the prolonged use of glutethimide.32

Methaqualone

Methaqualone (2-3-disubstituted quinazoline) was introduced in 1956 as another substitute for barbiturates. It has anticonvulsant, anesthetic, antihistaminic, and antispasmodic characteristics. Its effects as a tranquilizer and mood “elevator” have led to extensive abuse and led to its withdrawal from the market. The drug is

Methyprylon (3,3-diethyl-5-methyl-2,4-piperidinedione) was introduced in the 1950s and is used only as a hypnotic. It is rapidly absorbed from the gastrointestinal tract and is almost entirely hepatically metabolized by oxidation and dehydrogenation. Methyprylon is known to stimulate the hepatic microsomal enzyme system, as well as -aminolevulinic acid synthetase; therefore, it should be avoided in patients with intermittent porphyria. Because methyprylon is water soluble, hemodialysis has been used in severe cases, but this approach is rarely, if ever, indicated.35,142

Meprobamate/Carisoprodol

Meprobamate (2-methyl-2-n-propyl-propane-1,3-diol-dicarbamate) was introduced in 1950 and is used for its muscle-relaxant characteristics. Carisoprodol, which was introduced in 1955, is metabolized to meprobamate. The propanediol carbamates, typified by meprobamate, have pharmacologic effects on the GABAA receptor similar to those of the barbiturates. They are both rapidly absorbed from the GI tract. The drug is metabolized in the liver to inactive hydroxylated and glucuronidated metabolites that are excreted almost exclusively by the kidney. Of all the nonbarbiturate tranquilizers, meprobamate is the most likely to produce euphoria.84,85 Large masses or bezoars of pills have been noted in the stomach at autopsy.156 Thus, in significant meprobamate ingestion, orogastric lavage with a large-bore tube and multiple-dose activated charcoal may be indicated. Whole-bowel irrigation may be helpful if multiple pills or small concretions are noted. Because patients can experience recurrent toxic manifestations as a result of concretion formation and delayed absorption, careful monitoring of the clinical course is essential even following initial improvement.

CHAPTER 63

Bromides Bromides were previously used as a “nerve tonic” and headache remedy. Although methylated bromides are still extensively used in the fumigation of soil and warehouses, and for fruits and vegetables, pharmaceutical bromides have largely disappeared from the US pharmaceutical market, and acute bromide intoxication is rare in the United States. Cases continue to occur in immigrants and travelers from other countries where bromides are still therapeutically employed. The drug is irritating to the GI tract and it is difficult to ingest and retain a sufficient amount to achieve a toxic level without vomiting. Bromide has a long plasma half-life (12 days) and toxicity typically occurs over a period of time as tissue levels increase. Bromide and chloride ions have a similar distribution pattern in the extracellular fluid. It is postulated that the preferential excretion of chloride results from the bromide ion moving across membranes slightly more rapidly than the chloride ion, with the result that it is more quickly reabsorbed in the renal tubules from the glomerular filtrate than is the chloride ion. Although osmolar equilibrium persists, CNS function is progressively impaired by a poorly understood mechanism, with resulting inappropriateness of behavior, headache, apathy, irritability, confusion, muscle weakness, anorexia, weight loss, thickened speech, psychotic behavior, tremulousness, ataxia, and eventually coma.30,182 Delusions and hallucinations can occur. Bromide can also lead to hypertension, increased intracranial pressure, and papilledema. The chronic use of bromides can lead to dermatologic changes with the hallmark characteristic of a facial acneiform rash.75,168 Toxicity with bromides during pregnancy may lead to fetal accumulation of bromide in the fetus.141 A spurious hyperchloridemia may be found as a result of bromide’s interference with the chloride assay (Chap. 24).

Zolpidem

SEDATIVE-HYPNOTICS AGENTS

939

dose, no biologic or electrocardiographic abnormalities have been reported.62 Flumazenil has been used to reverse the effects of the drug,105,178 although withdrawal has been documented with abrupt discontinuation.176 Deaths have occurred when zolpidem was taken in large amounts with other central nervous system depressants.62

Zaleplon

NC N N

N

H3 C

C

N

CH 2 CH3

O Zaleplon (N3,3 cyanopyrazolo-pyrmidinyl-phenyl-ethylacetamide) is a pyrazolopyrimidine hypnotic agent. In a manner similar to zolpidem, it binds to the
1 subunit on the GABAA receptor and has many comparable clinical effects.74 Although structurally different than benzodiazepines, benzodiazepine sedative properties are demonstrated in animals.172 Animals given high doses chronically show dependence, and flumazenil can precipitate benzodiazepinelike withdrawal symptoms.9 There have been no reports of the development of tolerance with zolpidem and zaleplon.125

SHORT-TERM ANESTHETIC/ SEDATIVE-HYPNOTICS Propofol

Zolpidem (N,N,6-trimethyl-2-p-toyl-imidazopyridine-3-acetamide L-(+)-tartrate (2:1)) is an imidazopyridine hypnotic agent. Although zolpidem is structurally unrelated to the benzodiazepines, it binds preferentially to the type I benzodiazepine receptor subtype in the brain, specifically at the
1 GABAA subunit.45 Unlike benzodiazepines that prolong the first two stages of sleep and shorten stages 3 and 4 of rapid eye movement (REM) sleep, zolpidem has little effect on the stages of sleep. Because of its receptor selectivity, there appears to be a minimal effect at other sites on the GABA receptor that mediate anxiolytic, anticonvulsant, or muscle-relaxant effects.98 It is suggested to have less abuse and addiction potential than benzodiazepines.172 In overdoses, drowsiness and CNS depression are common, but coma and respiratory depression are exceptionally rare. Even at 40 times the therapeutic

Propofol (2,6-diisopropylphenol) is a rapidly acting intravenous sedative-hypnotic active at GABAA receptors. Propofol may also be active presynaptically, causing GABA release131 and inhibiting dopamine release.155 It is used for either the induction or maintenance of general anesthesia. Propofol is highly lipid soluble and therefore crosses the blood-brain barrier rapidly. Onset of anesthesia usually occurs in less than 1 minute with duration of action lasting 3–8 minutes because of its rapid redistribution from the central nervous system.50

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Propofol causes dose-related respiratory depression, and transient apnea may occur. The drug may also decrease systemic arterial pressure, and may cause myocardial depression. Although propofol typically does not cause dysrhythmias or myocardial ischemia, atropine-sensitive bradydysrhythmias have been noted, specifically sinus bradycardia and Mobitz type I atrioventricular block.166,175 Prolonged infusions of propofol are associated with fatal fatty myocardial failure in children and young adults.137 It is also associated with the development of profound lactic acidosis, especially in children.72 The unique nature of the carrier base, a milky soybean emulsion formulation, is associated with multiple adverse events. This carrier is a fertile medium for many organisms, such as enterococcal, pseudomonal, staphylococcal, streptococcal, and candidal strains. In 1990, the Centers for Disease Control (CDC) noted an infectious outbreak associated with Staphylococcus aureus-contaminated propofol. This carrier base is also associated with hypertriglyceridemia,51,93,107 abnormalities in blood coagulability and platelet function,8,40,76 and histamine-mediated anaphylactoid reactions.47,100,116

Etomidate

in the belief that GHB use was associated with release of growth hormone. Its use rapidly spread to people seeking its mood-altering and sedative-hypnotic effects. The popularity of this drug also arose at the same time as the popularity of the Internet. Because this is a relatively simple structure that is easily produced, many recipes and sources for supplies developed on the Internet. Obtaining GHBlike compounds, as well as methods for producing these compounds, were readily available, which led to a new wave of drugs of abuse. This drug has been labeled as the “Internet Drug” and “Date Rape Drug.” In the early 1990s, the Food and Drug Administration (FDA) began to restrict the commercial availability of GHB. However, similar to designer amphetamine use of the 1970s and 1980s, chemical analogues to GHB were popularized. Drugs such as γbutyrolactone (GBL), butanediol, and γ-valerolactone were promoted as alternatives. These were either analogues or precursors of GBH with similar effects and toxicities (Fig. 63–2). However, unlike the designer amphetamines, these analogues did not fall under the Controlled Substance Analogue Enforcement Act (the Designer Drug Law) that prohibits the commercial availability of analogues of illicit or “narcotic” agents. After ingestion, GHB is rapidly absorbed and quickly crosses the blood-brain barrier. It is not protein bound and is rapidly metabolized and excreted through the lungs.16 It has specific binding sites and selective brain distribution with the highest concentration in the basal ganglia. It indirectly interacts with GABAB and opioid receptors.56,64,82,108 Because it is structurally similar to GABA, it is unclear whether GHB or its metabolites (see Fig. 63–2) possess the greatest activity.53,73 Within the CNS, it causes increases in growth hormone and blunts central dopamine release. GHB may increase proenkephalin compounds.153 Clinically, it modulates sleep by increasing slow-wave sleep and promoting REM sleep.16,113 With larger doses, an anesthetic state occurs with deep

Etomidate is a nonbarbiturate hypnotic agent without analgesic properties that is primarily used as an induction agent. It is believed to be active at the GABAA receptor. The onset of action is less than 1 minute and its duration is less than 5 minutes. Etomidate has minimal effect on cardiac function, although rare cases of hypotension have been reported.65–67,164 It has unique proconvulsant and anticonvulsant properties. Involuntary muscle movements are common during induction. This may be caused by etomidate interaction with glycine receptors at the level of the spinal cord.39,127,128 Etomidate depresses adrenal production of cortisol and aldosterone even after a single dose.152,173,174 This adverse effect is associated with an increase in mortality with long-term use.177

GHB (γ-Hydroxybutyrate) GHB is a naturally occurring substance produced in mammalian brains. It has been described as a neurotransmitter and a neuromodulator with a four-carbon structure similar to GABA.31 Medicinally, it has been used as an anesthetic, as a treatment for narcolepsy, and as a treatment for ethanol and opioid withdrawal.16 GHB has gained popularity as a recreational drug of abuse and for its perception as a muscle-enhancing agent. Although GHB has been available since the 1960s, its popularity dramatically increased in the 1980s with use by “bodybuilders”

Figure 63–2. The metabolism of analogues and precursors of gammaamino butyric acid. ADH, Alcohol dehydrogenase; AIDH, Aldehyde Dehydrogenase; SSAD, SSA dehydrogenase.

CHAPTER 63

hypnosis, limited analgesia and amnesia, and no muscle relaxation. A characteristic random myoclonic motion of the extremities and face is often noted. With its increasing popularity, reports of significant overdoses and death first appeared in the 1990s. Patients usually presented with profound CNS and respiratory depression. In a case series of 88 patients, more than a third of GHB abusers also developed an unexplained bradycardia.34 However, unlike many other sedativehypnotics, GHB overdoses were characterized by episodes of combativeness interspersed with episodes of obtundation.106 Significant arousal and agitation occurred when intubation was attempted.106 The majority of patients rapidly recover without sequelae with solely supportive care, usually within 6 hours.34,106 Although GHB indirectly interacts with opioid and GABA receptors, reversal agents such as naloxone and flumazenil are not consistently effective in arousing patients in the clinical setting,106 nor animals in the laboratory setting.42,154 The actual mechanisms whereby flumazenil and naloxone interact with GHB remain unclear. Flumazenil inhibits GHB-induced release of growth hormone and may reverse other effects of GHB, including the anxiolytic and neuromuscular effects.154 Naloxone blunts the GHB-induced inhibition of central dopamine release.54,55 In controlled clinical trials of GBH for narcolepsy, withdrawal has not been documented. However, reports of withdrawal in patients who recreationally use GHB have been documented. Similar to withdrawal from GABAergic agents, anxiety, insomnia, disorientation, and auditory and visual hallucinations are reported.60,61 However, unlike withdrawal from GABAergic agents, deaths have not been reported.37

SUMMARY Sedative-hypnotics are among the leading causes of deaths caused by poisoning. Patients with sedative-hypnotic overdoses often present with the primary manifestation of CNS depression; however, death is typically a result of respiratory depression. Careful monitoring and supportive care are the cornerstones of treatment. Specific antidotes, such as flumazenil, and treatments, such as hemoperfusion, or hemodialysis, are rarely indicated.

ACKNOWLEDGMENT Harold Osborn contributed to this chapter in a previous edition.

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55. Feigenbaum JJ, Howard SG: Naloxone reverses the inhibitory effect of gamma-hydroxybutyrate on central DA release in vivo in awake animals: A microdialysis study. Neurosci Lett 1996;218:5–8. 56. Feigenbaum JJ, Simantov R: Lack of effect of gamma-hydroxybutyrate on mu, delta and kappa opioid receptor binding. Neurosci Lett 1996;212:5–8. 57. Finkle BS, McCloskey KL, Goodman LS: Diazepam and drug-associated deaths. A survey in the United States and Canada. JAMA 1979; 242:429–434. 58. Flemenbaum A, Gunby B: Ethchlorvynol (Placidyl) abuse and withdrawal (review of clinical picture and report of 2 cases). Dis Nerv Syst 1971;32:188–192. 59. Fujita M, Woods SW, Verhoeff NP, et al: Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. Eur J Pharmacol 1999;368:161–172. 60. Galloway GP, Frederick SL, Staggers F Jr: Physical dependence on sodium oxybate [letter]. Lancet 1994;343:357. 61. Galloway GP, Frederick SL, Staggers FE Jr, et al: Gamma-hydroxybutyrate: An emerging drug of abuse that causes physical dependence [see comments]. Addiction 1997;92:89–96. 62. Garnier R, Guerault E, Muzard D, et al: Acute zolpidem poisoning— Analysis of 344 cases. J Toxicol Clin Toxicol 1994;32:391–404. 63. Gavish M, Bachman I, Shoukrun R, et al: Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev 1999;51:629–650. 64. Gerra G, Caccavari R, Fontanesi B, et al: Naloxone and metergoline effects on growth hormone response to gamma-hydroxybutyric acid. Int Clin Psychopharmacol 1995;10:245–250. 65. Gooding JM, Corssen G: Effect of etomidate on the cardiovascular system. Anesth Analg 1977;56:717–719. 66. Gooding JM, Corssen G: Etomidate: An ultrashort-acting nonbarbiturate agent for anesthesia induction. Anesth Analg 1976;55: 286–289. 67. Gooding JM, Weng JT, Smith RA, et al: Cardiovascular and pulmonary responses following etomidate induction of anesthesia in patients with demonstrated cardiac disease. Anesth Analg 1979;58: 40–41. 68. Graham SR, Day RO, Lee R, et al: Overdose with chloral hydrate: A pharmacological and therapeutic review [see comments]. Med J Aust 1988;149:686–688. 69. Greenblatt DJ, Allen MD, Harmatz JS, et al: Correlates of outcome following acute glutethimide overdosage. J Forensic Sci 1979;24: 76–86. 70. Greenblatt DJ, Allen MD, Harmatz JS, et al: Overdosage with pentobarbital and secobarbital: Assessment of factors related to outcome. J Clin Pharmacol 1979;19:758–768. 71. Greenblatt DJ, Allen MD, Noel BJ, et al: Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther 1977;21:497–514. 72. Hatch DJ: Propofol-infusion syndrome in children [see comments]. Lancet 1999;353:1117–1118. 73. Hechler V, Ratomponirina C, Maitre M: γ-Hydroxybutyrate conversion into GABA induces displacement of GABAB binding that is blocked by valproate and ethosuximide. J Pharmacol Exp Ther 1997; 281:7537–7560. 74. Heydorn WE: Zaleplon—A review of a novel sedative hypnotic used in the treatment of insomnia. Expert Opin Investig Drugs 2000;9: 841–858. 75. Hezemans-Boer M, Toonstra J, Meulenbel J, et al: Skin lesions due to exposure to methyl bromide. Arch Dermatol 1988;124:917–921. 76. Hirakata H, Nakamura K, Yokubol B, et al: Propofol has both enhancing and suppressing effects on human platelet aggregation in vitro. Anesthesiology 1999;91:1361–1369. 77. Hoehns JD, Perry PJ: Zolpidem: A nonbenzodiazepine hypnotic for treatment of insomnia [published erratum appears in Clin Pharm 1993;12:881] [see comments]. Clin Pharm 1993;12:814–828. 78. Hu XJ, Ticku MK: Chronic benzodiazepine agonist treatment produces functional uncoupling of the gamma-aminobutyric acid-benzodiazepine receptor ionophore complex in cortical neurons. Mol Pharmacol 1994;45:618–625.

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79. Humphrey D: Final Exit. Hemlock Society, Denver, CO, 1991. 80. Hutchinson MA, Smith PF, Darlington CL: The behavioural and neuronal effects of the chronic administration of benzodiazepine anxiolytic and hypnotic drugs. Prog Neurobiol 1996;49:73–97. 81. Ionescu-Pioggia M, Bird M, Orzack MH, et al: Methaqualone. Int Clin Psychopharmacol 1988;3:97–109. 82. Ito Y, Ishige K, Zaitsu E, et al: γ-Hydroxybutyric acid increases intracellular Ca2+ concentration and nuclear cyclic AMP-responsive element- and activator protein 1 DNA-binding activities through GABAB receptor in cultured cerebellar granule cells. J Neurochem 1995;65:75–83. 83. Jacob MK, White RE: Diazepam, gamma-aminobutyric acid, and progesterone open K(+) channels in myocytes from coronary arteries. Eur J Pharmacol 2000;403:209–219. 84. Jacobsen D, Frederichsen PS, Knutsen KM, et al: Clinical course in acute self-poisonings: A prospective study of 1125 consecutively hospitalised adults. Hum Toxicol 1984;3:107–116. 85. Jacobsen D, Frederichsen PS, Knutsen KM, et al: A prospective study of 1212 cases of acute poisoning: General epidemiology. Hum Toxicol 1984;3:93–106. 86. Jacobsen D, Wiik-Larsen E, Dahl T, et al: Pharmacokinetic evaluation of haemoperfusion in phenobarbital poisoning. Eur J Clin Pharmacol 1984;26:109–112. 87. Jaffe JH, Martin WR: Opioid analgesics and antagonists. In: Gilman AG, Goodman LS, Gilman A, eds: The Pharmacological Basis of Therapeutics. 6th edition. New York, Macmillan, 1980, pp. 513–514. 88. Johanson WG Jr: Massive phenobarbital ingestion with survival. JAMA 1967;202:1106–1107. 89. Kathpalia SC, Haslitt JH, Lim VS: Charcoal hemoperfusion for treatment of ethchlorvynol overdose. Artif Organs 1983;7: 246–248. 90. Kemper B: Regulation of cytochrome P450 gene transcription by phenobarbital. Prog Nucleic Acid Res Mol Biol 1998;61:23–64. 91. Kuhlmann AC, Guilarte TR: The peripheral benzodiazepine receptor is a sensitive indicator of domoic acid neurotoxicity. Brain Res 1997;751:281–288. 92. Kuhlmann AC, Guilarte TR: Regional and temporal expression of the peripheral benzodiazepine receptor in MPTP neurotoxicity. Toxicol Sci 1999;48:107–116. 93. Kunst G, Bohrer H: Serum triglyceride levels and propofol infusion. Anaesthesia 1995;50:1101. 94. Lader M: Anxiolytic drugs: Dependence, addiction and abuse. Eur Neuropsychopharmacol 1994;4:85–91. 95. Lader M: Biological processes in benzodiazepine dependence. Addiction 1994;89:1413–1418. 96. Laine GA, Hossain SM, Solis RT, et al: Polyethylene glycol nephrotoxicity secondary to prolonged high-dose intravenous lorazepam. Ann Pharmacother 1995;29:1110–1114. 97. Lallement G, Delamanche IS, Pernot-Marino I, et al: Neuroprotective activity of glutamate receptor antagonists against somaninduced hippocampal damage: Quantification with an omega 3 site ligand. Brain Res 1993;618:227–237. 98. Langtry HD, Benfield P: Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1990;40:291–313. 99. Lavoie J, Layrargues GP, Butterworth RF: Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology 1990;11:874–878. 100. Laxenaire MC, Mata-Bermejo E, Moneret-Vautrin DA, et al: Lifethreatening anaphylactoid reactions to propofol (Diprivan). Anesthesiology 1992;77:275–280. 101. Le Fur G, Mestre M, Carriot T, et al: Pharmacology of peripheral type benzodiazepine receptors in the heart. Prog Clin Biol Res 1985; 192:175–186. 102. Lee DC, Vassalluzzo C: Acute gastric perforation in a chloral hydrate overdose [letter]. Am J Emerg Med 1998;16:545–546.

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103. Leong DK, Le O, Oliva L, et al: Increased densities of binding sites for the “peripheral-type” benzodiazepine receptor ligand [3H]PK11195 in vulnerable regions of the rat brain in thiamine deficiency encephalopathy. J Cereb Blood Flow Metab 1994;14: 100–105. 104. Levy ML, Aranda M, Zelman V, et al: Propylene glycol toxicity following continuous etomidate infusion for the control of refractory cerebral edema. Neurosurgery 1995;37:363–369; discussion 369–371. 105. Lheureux P, Debailleul G, De Witte O, et al: Zolpidem intoxication mimicking narcotic overdose: Response to flumazenil. Hum Exp Toxicol 1990;9:105–107. 106. Li J, Stokes SA, Woeckener A: A tale of novel intoxication: seven cases of gamma-hydroxybutyric acid overdose [see comments]. Ann Emerg Med 1998;31:723–728. 107. Lindholm M: Critically ill patients and fat emulsions. Minerva Anestesiol 1992;58:875–879. 108. Lingenhoehl K, Brom R, Heid J, et al: Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors. Neuropharmacology 1999;38:1667–673. 109. Lorente P, Lacampagne A, Pouzeratte Y, et al: γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes. Proc Natl Acad Sci U S A 2000;97:8664–8669. 110. Lucki I, Rickels K: The effect of anxiolytic drugs on memory in anxious subjects. Psychopharmacol Ser 1988;6:128–139. 111. Madden TE, Johnson SW: Gamma-hydroxybutyrate is a GABAB receptor agonist that increases a potassium conductance in rat ventral tegmental dopamine neurons. J Pharmacol Exp Ther 1998;287: 261–265. 112. Malis DJ, Burton DM: Safe pediatric outpatient sedation: The chloral hydrate debate revisited. Otolaryngol Head Neck Surg 1997;116: 535–537. 113. Mamelak M, Escriu JM, Stokan O: The effects of gamma-hydroxybutyrate on sleep. Biol Psychiatry 1977;12:273–288. 114. Marazziti D, Rotondo A, Martini C, et al: Changes in peripheral benzodiazepine receptors in patients with panic disorder and obsessivecompulsive disorder. Neuropsychobiology 1994;29:8–11. 115. Marks J: Techniques of benzodiazepine withdrawal in clinical practice. A consensus workshop report. Med Toxicol Adverse Drug Exp 1988;3:324–333. 116. Marone G, Stellato C, Mastronardi P, et al: Mechanisms of activation of human mast cells and basophils by general anesthetic drugs. Ann Fr Anesth Reanim 1993;12:116–125. 117. Marti-Bonmati L, Ronchera-Oms CL, Casillas C, et al: Randomised double-blind clinical trial of intermediate- versus high-dose chloral hydrate for neuroimaging of children. Neuroradiology 1995;37: 687–691. 118. McKinnon NE: Triazolam intoxication [letter]. Can Med Assoc J 1982;126:893–894. 119. Mehta AK, Ticku MK: An update on GABAA receptors. Brain Res Brain Res Rev 1999;29:196–217. 120. Mestre M, Belin C, Uzan A, et al: Modulation of voltage-operated, but not receptor-operated, calcium channels in the rabbit aorta by PK 11195, an antagonist of peripheral-type benzodiazepine receptors. J Cardiovasc Pharmacol 1986;8:729–734. 121. Mestre M, Bouetard G, Uzan A, et al: PK 11195, an antagonist of peripheral benzodiazepine receptors, reduces ventricular arrhythmias during myocardial ischemia and reperfusion in the dog. Eur J Pharmacol 1985;112:257–260. 122. Mestre M, Carriot T, Belin C, et al: Electrophysiological and pharmacological evidence that peripheral type benzodiazepine receptors are coupled to calcium channels in the heart. Life Sci 1985;36: 391–400. 123. Mestre M, Carriot T, Neliat G, et al: PK 11195, an antagonist of peripheral type benzodiazepine receptors, modulates Bay K8644 sensitive but not beta- or H2-receptor sensitive voltage operated calcium channels in the guinea pig heart. Life Sci 1986;39:329–339.

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124. Meyer BR: Benzodiazepines in the elderly. Med Clin North Am 1982;66:1017–1035. 125. Mitler MM: Nonselective and selective benzodiazepine receptor agonists—Where are we today? Sleep 2000;23(Suppl 1):S39–S47. 126. Modi NB, Veng-Pedersen P, Wurster DE, et al: Phenobarbital removal characteristics of three brands of activated charcoals: A system analysis approach. Pharm Res 1994;11:318–323. 127. Modica PA, Tempelhoff R, White PF: Pro- and anticonvulsant effects of anesthetics (Part I). Anesth Analg 1990;70:303–315. 128. Modica PA, Tempelhoff R, White PF: Pro- and anticonvulsant effects of anesthetics (Part II). Anesth Analg 1990;70:433–444. 129. Morris HH, dEstes ML: Traveler’s amnesia. Transient global amnesia secondary to triazolam. JAMA 1987;258:945–946. 130. Mullins ME: First-degree atrioventricular block in alprazolam overdose reversed by flumazenil. J Pharm Pharmacol 1999;51:367–370. 131. Murugaiah KD, Hemmings HC Jr: Effects of intravenous general anesthetics on [3H]GABA release from rat cortical synaptosomes. Anesthesiology 1998;89:919–928. 132. Nudmamud S, Siripurkpong P, Chindaduangratana C, et al: Stress, anxiety and peripheral benzodiazepine receptor mRNA levels in human lymphocytes. Life Sci 2000;67:2221–2231. 133. Ogino K, Hobara T, Kobayashi H, et al: Gastric mucosal injury induced by chloral hydrate. Toxicol Lett 1990;52:129–133. 134. Olkkola KT, Backman JT, Neuvonen PJ: Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994;55:481–485. 135. Olson JM, Ciliax BJ, Mancini WR, et al: Presence of peripheral-type benzodiazepine binding sites on human erythrocyte membranes. Eur J Pharmacol 1988;152:47–53. 136. Orser BA, McAdam LC, Roder S, et al: General anaesthetics and their effects on GABA(A) receptor desensitization. Toxicol Lett 1998;100–101:217–224. 137. Parke TJ, Stevens JE, Rice AS, et al: Metabolic acidosis and fatal myocardial failure after propofol infusion in children: Five case reports [see comments]. BMJ 1992;305:613–616. 138. Patel PM, Goskowicz RL, Drummond JC, et al: Etomidate reduces ischemia-induced glutamate release in the hippocampus in rats subjected to incomplete forebrain ischemia. Anesth Analg 1995;80: 933–939. 139. Pavese N, Giannaccini G, Betti L, et al: Peripheral-type benzodiazepine receptors in human blood cells of patients affected by migraine without aura. Neurochem Int 2000;37:363–368. 140. Peoples RW, Weight FF: Trichloroethanol potentiation of gammaaminobutyric acid-activated chloride current in mouse hippocampal neurones. Br J Pharmacol 1994;113:555–563. 141. Pleasure JR, Blackburn MG: Neonatal bromide intoxication: Prenatal ingestion of a large quantity of bromides with transplacental accumulation in the fetus. Pediatrics 1975;55:503–506. 142. Polin RA, Henry D, Pippinger CE: Peritoneal dialysis for severe methyprylon intoxication. J Pediatr 1977;90:831–833. 143. Pond SM, Olson KR, Osterloh JD, et al: Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA 1984;251:3104–3108. 144. Potokar J, Coupland N, Wilson S, et al: Assessment of GABA(A) benzodiazepine receptor (GBzR) sensitivity in patients on benzodiazepines. Psychopharmacology (Berl) 1999;146:180–184. 145. Reed MD, Blumer JL: Propofol bashing: The time to stop is now! Crit Care Med 1996;24:175–176. 146. Reimche LD, Sankaran K, Hindmarsh KW, et al: Chloral hydrate sedation in neonates and infants—Clinical and pharmacologic considerations. Dev Pharmacol Ther 1989;12:57–64. 147. Reynolds C: Alternatives to barbiturates. Oral Health 1966;56:253. 148. Reynolds HN, Teiken P, Regan ME, et al: Hyperlactatemia, increased osmolar gap, and renal dysfunction during continuous lorazepam infusion. Crit Care Med 2000;28:1631–1634.

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179. White JF, Carlson GP: Epinephrine-induced cardiac arrhythmias in rabbits exposed to trichloroethylene: Role of trichloroethylene metabolites. Toxicol Appl Pharmacol 1981;60:458–465. 180. Wiley CC, Wiley JF 2nd: Pediatric benzodiazepine ingestion resulting in hospitalization. J Toxicol Clin Toxicol 1998;36:227–231. 181. Zahedi A, Grant MH, Wong DT: Successful treatment of chloral hydrate cardiac toxicity with propranolol. Am J Emerg Med 1999;17: 490–491. 182. Zatuchni J, Hong K: Methyl bromide poisoning seen initially as psychosis. Arch Neurol 1981;38:529–530. 183. Zavala F: Benzodiazepines, anxiety, and immunity. Pharmacol Ther 1997;75:199–216. 184. Zhu H, Cottrell JE, Kass IS: The effect of thiopental and propofol on NMDA- and AMPA-mediated glutamate excitotoxicity. Anesthesiology 1997;87:944–951.

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ANTIDOTES IN DEPTH

Flumazenil

cule to act as potential tranquilizers. Hunkeler attempted to produce benzodiazepines with potent anxiolytic and anticonvulsant activity and diminished sedative and muscle-relaxing properties. Testing revealed that these derivatives had high in vitro binding affinities but lacked in vivo activity. An inability to enter the central nervous system was considered as an explanation for this discordance. During an experiment that attempted to demonstrate CNS penetration for these derivatives, it was noted that when diazepam was given to incapacitate the animals it surprisingly had a very weak effect. This lack of potency led to the discovery of a benzodiazepine antagonist. Further modifications led to the synthesis of RO-15–1788, flumazenil.

Mary Ann Howland Flumazenil is a competitive benzodiazepine antagonist. It has no role in the unknown overdose because seizures and dysrhythmias may occur when the effects of a benzodiazepine are reversed in a mixed overdose. Flumazenil has the potential to induce benzodiazepine withdrawal symptoms, including seizures in patients who are benzodiazepine tolerant. Flumazenil does not reverse the respiratory depression induced by intravenous benzodiazepines, but does reverse the central nervous system (CNS) depression. Flumazenil is ideal for the few patients who are naïve to benzodiazepine and who overdose solely on a benzodiazepine. Because the duration of effect of flumazenil is shorter than that of most benzodiazepines, repeat doses may be necessary and vigilance is warranted. Flumazenil has no role in the management of ethanol intoxication and its role in the treatment of hepatic encephalopathy is under study. Recent case reports raise the possibility of a role for flumazenil for patients with paradoxical reactions to therapeutic doses of midazolam. Flumazenil is not expected to be effective in overdoses such as baclofen in which a benzodiazepine receptor is not involved.9 However, it is effective for overdoses of zolpidem, an imidazopyridine derivative that interacts with ω1 receptors, a subclass of central benzodiazepine receptors.32,41

PHARMACOLOGY Flumazenil is a water-soluble benzodiazepine analogue with a molecular weight of 303 daltons. It is a competitive antagonist with very weak agonist properties at the benzodiazepine receptor. The benzodiazepine receptor modulates the effect of GABA on the GABAA receptor by increasing the frequency of opening of the Cl channel, leading to hyperpolarization. Agonists such as diazepam stimulate the benzodiazepine receptor to produce anxiolytic, anticonvulsant, sedative, amnestic, and muscle-relaxant effects at low doses and hypnosis at high doses. Inverse agonists stimulate the benzodiazepine receptor and result in the opposite effects: anxiety, agitation, and seizures. Antagonists, such as flumazenil, competitively occupy the benzodiazepine receptor without causing any functional change and without allowing an agonist or inverse agonist access to the receptor. It has been suggested that the zero set point of intrinsic activity may be influenced by the activity of the GABA system or by chronic treatment with benzodiazepines.18 Positron emission tomography (PET) investigations reveal that 1.5 mg of flumazenil leads to an initial receptor occupancy of 55%, whereas 15 mg causes almost total blockade of benzodiazepine receptor sites.45 The structures of flumazenil, diazepam, and midazolam are shown in the figure. Table 63–4 summarizes the physiochemical and pharmacokinetic properties of flumazenil.28

HISTORY Haefely and Hunkeler’s initial work on synthesis of chlordiazepoxide led to an attempt to develop benzodiazepine derivatives that would act as antagonists.23 This endeavor was initially unsuccessful, so they investigated the promising γ-aminobutyric acid (GABA) hypothesis of benzodiazepine mechanism of action. In 1977, the then-new technique of radioligand binding identified specific high-affinity benzodiazepine binding sites. Other investigators had simultaneously isolated a product produced by a Streptomyces species that had the basic 1,4-benzodiazepine structure; subsequently, synthetic compounds were derived from this mole-

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TABLE 63–4. Physicochemical and Pharmacologic Properties of Flumazenil pKa Partition coefficient at pH 7.4 Volume of distribution Distribution half-life (t1/2α) Metabolism Elimination Protein binding Half-life (t1/2β) Onset of action Duration of action

Weak base 14 (octanol/aqueous PO4 buffer) 1.06 L/kg ≤5 minutes Hepatic: three inactive metabolites High clearance First order 54–64% 53 minutes 1–2 minutes Dependent on dose and elimination of benzodiazepine, time interval, dose of flumazenil, and hepatic function

Volunteer Studies Volunteer studies demonstrate flumazenil’s ability to reverse the effect of benzodiazepines.13 Reversal is both immediate and dose dependent. Most individuals achieve complete reversal of benzodiazepine effect with a total IV dose of 1 mg.1,8 A 3-mg IV dose produces similar effects that last approximately twice as long as the 1-mg dose.

Conscious Sedation There are a number of studies evaluating patients undergoing conscious sedation for endoscopy or cardioversion who received diazepam or midazolam.2,7,8,30,31 When a benzodiazepine is given to achieve conscious sedation during a procedure, flumazenil appears safe and effective in the reversal of sedation and the partial reversal of amnesia. Most patients respond to doses of 0.6–1 mg. Administering flumazenil slowly, at a rate of 0.1 mg/min, minimizes the disconcerting symptoms associated with rapid arousal, such as confusion, agitation, and emotional lability. Resedation occurs within 20–120 minutes, depending on the dose and pharmacokinetics of the benzodiazepine, as well as the dose of flumazenil. For this reason, patients must be carefully monitored, and subsequent doses of flumazenil given as needed. Because the amnestic effect of benzodiazepines is not consistently reversed, posttreatment instructions should be reinforced in writing and given to a responsible caretaker accompanying the patient.12 Because of the risk of resedation, many endoscopists elect not to use flumazenil. There are two case reports of patients undergoing endoscopy who developed seizures following benzodiazepine reversal.48 One patient had a history of seizures and the other had no obvious etiology. Both recovered uneventfully.

Use for Paradoxical Reaction to Midazolam Paradoxical reactions to benzodiazepines are uncommon.20,37 The mechanism is unclear and has been attributed to a disinhibition reaction akin to ethanol intoxication or a perceived threat to oversedation with a protective response.17 Management strategies include administering higher doses of the benzodiazepines, adding other agents such as opioids or droperidol, stopping the procedure, or using flumazenil.27,43,49,50 Three patients undergoing endoscopy were premedicated with meperidine, droperidol, and midazolam in doses up to 10 mg.17 Each patient exhibited paradoxical agitation and restlessness. Following flumazenil 0.5 mg IV the patients be-

SEDATIVE HYPNOTICS

947

came calm and sedated, allowing successful completion of endoscopy. A satisfactory explanation has not been established.

Effects on Benzodiazepine-Induced Respiratory Depression Flumazenil has not consistently reversed benzodiazepine-induced respiratory depression.46 If respiratory depression is mediated through the benzodiazepine receptor, then flumazenil should be effective as a reversal agent, but this effect does not occur consistently.10,21,35,39,46 Using oxygen saturation measurements and plethysmography to determine minute ventilation volumes, the effect of IV midazolam on respiratory depression was examined in patients undergoing endoscopy.10 Flumazenil awakened patients rapidly but failed to affect minute ventilation and had little effect on oxygen saturation. When a benzodiazepine was used concomitantly with an opioid, the effects on ventilation were even more confusing.54,56 Rebound respiratory depression and prolonged hypoxic episodes were documented. It is suggested that flumazenil may even have a slight respiratory depressant effect when combined with an opioid.54 Clinical assessment of respiratory rate is inadequate to detect hypoxia. Benzodiazepine-induced apnea should be managed with fundamental procedures such as supplemental oxygen, airway stabilization, bag-valve mask ventilation, and endotracheal intubation, if indicated.

Use in the Overdose Setting The use of flumazenil in the overdose setting has provoked substantial controversy. The first argument against its use is that benzodiazepines rarely cause morbidity and mortality. An analysis of 702 patients admitted to a medical intensive care unit (ICU) over a 14-year time period, who had taken benzodiazepines alone or in combination with ethanol or other drugs, resulted in 5 fatalities (0.7%) and 69 patients (9.8%) experienced complications.26 By comparison, the fatality rate was 1.6% (55 of 3430) for patients with nonbenzodiazepine-related overdoses. In the pure benzodiazepine group, 2 patients died and 18 of 144 patients (12.5%) had complications, mostly aspiration pneumonitis and decubitus ulcers. Proponents of flumazenil therapy suggest that some of the 29 diagnostic procedures used in these patients would have been unnecessary, and possibly some of the complications that occurred could have been avoided. Opponents of flumazenil suggest that many of the cases of aspiration pneumonitis occurred prior to hospital admission and that these patients also often suffer from trauma and infectious disease, making most diagnostic procedures necessary in any event. In an effort to develop indications for the safe and effective use of flumazenil, overdosed comatose patients were retrospectively assigned to either a low-risk or non-low-risk group.22 Low-risk patients had CNS depression with normal vital signs, no other neurologic findings, no evidence of ingestion of a tricyclic antidepressant by history or electrocardiogram (ECG), no seizure history, and absence of an available history of chronic benzodiazepine ingestion. All other patients fell into the non-low-risk category. Of 35 consecutive comatose patients, 4 patients were assigned to the low-risk group. Flumazenil caused complete awakening in 3 patients, and partial awakening in the fourth patient, in the low-risk group with no adverse effects. In the non-low-risk group of 31 patients, flumazenil caused complete awakening in 4 patients, and partial awakening in 5 patients. Seizures occurred in 5 patients. Of the 5 patients with seizures, 1 had a history of

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seizures, all 5 were long-term benzodiazepine users, 4 had abnormal vital signs, and 3 had evidence of hyperreflexia or myoclonus. Therefore, although the use of flumazenil was safe and effective in the low-risk group, unfortunately very few patients met the criteria for inclusion in that risk group. The risk of seizures is substantial in the non-low-risk group. In conclusion, the benefit of flumazenil appears to outweigh the risks in those patients for whom benzodiazepines are used therapeutically to perform a diagnostic or therapeutic procedure. When benzodiazepines are ingested alone in the overdose setting by non-benzodiazepine-dependent patients, as very rarely occurs in adults but might be expected in children, the risks associated with the use of flumazenil may be limited. Table 63–5 summarizes the indications for flumazenil in the overdose setting.

Adverse Effects and Safety Issues Flumazenil has been studied in more than 3500 patients worldwide, including healthy volunteers and overdosed or consciously sedated patients. Its safety in healthy volunteers is well established, with no discernible objective or subjective effects. The ability of flumazenil to precipitate acute benzodiazepine withdrawal seizures in a more controlled setting than the overdose setting was demonstrated by the reversal of long-term benzodiazepine sedation in the ICU. A study involving 1700 patients revealed that 14 patients developed adverse drug reactions with perhaps half related to abrupt arousal.2 Two patients with a history of epilepsy developed tonic-clonic seizures and one patient developed myoclonic seizures.2 A dose dependency toward inducing withdrawal reactions has been suggested. It may be that small doses of flumazenil (4.03 mmol/L

=

60 Daltons

=

32 Daltons

= >25 mg/dL = >7.8 mmol/L Values greater than or equal to the action level necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical condition of the patient.

A 35-year-old man was brought to the Emergency Department (ED) for bizarre behavior. According to his family, the patient stated that he wanted to kill himself. The patient was found holding a large fast-food beverage cup filled with a fluorescent green liquid. The patient, who was somnolent, said that he had been drinking this liquid for the last several hours. He appeared well nourished and well developed. Initial vital signs were blood pressure, 140/100 mm Hg; pulse, 80 beats/min; respiratory rate, 18 breaths/min; temperature 99.2°F (37.3°C). His skin was dry, anicteric, and acyanotic. Examination of his head, ears, eyes, nose, and throat was unremarkable. Pupils were 5 mm and reactive, no nystagmus was noted, and funduscopy was normal. Chest, heart, and abdominal examinations were also noted to be normal. An intravenous line was started with 0.9% NaCl solution and blood was drawn for glucose, electrolytes, blood urea nitrogen (BUN), creatinine, osmolality, ethanol, and acetaminophen levels. A urinary catheter was placed and a specimen was sent for analysis. An electrocardiogram (ECG) was performed and the patient was placed on a cardiac monitor. Initial fingerstick glucose was 88 mg/dL and a urine specimen did not fluoresce under Wood’s lamp examination. The patient was given 100 mg of thiamine HCl and 50 mg of pyridoxine intravenously. Activated charcoal was not administered. While awaiting results of the blood tests, the patient’s clinical status remained stable. Arterial blood gas determination on room air revealed pH, 7.01; PCO2, 15 mm Hg; and PO2, 95 mm Hg. His electrolytes were Na+, 149 mEq/L; K+, 6.0 mEq/L; Cl
, 105 mEq/L; and HCO3
, 7 mEq/L. His other laboratory data were BUN, 9 mg/dL; Ca2+, 9.2 mg/dL;

creatinine, 1.3 mg/dL; and glucose, 147 mg/dL. The calculated anion gap was 37 mEq/L (Chap. 24). Serum osmolality was measured at 370 mOsm/kg and the calculated osmolarity was 300 mOsm/L (Chap. 24). Because the ethanol level was undetectable, the osmol gap was calculated to be 70 mOsm/L. The patient was then loaded with 15-mg/kg of fomepizole and admitted to the medical intensive care unit (ICU). Within 5 hours of admission, he received his first hemodialysis treatment. The patient’s initial serum ethylene glycol concentration was determined to be 222.6 mg/dL and his postdialysis level was 97.2 mg/dL. Therefore, he was dialyzed a second time, approximately 16 hours after admission. Appropriate psychiatric consultation was obtained and the patient had an uneventful recovery without evidence of sequelae on discharge from the hospital.

Alcohols are hydrocarbons that contain a hydroxyl (OH) group(s). Primary alcohols contain the hydroxyl group on a terminal carbon, as in the case of ethanol and methanol. In secondary alcohols, such as, isopropyl alcohol, the hydroxyl group is on a carbon bound to two other carbon atoms. A compound with two hydroxyl groups is commonly classified as a diol (butanediol), but may also be referred to as a glycol (ethylene glycol). All alcohols have potential toxicity, however, the term toxic alcohols commonly refers to ethylene glycol, methanol and isopropanol. Other less-common, but still consequential toxic alcohols include diethylene glycol, benzyl alcohol, and the glycol ethers, such as butoxyethanol (ethylene glycol butyl ether); and methoxyethanol (ethylene glycol methyl ether) (Chaps. 2 and 56).

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Although used in a wide range of preparations, most alcohols are not intended for human consumption. The addition of ethylene glycol to water lowers the freezing point and raises the boiling point. Thus, more than a quarter of ethylene glycol produced is used in coolant mixtures, antifreeze for motor vehicles, and aircraft deicing solutions. Ethylene glycol is also used as a solvent in inks, pesticides, and adhesives. It is used in brake fluid and in heat exchangers and condensers. Ethylene glycol is used as a glycerin substitute in products such as cosmetics, paints, lacquers and detergents. Because most household exposures (particularly in children) to ethylene glycol result from the ingestion of automobile antifreeze, some companies have developed a propylene glycol product in an attempt to limit the potential toxicity. Methanol is also used as antifreeze, specifically in window washer fluid (30%) or added to fuel as an anti-icing agent or octane booster (≈100%). It is also used as an ethanol denaturant, an extraction agent and solvent, and as a fuel source, specifically for picnic stoves (4%) and soldering torches. Methanol is commonly used in varnish removers and paint, and as an industrial solvent. It is used in the manufacture of acetic acid, formaldehyde, methyl derivatives, and inorganic acids. Most household exposures result from the ingestion of windshield washing fluids and fuel deicing agents. Isopropanol is produced from the hydration of propylene with sulfuric acid. It is a raw material used for the synthesis of acetone, glycerin, and other chemicals. Isopropanol is also used as a solvent for oils, gums, and resins and as a deicing agent for liquid fuels. Isopropanol is commonly used as rubbing alcohol in a 70% solution and as a solvent in hair-care products, skin lotion, and home aerosols. It is often ingested as an inexpensive and convenient substitute for ethanol. Propylene glycol is commonly used as a diluent for parenteral preparations such as diazepam and phenytoin. It is also used as an environmentally safe alternative to ethylene glycol as automobile antifreeze or as a deicing agent, in food and cosmetic preparations, but it is more expensive to produce than ethylene glycol. Diethylene glycol is used as a solvent and sprinkler antifreeze, and in paints and cosmetics. The ethylene glycol ethers, monomethyl [CH3OCH2CH2OH] and monobutyl [CH3(CH2)3 OCH2CH2OH] are two commonly used solvents called cellusolves. They are found in paints, resins, and industrial coatings. Alcohols have numerous applications and as such are contained in a myriad of household products. Ethanol is likely the world’s commonest substance of abuse. Exposures to toxic alcohols may be intentional either as an ethanol substitute or for the purpose of self-harm. Unintentional exposures are often secondary to the ubiquitous nature of the products. Whatever the exposure, a thorough understanding of the pathophysiology and pharmacology is essential to providing appropriate therapy.

HISTORY AND EPIDEMIOLOGY Although toxic alcohol ingestions usually involves a single patient, a number of mass exposures have occurred, often as a result of a failure of quality control. Diethylene glycol-contaminated glycerin has repeatedly been used in the preparation of medications in numerous developing countries including India, Bangladesh, Haiti, South Africa, and Nigeria.27,45,72 These contaminated medications, usually acetaminophen elixirs, have led to the deaths of hundreds of children from renal failure in countries

Figure 66–1.

TOXIC ALCOHOLS

981

Major pathways of ethylene glycol metabolism.

where dialysis is not readily available. In the United States, a contaminated water supply containing 9% ethylene glycol led to an epidemic of poisoning in children who developed somnolence, ataxia, vomiting, hematuria, and crystalluria.38 Death after hemodialysis has occurred because air conditioning cooling fluid, consisting of ethylene glycol, contaminated a hospital’s water supply.63 These types of exposures occur repeatedly and could be avoided with stricter quality control of pharmaceuticals and better engineering controls. Because the glycol ethers have common commercial and industrial uses, occupational exposures account for the majority of toxicity. First introduced in the mid-1930s, the glycol ether methoxyethanol was used as a solvent in the garment industry in the production of stiffened or “fused” shirt collars. Shortly thereafter, reports were published describing encephalopathy and bone marrow suppression in workers exposed to methoxyethanol in the garment industry.9 Since that time industrial use has grown exponentially, increasing the risk of toxicity to workers and necessitating specific safety protocols. Additionally, use of these solvents in household cleaning products (window cleaners) has resulted in a number of household exposures.18 Approximately 250 deaths attributable to toxic alcohol poisoning were reported to poison centers for the 10-year period from 1990–1999. Most of these deaths were related to methanol (134) and ethylene glycol (84) according to data from the American Association of Poison Control Centers (AAPCC) (see p. 1752, Chap.

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116). Children and animals often consume larger-than-expected amounts of ethylene glycol, presumably because of its sweet taste. The high concentration of methanol in certain preparations (often in excess of 90%) results in significant toxicity, even with the ingestion of an apparently small quantity of the substance in question. Finally, the widespread availability and low cost of rubbing alcohol makes isopropanol the most frequently reported toxic alcohol exposure, accounting for more exposures than ethylene glycol and methanol combined.

PHARMACOLOGY AND TOXICOKINETICS Exposure to toxic alcohols can occur via dermal, pulmonary, and gastrointestinal routes.2,25,37,69 Most of the alcohols have a high vapor pressure and can be absorbed via inhalation, except for ethylene glycol, which has a low vapor pressure (0.6 mm Hg at 20°C (68°F)). Volunteer studies demonstrate that irritation of the upper respiratory tract limits toxic exposures to ethylene glycol mist and no evidence of absorption occurred following exposure of up to 27 parts per million (ppm) for 4 weeks.73 Similarly, the dermal absorption of ethylene glycol is also very poor. An in vitro study of donor thigh skin samples of 3 white males exposed to 8 µg of 14 C-labeled ethylene glycol/cm2 for 24 hours yielded an average flux of 0.009 µg/cm2/h.20 By contrast, dermal exposures to methanol, isopropanol and glycol ethers have led to toxicity.2,42,69 All alcohols are absorbed rapidly from the gastrointestinal tract. The rate of absorption ranges from ethanol at 0.57 mg/cm2/h to methanol at 8.4 mg/cm2/h and the glycol ethers approximately 2.82 mg/cm2/h.21,41 Time to peak serum concentration ranges from 1 to 4 hours after ingestion of ethylene glycol and 30–60 minutes for methanol, the glycol ethers, and isopropanol.3,56 Alcohols share a common volume of distribution (see pharmacokinetics) with an approximate Vd of 0.6 L/kg (range 0.5–0.8 L/kg). Ethylene glycol, methanol, and isopropanol are all metabolized by oxidation via alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (see Figs. 66–1, 66–2, and 66–3). Although ADH metabolizes all alcohols, enzyme-binding affinities vary. The affinity of ADH for ethanol is 4 times greater than its affinity for methanol and 8 times greater than its affinity for ethylene glycol. These variable affinities have significant therapeutic importance. Although peak methanol concentrations are achieved rapidly, metabolism may not be evident until 24 hours (range, 1–72 hours), delaying the development of acidosis and toxic symptoms.6 In the liver, ADH metabolizes approximately 75–85% of methanol to formaldehyde, which is then oxidized by aldehyde dehydrogenase to formic acid. In the presence of folate, formic acid is converted to carbon dioxide and water.52,53 This beneficial aspect of folate has been demonstrated both in mice and in nonhuman primates. Folatedeficient rats were more susceptible to methanol toxicity than were folate-rich rats.66 Monkeys treated with folate after methanol ad-

ministration were relatively resistant to methanol toxicity, and when methanol toxicity was allowed to develop, it was reversed after folate treatment.52,53 Because of its volatility, methanol can be eliminated unchanged by the lungs (10–20%) and about 3% is excreted unchanged via the kidneys. At low concentrations methanol metabolism follows zero-order kinetics at a rate of 8.5 mg/dL/h.36 At much higher methanol concentrations first-order kinetics occur, possibly because of increased pulmonary elimination. In the presence of therapeutic levels of ethanol, the half-life ranges from 30 to 52 hours with a median of 43 hours.55 In the presence of fomepizole, the mean half-life is 54 hours.7 Ethylene glycol is slowly metabolized over several hours (3–8) to glycoaldehyde.57 Because it is a diol, it undergoes successive oxidations to yield glycolate, glyoxylate, and oxalate. As in the case of other aldehydes, glycoaldehyde is rapidly metabolized by aldehyde dehydrogenase to glycolate. The conversion of glycolate to glyoxylate is the rate-limiting step in this process.50 Glyoxylate can follow alternate metabolic pathways; glycolic acid can be metabolized to hippurate in the presence of pyridoxine or to -hydroxy--ketoadipic acid in the presence of magnesium and thiamine.34,59 The majority of this elimination (80%) occurs in the liver. The remaining 20% is excreted unchanged by the kidneys. Virtually no ethylene glycol is eliminated via the lungs because of its chemical characteristics. The half-life of ethylene glycol and methanol have been described under various therapeutic conditions (see Table 66–1).7,8 Isopropanol is rapidly metabolized via alcohol dehydrogenase to acetone. However, as a result of its secondary alcohol characteristics, the initial oxidation forms a ketone and not an aldehyde, which permits no further oxidation or metabolism. Unlike the other alcohols, isopropanol follows first-order kinetics with regard to its elimination. This may be a consequence of the significant renal and pulmonary elimination of acetone. Approximately 80% of isopropanol is metabolized to acetone. The remainder is excreted unchanged in the urine with a small amount excreted through the lungs. The half-lives of isopropanol and acetone in adults are 2.9–16.2 hours and 7.6–26.2 hours, respectively.17,56 The half-life of isopropanol can be doubled in the presence of ethanol, but there is no effect on acetone elimination. The kidneys excrete the majority of acetone, whereas the lungs excrete only a minority of acetone. The metabolism of the glycol ethers varies substantially. ADH metabolizes monoalkyl ethers of ethylene glycol to their respective alkoxyacetic acids; for example, butoxyethanol is metabolized to butoxyacetic acid with butoxyacetaldehyde as an intermediate.13,29 The metabolism of other glycol ethers and esters of ethylene glycol is not completely understood; some may undergo cleavage of the ether bond to produce ethylene glycol. This latter pathway is a speculative one based on reports of urinary oxalate crystals in 2 patients who ingested methoxyethanol and of a patient who ingested butoxyethanol.51,58 None of these patients had detectable methanol levels, the other expected product of methoxyethanol cleavage. Most glycol ether exposures do not re-

Figure 66–2. Methanol metabolism. Therapy is aimed at interfering with this conversion. Ethanol is a preferential substrate for alcohol dehydrogenase (ADH). 4-Methylpyrazole is a competitive inhibitor of the enzyme ADH. (ALDH = aldehyde dehydrogenase.)

CHAPTER 66

Figure 66–3.

Isopropanol metabolism.

sult in the toxicity associated with ethylene glycol metabolism, suggesting that a different metabolic pathway exists (see examples of metabolism in Figure 66–4).

CLINICAL MANIFESTATIONS Toxic alcohols have multiple effects. In general, the common symptoms are related to the parent alcohol and the specific effects are related to the resultant metabolites. Table 66–2 summarizes symptoms by systems and associated alcohols. It is important to remember that there may be an initial asymptomatic period following exposure. As a class, alcohols can cause inebriation, but the degree of inebriation present after consumption of a given amount of alcohol appears to be based on the number of carbon molecules present in its chemical structure.71 Thus, methanol is less intoxicating than ethanol or ethylene glycol, which are less intoxicating than isopropanol. Inebriation can occur after ingestion of a toxic alcohol and may be the only presenting symptom. However, the absence of inebriation does not exclude significant toxic alcohol ingestion; thus, inebriation is an unreliable symptom. For example, a methanol level of 50 mg/dL may not result in inebriation, but it does have the potential for toxicity. However, a similar serum ethanol concentration may have obvious central nervous system (CNS) effects. All alcohols can cause CNS depression that may present as lethargy or coma and respiratory depression. The CNS depressant effect of isopropanol may be potentiated by its metabolism to acetone, a CNS depressant as well. Animal studies suggest that isopropanol is 2–3 times more potent than ethanol as a CNS depressant, while acetone’s depressant effects are comparable to those of ethanol.71 The ingestion of glycol ether has resulted in acute encephalopathy and may present as agitation, confusion, or coma. CNS depression occurred rapidly following the ingestion of butoxyethanol and ethanol, whereas a delay of 8–18 hours followed the ingestion of pure methoxyethanol.9 Alcohols are also vasodilators. As such, consumption can result in hypotension and reflex tachycardia. Occasionally, hypotension may be further exacerbated by bradycardia secondary to CNS depression.

TABLE 66–1. Apparent Plasma Half-lives (Hours) of Ethylene Glycol and Methanol Under Diverse Conditions Ethylene Glycol Alone With Ethanol With Fomepizole With Ethanol and Dialysis *With normal renal function

3–8.6* 17–18 14–17* 2.5–3.5

Methanol zero order 8.5 mg/dL/h 43 54 2.5–3.5

TOXIC ALCOHOLS

983

Additionally, the oxidation of an alcohol by ADH results in increased formation of nicotinamide adenine dinucleotide (NADH) resulting in a high NADH to NAD+ ratio (Chap. 64). This low redox ratio favors the conversion of pyruvate to lactate, but rarely results in significant lactic acidosis. The decrease in pyruvate removes substrate form the Krebs’ cycle, impairing energy production. This low redox effect combined with alcohol’s inhibition of gluconeogenesis can cause hypoglycemia in susceptible individuals—small children and those with poor nutritional status such as alcoholics. The number of oxidative steps affects the NADH:NAD ratio and as such the effect is greater for ethylene glycol (4 oxidative steps) than for isopropanol (1 oxidative step). An anion gap metabolic acidosis is another common feature of ethylene glycol and methanol toxicity. This acidosis is the result of the different organic acids formed from the metabolism of the parent compounds.26 Although ethylene glycol is metabolized to glycolic, glyoxylic, and oxalic acid, glycolic acid is most responsible for the production of the acidosis.50 Metabolic acidosis from methanol poisoning is caused by formic acid, but may be exacerbated by the increase in lactate production from formate’s inhibition of the cytochrome oxidase chain. The alkoxyacetic acids formed from ADH metabolism of the monoalkyl ethers of ethylene glycol can also result in acidosis. For example, butoxyethanol metabolism results in butoxyacetic acid.9 Visual symptoms, if they develop, usually develop within 24 hours after methanol exposure.46 The patient may complain of blurred or “snow field” vision. This is the result of formic acidmediated retinal toxicity. In primate studies, formate produced retinal toxicity despite pH buffering, implicating the metabolite and not the associated acidosis in the development of the retinal effects.48,49 If formate production persists, the toxin may result in permanent visual loss.46,47 Ophthalmologic examination may reveal hyperemia of the optic disc and/or retinal edema.5 Papilledema, ophthalmoplegia, and loss of pupillary light reflexes may be present. Rarely, these same symptoms may occur following exposure to ethylene glycol. The oxalate formed form ethylene glycol metabolism can chelate calcium out of serum resulting in QT prolongation on the ECG and cardiac dysrhythmias secondary to hypocalcemia.64 Furthermore, calcium oxalate precipitates in the renal tubules and can cause acute tubular necrosis within 12–48 hours after ingestion.16 Multiple cranial nerve (CN) deficits may occur after ethylene glycol poisoning. In addition to pupillary deficits and ophthalmoplegia (CN II, III, and VI), facial paresthesias, facial weakness, hearing loss, dysarthria, and dysphagia (CN V, VII, VIII, IX, and X respectively), are reported.68 These neurologic manifestations may resolve over a period of time from weeks to months. Postmortem analysis in 1 patient demonstrated dense crystals along the subarachnoid portion of CN VII and VIII.1 Other authors suggest that an ethylene glycol-induced pyridoxine deficiency is responsible, but evidence is lacking.68 The adult respiratory distress syndrome has been described in an ethylene glycol-poisoned patient, but this more likely represents a nonspecific complication of profound illness.14 As a result of its metabolic pathway, isopropanol does not manifest major toxicity unless extremely large doses are ingested. Patients with isopropanol ingestions manifest CNS depression, hemorrhagic gastritis, and tracheobronchitis. Following exposure to monomethyl or monobutyl ethers of ethylene glycol the parent compound or its metabolite can result in acute tubular necrosis (without oxaluria), hepatitis, pancreatitis,

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY TABLE 66–2.

Signs and Symptoms of Toxic Alcohol Exposures

Organ System

Ethylene Glycol

Isopropanol

Methanol

Cardiovascular

Tachycardia Hypertension/hypotension Dysrhythmias Myocarditis Ataxia Meningoencephalitis Convulsions CNS depression Inebriation Myoclonus

Tachycardia Hypotension Myocardial depression

Tachycardia Hypotension

Areflexia Ataxia CNS depression Dizziness Headache Inebriation Muscle weakness Hypothermia Abdominal pain, cramping Gastritis Hematemesis Nausea, vomiting

CNS depression Convulsions Dizziness Headache Hypothermia Inebriation

Central nervous

Gastrointestinal

Nausea, vomiting

Ophthalmic

Ophthalmoplegia Nystagmus

Pulmonary

Hyperventilation, Tachypnea Pneumonitis Respiratory depression Crystalluria Renal insufficiency

Renal Other

Odor of acetone Respiratory depression Hemorrhagic tracheobronchitis Renal tubular acidosis Rhabdomyolysis Hemolytic anemia

Figure 66–4. The structure and metabolic fates of butoxyethanol (ethylene glycol butylether). In humans it appears that butoxyacetic acid is the primary pathway, but concern with regard to hydrolysis to ethylene glycol exists.

Abdominal pain Anorexia Gastritis Nausea, vomiting Pancreatitis “Snow fields” Blurred vision Hyperemic optic discs Mydriasis Papilledema, blindness Respiratory depression

Figure 66–5. Propylene glycol metabolism to lactic acid. Under normal conditions, lactate is converted to pyruvate which, following decarboxylation, enters the Krebs’ cycle.

CHAPTER 66

CNS depression, and metabolic acidosis. Bone marrow depression and toxic encephalopathy can result from the chronic inhalation of these ethers.9,51,58 Butoxyacetic acid, the metabolite of butoxyethanol can result in hemolysis.13

Propylene Glycol and Benzyl Alcohol

TOXIC ALCOHOLS

985

els 12 times that of controls accounted for the demonstrated anion gap in neonates whose IVs had been flushed with bacteriostatic normal saline solution. These patients developed a symptom complex that included gasping reactions, hypotension, neurologic deterioration, hepatic and renal failure, and death.28,44 For this reason benzyl alcohol is no longer used as an antimicrobial preservative in neonatal medicine (Chaps. 2 and 56).

DIAGNOSTIC TESTING

Propylene glycol is metabolized to lactic acid (Fig. 66–5). Profound lactic acidosis is reported following the infusion of large quantities of medications that employ propylene glycol as a diluent. Patients can develop hypotension, cardiac conduction abnormalities (QRS widening), dysrhythmias, and asystole when rapid IV infusions containing propylene glycol are administered. However, most propylene glycol ingestions result in a transient and clinically insignificant rise in serum lactate. Transdermal absorption of propylene glycol contained in silver sulfadiazine cream has resulted in hypoglycemia, seizures, and CNS depression in children with severe burns treated with this cream.39 Benzyl alcohol is interesting from a historical prospective. Most patients are exposed only to minimal amounts of benzyl alcohol, which is commonly used as a preservative for intravenous preparations.43 However, use of these preparations in preterm neonates has resulted in lethal metabolic acidosis caused by the formation of hippuric acid and benzoic acid, the products of the hepatic oxidative metabolism of benzyl alcohol. Benzoic acid lev-

A Figure 66–6. glycol.

Several diagnostic tests are available to the clinician managing a patient with suspected toxic alcohol poisoning. The serum should be analyzed for BUN, creatinine, glucose, and electrolytes, including calcium. Ethylene glycol and methanol result in an anion gap metabolic acidosis, whereas isopropanol usually does not. Ethylene glycol can result in hypocalcemia or renal injury, and establishing baseline renal function in patients with any toxic alcohol ingestion is appropriate. Urine dipsticks can provide information as to the presence of ketones (suggesting isopropanol ingestion), while urine microscopy can determine the presence of crystals (Fig. 66–6). Calcium oxalate can form either monohydrate (spindlelike) or dihydrate crystals (envelope shaped). The dihydrate crystals are easily recognizable and diagnostic, whereas monohydrate spindles may be indistinguishable from hippurate crystals.34 However, crystals are only present in approximately 50–65% of cases, therefore the absence of crystals is an unreliable finding.8,34 In patients with normal renal function urine can be examined for the presence of fluorescence. Urinary fluorescence persists for only a few hours after ingestion of fluorescein containing radiator antifreeze. A volunteer study of 6 men who ingested fluorescein and then gave hourly urine samples, demonstrated that urinary fluorescence was short-lived, present 100% of the time at 2 hours, 60% of the time at 4 hours, and 20% of the time at 6 hours.74 When present, it is best appreciated by examining urine on white gauze or filter paper with a black light (Wood’s lamp).

B

Calcium oxalate crystals (dehydrate forms) under low (A) and high (B) power, found in the urine of a patient following the ingestion of ethylene

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Foley bags and urine tubes (glass or plastic) all possess inherent fluorescence and may result in false-positive results.

Osmol Gap The ingestion of any toxic alcohol can raise the serum osmolality.23,33 Since the calculated osmolarity consists of simply twice the serum sodium, in mEq, plus the molar sums of the glucose and BUN, it is not altered in the presence of additional osmotically active particles in the serum. However, these additional molecules raise the measured osmolality so that the gap between measured and calculated osmols increases. Laboratories should measure the osmolality by performing freezing-point depression studies as boiling-point elevation techniques volatilize many alcohols. The calculated serum osmolarity (Chap. 24) can then be subtracted from the measured osmolality resulting in the osmol gap. To avoid confusion any calculation of the serum osmolarity should also include ethanol, serum ethanol concentrations should be obtained on all patients with suspected toxic alcohol ingestion.60 When the osmol gap is greater than 50 mOsm/L it should be considered nearly diagnostic of toxic alcohol ingestion. However, a normal or even negative osmol gap does not exclude the presence of toxic alcohols. This limitiation occurs because the range of normal osmol gaps within the population is large (perhaps −2 ± 6 mOsm/L) and it is the individual patient’s change from baseline that is relevant. That is, if a patient has a baseline osmol gap of −2 mOsm/L and it is currently 8 mOsm/L (within the population norm), the patient actually has 10 mOsm/L of osmols left unaccounted. This may represent a methanol level of 32 mg/dL or an ethylene glycol level of 64 mg/dL, both of which are consequential.70 Additionally, a number of conditions create an increase in the osmol gap. One study found that both alcoholic ketoacidosis (AKA) and lactic acidosis raised the osmol gap by 10–11 mOsm/L. These authors found that an osmol gap greater than 25 mOsm/L was indicative of a toxic alcohol ingestion with a specificity of 88%.62 Another study found that the osmol gap could be elevated in patients with chronic, but not acute renal failure.65

Acid-Base Status Arterial blood gas analysis is a rapid way of determining serum pH, but this study’s utility is limited by the presence of a normal serum bicarbonate during the first hours following toxic alcohol ingestion. This latter concept is of importance, as clinicians must recognize the temporal relationship between the anion and osmol gaps. Alcohols are effective osmols and raise the osmol gap. As the alcohols are metabolized to their acid products the body uses bicarbonate to buffer the serum pH. This results in a drop in serum bicarbonate and the development of an increased anion gap. As time passes and metabolism progresses, the osmol gap decreases while the anion gap increases. Abnormalities in the two gaps may or may not be present at the same time (see Fig. 66–7). Late in toxic alcohol ingestions the patient may have a large anion gap acidosis but a normal osmol gap. This explanation is another reason why both the osmol gap and anion gap are only useful when abnormal, but should never be used to exclude toxicity. Isopropanol causes a large osmol gap without an anion gap; this increased gap persists while metabolism to acetone occurs (a ketone, not an acid).

Figure 66–7. The relationship between the anion gap (— — —) and the osmol gap (—) over time.

QUANTITATIVE TESTING When available, quantitative serum alcohol concentrations eliminate all of the guesswork from the management of a patient with a suspected toxic alcohol ingestion. Serum ethanol, methanol, and ethylene glycol concentrations; if rapidly available, can be used to determine the proper course of management, but may be less helpful if significant metabolism has already occurred. Substantially elevated serum ethanol concentrations can afford some protection to the patient and should always be determined. Several techniques are available to obtain quantitative levels. The best method uses gas chromatography (GC) with flame ionization for the detection of toxic alcohols or their derivatives.22 False-positive results can occur in the presence of propylene glycol (found in IV preparations such as phenytoin or diazepam), propionic acid, or 2,3 butanediol. For this reason, GC findings are often confirmed by mass spectrometry (MS). This technique also requires a dedicated GC column, which is a significant laboratory expense. Other techniques include variations on high-performance liquid chromatography and the GC method described.67 The variation of the GC method has the advantage of limiting false-positive results, but this technique is not widely practiced (Chap. 7). An available enzymatic screening test utilizes glycerol dehydrogenase to catalyze the oxidation of ethylene glycol, producing NADH, which is then measured spectrophotometrically. While this enzymatic test has the advantage of being rapid and unaffected by methanol, ethanol, isopropanol, or the metabolites of ethylene glycol, it may cross-react with lactate, yielding false-positive results.22 In addition, this screening test requires confirmation via GC-MS, limiting its usefulness. Unfortunately, many hospital laboratories are not equipped to determine toxic alcohol levels rapidly and usually rely on reference laboratories for these assays. The delays involved in sending specimens to another site and awaiting results may prohibit timely management of these patients. Delayed testing is not of benefit in the initial management of toxic alcohol ingestion.

MANAGEMENT The initial management should include airway stabilization, ventilation, establishing intravenous access, and attention to any vital sign aberrations. Decontamination can be attempted with nasogastric (NG) aspiration of a toxic liquid if the patient presents within

CHAPTER 66

several hours of ingestion. Activated charcoal (AC), syrup of ipecac, and orogastric lavage all have extremely limited roles in the management of toxic-alcohol-poisoned patients, but should be applied, as appropriate for any suspected or known coingestants. Although AC adsorbs alcohols to varying extents, the dose needed to approach a beneficial AC-to-drug ratio is usually in excess of tolerable amounts.11,19 In addition to the risk of aspiration, orogastric lavage poses a risk of injury in patients who are most likely to ingest toxic alcohols, that is alcoholics who are at risk for esophageal injury. Moreover, NG aspiration may prove adequate to remove a liquid ingestion. Finally, syrup of ipecac offers little advantage over NG aspiration and carries with it the risk of esophageal injury. Hypotensive patients should receive fluid resuscitation as guided by volume status and renal function prior to the institution of vasopressor therapy. When maintenance fluids are given, special attention should be paid to the addition of specific vitamins as adjuvant therapy. Thiamine and pyridoxine therapy should be administered to anyone suspected of ethylene glycol ingestion at doses of 100 mg and 50 mg IV every 6 hours, respectively (see Fig. 66–1 and Antidotes in Depth: Thiamine Hydrochloride and Pyridoxine). Thiamine will shift the metabolism of the intermediate glyoxylic acid to -hydroxy--ketoadipic acid, reducing the production of oxalic acid.34,59 Evidence suggests that pyridoxine, in the presence of magnesium, will promote the conversion of glyoxylic acid to glycine and benzoic acid, which can further be metabolized to hippuric acid. The net effect of these adjuvants is to decrease the total amount of oxalic acid formed. While theoretically beneficial, no human data exists that demonstrates benefit. In animal studies, folic acid enhances the metabolism of formic acid to CO2 and water.66 Thus, 50–75 mg of folate should be given IV every 4 hours for the first 24 hours of a suspected methanol ingestion or while elevated methanol levels are present. In addition to vitamins, sodium bicarbonate should also be added to maintenance fluids or given as boluses, depending on the clinical situation. Sodium bicarbonate infusion can help correct a profound metabolic acidosis and should probably be used when the pH is less than 7.20 (see Antidotes in Depth: Sodium Bicarbonate). Because restoration of normal pH may require large volumes of bicarbonate, fluid and electrolyte balance should be monitored carefully. Additionally, alkalinization of serum is helpful in maintaining acids in the ionic form, which not only enhances the renal clearance of formate, but may also prevent formic acid from entering the CNS, particularly the optic nerves.34 The decision to inhibit the ADH-mediated metabolism of toxic alcohols should be made in any patient with a known (admitted or witnessed) ingestion; a high index of suspicion based on history, clinical manifestations of poisoning (ie, metabolic acidosis with normal serum lactate or elevated serum osmolality); or a serum concentration of a toxic alcohol (when possible) that exceeds treatment thresholds. The clinician must choose between ethanol and fomepizole as the ADH blocking agent to be administered (see Antidotes in Depth: Ethanol and Fomepizole). Currently FDA approval for fomepizole exists for the treatment of ethylene glycol and methanol poisoning. As the availability and awareness of fomepizole has increased, its appropriate use has gained widespread acceptance as a first-line therapy for toxic alcohol ingestions.3 Fomepizole has several benefits over an ethanol infusion. It is as effective as ethanol without the complications commonly associated with ethanol infusions.35 That is, fomepizole does not cause hypotension, hypoglycemia, inebria-

TOXIC ALCOHOLS

987

tion, pancreatitis, gastritis, or phlebitis. Fomepizole is administered every 12 hours, eliminating the need for monitoring a continuous ethanol infusion with its associated risks of supra- and subtherapeutic levels. Therefore, clinically stable patients treated with fomepizole will not necessitate intensive care, reducing this element of the cost of treatment. Although not specifically studied, fomepizole has been safely administered to children, including infants.4,31 In this specific population the short term use is unlikely to be problematic. The dosing of fomepizole is simpler than that of ethanol in patients undergoing hemodialysis. The greatest limitation of fomepizole is its cost, which is substantially greater than ethanol, although when the total cost of treatment, including the therapeutic agent, ICU time, and hemodialysis, is considered, the difference in cost is less obvious. However, fomepizole is not a substitute for hemodialysis under many circumstances. Although fomepizole prevents the formation of toxic metabolites, it has no effect on those metabolites already formed and their resultant toxicity. In the META study (Methylpyrazole for Toxic Alcohols), 9 patients who had initially elevated serum creatinine levels had persistent renal compromise despite fomepizole therapy, although they had a decrease in urinary oxalate excretion following therapy.8 Furthermore, the prolonged elimination of the parent compound following inhibition of its metabolism would require prolonged use of fomepizole, which is unstudied. Therefore, although it may be possible to treat patients with fomepizole alone, its use will be case dependent and the agent will not entirely replace hemodialysis. Methanol or ethylene glycol concentrations greater than 25 mg/dL are considered traditional indications for hemodialysis.15,30 Some authors suggest formate concentrations be used as an indication for hemodialysis of methanol poisoned patients.36,54 However, in some situations, the clinical status of the patient is a better measure of when hemodialysis is indicated. Ideally, toxic alcohols should be dialyzed before they produce toxic manifestations. The early initiation of hemodialysis requires rapid determination of toxic alcohol concentration. Unfortunately, not all hospitals are capable of ascertaining toxic alcohol concentrations rapidly. Thus, the decision is often delayed until evidence of toxicity manifests. When serum levels are not immediately available patients with established toxicity should be dialyzed.32 These conditions exist for patients with significant metabolic acidosis in the absence of another cause of end-organ manifestations of toxicity (impaired vision or renal function), or when ADH inhibition is not possible, either because of the unavailability of an antidote or when patients cannot tolerate the antidote (ie, IV ethanol in the hypotensive patient). Current practice guidelines recommend considering hemodialysis for patients with the following: worsening vital signs despite intensive supportive care, significant persistent metabolic acidosis (pH 90%.24 In these experiments, the dose of methanol was kept constant at about 1 g/kg ( 31 mmol/kg) while the dose of ethanol was varied. Although the methanol serum concentration was not measured, a calculation using the dose and a volume of distribution of 0.6 L/kg would predict a serum concentration of about 166 mg/dL. Methanol, even in molar ratios as high as 8:1, did not inhibit ethanol metabolism, and ethylene glycol did not inhibit methanol metabolism.24 Even smaller amounts of ethanol are required to block the metabolism of ethyl-

ene glycol, as the affinity of ethylene glycol for alcohol dehydrogenase is less than that of methanol, and much less than that of ethanol.16,22,33,34,36,39 Most authors1,16,39 recommend a serum concentration of ethanol of 100 mg/dL, or at least a 1:4 molar ratio of ethanol to methanol or ethylene glycol, whichever is greater. One hundred mg/dL (≈22 mmol/L) protects against 88 mmol/L (286 mg/dL) of methanol and 88 mmol/L (546 mg/dL) of ethylene glycol. Inhibiting the metabolism of methanol and ethylene glycol impedes the formation of toxic metabolites and prevents the development of metabolic acidosis.12,15,39 Renal, pulmonary, and extracorporeal routes of toxic alcohol removal then become the sole mechanisms for elimination.

CASE STUDIES Case reports have attested to the efficacy of ethanol in preventing the sequelae of methanol and ethylene glycol poisoning when administered in a timely fashion after the ingestion and before the accumulation of the toxic metabolites.4,6,18,31,43 Once blocked with ethanol, the half-life of ethylene glycol in two patients with normal kidney function was 17.5 hours, which was comparable to 17 hours in a case series of patients on fomepizole with normal kidney function.4,31,37 Similarly, a methanol half-life of 46.5 hours was reported in a patient with methanol poisoning, which is quite similar to the 54 hours reported in a case series of patients treated with fomepizole.2,18

PHARMACOKINETICS AND DOSING Ethanol can be given orally or IV (Tables 66–4 and 66–5). Concentrations of 20–30% (orally) and 5–10% IV are well tolerated. Intravenous administration has the advantage of complete absorption,20 avoids gastrointestinal symptoms, and can be given to an unconscious or uncooperative patient. The disadvantages include the procurement of ethanol, the preparation of an intravenous solution, the hyperosmolarity of a 5% ethanol solution (about 950 mOsm/L), the possibility of osmotic dehydration and venous irritation. Ethanol can also be administered orally and is rapidly absorbed with peak concentrations achieved in about 1–1.5 hours.5,11,40 The amount of ethanol absorbed after oral administration is dependent on a number of factors, but increases with fasting, nutritional status, accelerated gastric emptying, female gender, genetics, chronic alcoholism, lean body mass, increasing age, as well as in the presence of certain H2 antagonists.3,6,11,21,42,44 Sufficient concentrations are generally achieved when 0.8 g/kg of ethanol is given orally over 20 minutes.3,5,6,11,21,40 The objective, regardless of route, is rapidly to achieve and maintain a level of at least 100 mg/dL of ethanol, which proves adequate to achieve enzyme inhibition in most cases. Inhibition is best achieved by administering a loading dose of ethanol followed by a maintenance dose. The volume of distribution for ethanol is

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

approximately 0.6 L/kg.45 Therefore, the loading dose of ethanol is given by the following formula: Loading dose = C p × Vd = 1 g / L (100 mg / dL) × 0.6 L / kg = 0.6 g / kg C p = plasma concentration which for this agent is comparable to the serum concentration For a 70-kg person, this would be 42 g (70 kg × 0.6 g/kg) of ethanol or 420 mL of 10% V/V ethanol. However, 0.8 g/kg or 8 mL/kg loading dose of a 10% ethanol solution is recommended in order to provide a margin of safety because of the variability in bioavailability and the ongoing metabolism that occurs during administration. The IV loading dose should be administered over 20–60 minutes as tolerated by the patient. The 10% ethanol concentration is preferable to the 5% concentration so as to limit the volume of fluid administered and is preferred to the more concentrated solutions thereby limiting local venous irritation and avoiding postinfusion phlebitis. Because of the free water content and significant hypertonicity of this solution, the patient should be closely observed for the development of hyponatremia. A second IV line using 0.9% sodium chloride solution may be necessary to avoid this complication which is not associated with oral administration. To maintain an ethanol concentration of 100 mg/dL, enough ethanol has to be administered to replace that which is being eliminated (66–130 mg/kg/h). The average hourly dose for a 70-kg person is 4.6 g, but higher doses are required in chronic alcoholics

TABLE 66–4.

(100–154 mg/kg/h) and in those undergoing hemodialysis (250–350 mg/kg/h; Chap. 6).8,16,26,31 Because ethanol elimination varies in each individual, frequent serum ethanol determinations should be made to ensure adequate dosing. Any increase in the anion gap or decrease in bicarbonate concentration implies that the ethanol dose is inadequate to achieve blockade of alcohol dehydrogenase. Problems encountered with the administration of ethanol include further risk of central nervous system depression or ethanol related toxicities such as hepatitis and pancreatitis, hypoglycemia, dehydration, and fluctuating serum concentrations. Therefore, blood glucose and serum ethanol concentrations should be monitored and attention paid to adequate fluid management.

AVAILABILITY A more practical problem often involves finding or preparing the ethanol to be given. Hospital pharmacies and emergency departments should stock ethanol for such a purpose. Commercial preparations of 5% ethanol in 5% dextrose are available for IV administration. Alternatively, sterile ethanol USP (absolute ethanol) can be added to 5% dextrose to make a solution of approximately 10% ethanol concentration. A 10% ethanol solution is preferred to limit the volume of fluid administered. Then 55 mL (not 50 mL) of absolute ethanol is added to 500 mL of 5% dextrose, to produce a total end volume of 555 mL (10% = 10 mL in 100 mL, in this case, 55 mL in 555 mL or 55/555). If oral administration is chosen, it is important to remember that 100-proof ethanol is 50% ethanol. Oral ethanol is preferable if this route is

Intravenous Administration of 10% Ethanol

c

Volume (mL)b (given over 1 hour as tolerated)

Loading Dose

Loading dose of 0.8 g/kg of 10% ethanol (infused over 1 hour as tolerated)

10 kg

15 kg

30 kg

50 kg

70 kg

100 kg

80

120

240

400

560

800

Maintenance Dosea

Infusion Rateb (mL/h for various weights)d 10 kg

15 kg

30 kg

50 kg

70 kg

100 kg

Normal Maintenance Range 80 mg/kg/h 110 mg/kg/h 130 mg/kg/h

8 11 13

12 16 19

24 33 39

40 55 65

56 77 91

80 110 130

Approximate Maintenance Dose for Chronic Alcoholic 150 mg/kg/h

15

22

45

75

105

150

Range Required During Hemodialysis 250 mg/kg/h 300 mg/kg/h 350 mg/kg/h

25 30 35

38 45 53

75 90 105

125 150 175

175 210 245

250 300 350

a

Infusion to be started immediately following the loading dose. Concentrations above 10% are not recommended for IV administration. The dose schedule is based on the premise that the patient initially has a zero ethanol level. The aim of therapy is to maintain a serum ethanol level of 100–150 mg/dL, but constant monitoring of the ethanol level is required because of wide variations in endogenous metabolic capacity. Ethanol will be removed by hemodialysis, and the infusion rate of ethanol must be increased during hemodialysis. Prolonged ethanol administration may lead to hypoglycemia. b For a 5% concentration, multiply the amount by 2. c A 10% V/V concentration yields approximately 100 mg/mL. d Rounded to the nearest mL. Reprinted, with permission, from Roberts JR, Hedges J, eds: Clinical Procedures in Emergency Medicine. Philadelphia, WB Saunders, 1985, pp.1073–1074.

CHAPTER 66

TABLE 66–5.

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TOXIC ALCOHOLS

Oral Administration of 20% Ethanol

b

Loading Dose

Loading dose of 0.8 g/kg of 20% ethanol, diluted in juice. May be administered orally or via nasogastric tube

Volume (mL) 10 kg

15 kg

30 kg

50 kg

70 kg

100 kg

40

60

120

200

280

400

Maintenance Dosea

mL/h for various weightsc,d 10 kg

15 kg

30 kg

50 kg

70 kg

100 kg

Normal Maintenance Range 80 mg/kg/h 110 mg/kg/h 130 mg/kg/h

4 6 7

6 8 10

12 17 20

20 27 33

28 39 46

40 55 66

Approximate Range for Chronic Alcoholic or Patient Receiving Continuous Oral Activated Charcoal 150 mg/kg/h

8

11

22

38

53

75

Range Required During Hemodialysis 250 mg/kg/h 300 mg/kg/h 350 mg/kg/h

13 15 18

19 23 26

38 46 53

63 75 88

88 105 123

125 150 175

a

Concentrations above 30% (60 proof) are not recommended for oral administration. The dose schedule is based on the premise that the patient initially has a zero ethanol level. The aim of therapy is to maintain a serum ethanol level of 100–150 mg/dL, but constant monitoring of the ethanol level is required because of wide variations in endogenous metabolic capacity. Ethanol will be removed by hemodialysis, and the dose of ethanol must be increasing during hemodialysis. Prolonged ethanol administration may lead to hypoglycemia. b A 20% V/V concentration yields approximately 200 mg/mL. c Rounded to the nearest mL. d For a 30% concentration, multiply the amount by 0.66. Reprinted, with permission, from Roberts JR, Hedges J, eds: Clinical Procedures in Emergency Medicine. Philadelphia, WB Saunders, 1985, pp. 1073–1074.

acceptable. If there will be any delay in obtaining ethanol for intravenous use, oral therapy with ethanol should be initiated immediately.

ing organs, how well the body can eliminate the parent compound, and the amount of toxic metabolites already present in the body.

COMPARISON TO FOMEPIZOLE

REFERENCES

Although ethanol has been used as an antidote for years and has the advantages of easy access and low cost, fomepizole is a very potent inhibitor of alcohol dehydrogenase with many favorable attributes. Fomepizole does not produce central nervous system (CNS) depression. Fomepizole is easier to dose and does not require serum concentration monitoring. Adverse effects currently reported are limited and include nausea, dizziness, anxiety, headache, with fewer reports of rash, transient elevated aminotransferases, eosinophilia, and local reactions at the site of infusion when concentrated solutions are used (see Antidote in Depth: Fomepizole and Chap. 66).

SUMMARY When administered appropriately, ethanol is an excellent first step in preventing further metabolism of methanol and ethylene glycol. This is particularly true when CNS depression is not an immediate concern. However, both fomepizole and ethanol do not affect the toxic metabolites that are already present in the body. Once alcohol dehydrogenase is blocked, the decision to use hemodialysis will depend on how much damage has been done to the eliminat-

1. Agner K, Hook O, Von Porat B: The treatment of methanol poisoning with ethanol. J Stud Alcohol 1949;9:515–522. 2. Brent J, McMartin K, Phillips SP, et al: Fomepizole for the treatment of methanol poisoning. N Engl J Med 2001;344:424–429. 3. Caballeria L: First-pass metabolism of ethanol: Its role as a determinant of blood alcohol levels after drinking. Hepatogastroenterology 1992;39:62–66. 4. Cheng JT, Beysolow TD, Kaul B, Weisman R, Feinfeld DA: Clearance of ethylene glycol by kidneys and hemodialysis. J Toxicol Clin Toxicol 1987;25:95–108. 5. Cobaugh DJ, Gibbs M, Shapiro DE, et al: A comparison of the bioavailabilities of oral and intravenous ethanol in healthy male volunteers. Acad Emerg Med 1999;6:984–988. 6. Cole-Harding S, Wilson JR: Ethanol metabolism in men and women. J Stud Alcohol 1987;48:380–387. 7. Davis DP, Bramwell KJ, Hamilton RS, Williams SR: Ethylene glycol poisoning: Case report of a record-high level and a review. J Emerg Med 1997;15:653–667. 8. Ekins BR, Rollins DE, Duffy DP, Gregory MC: Standardized treatment of severe methanol poisoning with ethanol and hemodialysis. West J Med 1985;142:337–340. 9. Faci A, Plaa GL, Sharkawi M: Chloral hydrate enhances ethanolinduced inhibition of methanol oxidation in mice. Toxicology 1998; 131:1–7.

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10. Fillmore MT, Vogel-Sprott M: Behavioral impairment under alcohol: Cognitive and pharmacokinetic factors. Alcohol Clin Exp Res 1998; 22:1476–1482. 11. Fraser AG, Hudson M, Sawyer AM, et al: Ranitidine, cimetidine, famotidine have no effect on post-prandial absorption of ethanol (0.8 g/kg) taken after an evening meal. Aliment Pharmacol Ther 1992;6: 693–700. 12. Grauer G, Thrall MA, Henre B, et al: Comparison of the effects of ethanol on 4-methylpyrazole on the pharmacokinetics and toxicity of ethylene glycol in the dog. Toxicol Lett 1987;35:307–314. 13. Hantson P, Wallemacq P, Brau M: Two cases of acute methanol poisoning partially treated by oral 4-methylpyrazole. Intensive Care Med 1999;25:528–531. 14. Hauser J, Szabo S: Extremely long protection by pyrazole derivatives against chemically induced gastric mucosal injury. J Pharmacol Exper Ther 1991;256:592–598. 15. Jacobsen D, Jansen H, Wiik-Larsen E, et al: Studies on methanol poisoning. Acta Med Scand 1982;212:5–10. 16. Jacobsen D, McMartin KE: Methanol and ethylene glycol poisonings: Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1:309–334. 17. Jacobsen D, Sebastian CS, Barron SK, et al: Effects of 4-methylpyrazole, methanol/ethylene glycol antidote, in healthy humans. J Emerg Med 1990;8:455–461. 18. Jacobsen D, Webb R, Collins TD, McMartin KE: Methanol and formate kinetics in late diagnosed methanol intoxication. Med Toxicol 1988;3:418–423. 19. Jones AW, Jönsson KA, Kechagias S: Effect of high-fat, high-protein, and high-carbohydrate meals on the pharmacokinetics of a small dose of ethanol. Br J Clin Pharmcol 1997;44:521–526. 20. Julkunen RJ, Tannenbaum L, Baradna E, et al: First pass metabolism of ethanol: An important determinant of blood levels after alcohol consumption. Alcohol 1985;2:437–441. 21. Korman MG, Bolin TD: Alcohol and H2-receptor antagonists. Med J Aust 1992;157:730–731. 22. Li TK, Theorell H: Human liver alcohol dehydrogenase: Inhibition by pyrazole and pyrazole analogs. Acta Chem Scand 1969;23:892–902. 23. Lieber CS: Gastric ethanol metabolism and gastritis: Interactions with other drugs, Helicobacter pylori, and antibiotic therapy (1957– 1997)—A review. Alcohol Clin Exp Res 1997;21:1360–1366. 24. Makar AB, Tephly TR, Mannering GJ: Methanol metabolism in the monkey. Mol Pharmacol 1968;4:471–483. 25. Makar AB, Tephly TR: Inhibition of monkey liver alcohol dehydrogenase by 4-methylpyrazole. Biochem Med 1975;13:334–342. 26. McCoy HG, Cipolle RJ, Ehlers SM, et al: Severe methanol poisoning: Application of a pharmacokinetic model for ethanol therapy and hemodialysis. Am J Med 1979;67:804–807. 27. McKnight AJ, Langston EA, Marques PR, Tippetts AS: Estimating blood alcohol level from observable signs. Accid Anal Prev 1997;29: 247–255. 28. McMartin KE, Hedström K, Told B, et al: Studies on the metabolic interactions between 4-methylpyrazole and methanol using the monkey as an animal model. Archiv Biochem Biophys 1980;199:606–614.

29. McMartin KE, Makar AB, Palese MA, Tephly TR: Methanol Poisoning I. The role of formic acid in the development of metabolic acidosis in the monkey and the reversal by 4-methylpyrazole. Biochem Med 1975;13:319–333. 30. Papineau KL, Roehrs TA, Petrucelli N, et al: Electrophysiological assessment (the multiple sleep latency test) of the biphasic effects of ethanol in humans. Alcohol Clin Exp Res 1998;22:231–235. 31. Peterson C: Oral ethanol doses in patients with methanol poisoning. Am J Hosp Pharm 1981;38:1024–1027. 32. Peterson CD, Collins AJ, Himes JM, et al: Ethylene glycol poisoning: Pharmacokinetics during therapy with ethanol and hemodialysis. N Engl J Med 1981;304:21–23. 33. Pietruszko R: Human liver alcohol dehydrogenase inhibition of methanol activity by pyrazole, 4-methylpyrazole, 4-hydroxymethylpyrazole and 4-carboxypyrazole. Biochem Pharmacol 1975;24: 1603–1607. 34. Pietruszko R, Voigtlander K, Lester D: Alcohol dehydrogenase from human and horse liver—Substance specificity with diols. Biochem Pharmacol 1978;27:1296–1297. 35. Rainey PM: Relation between serum and whole-blood ethanol concentrations. Clin Chem 1993;39:2288–2292. 36. Roe O: Methanol poisoning: Its clinical course, pathogenesis and treatment. Acta Med Scand 1946;126(Suppl 182):1–253. 37. Sivilotti ML, Burns MJ, McMartin KE, Brent J: Toxicokinetics of ethylene glycol during fomepizole therapy: Implications for management. For the Methylpyrazole for Toxic Alcohols Study Group. Ann Emerg Med 2000;36:114–125. 38. Sullivan M, Chen C, Madden JF: Absence of metabolic acidosis in toxic methanol ingestion: A case report and review. Del Med J 1999; 71:421–426. 39. Tarr B, Winters L, Moore M, et al: Low-dose ethanol in the treatment of ethylene glycol poisoning. J Vet Pharm Ther 1985;8:254–262. 40. Tomaszewski C, Cline DM, Whitley TW, Grant T: Effect of acute ethanol ingestion on orthostatic vital signs. Ann Emerg Med 1995; 25:636–641. 41. Vassiliadis J, Graudins A, Dowsett RP: Triethylene glycol poisoning treated with intravenous ethanol infusion. J Toxicol Clin Toxicol 1999;37:773–776. 42. Vestal RE, McGuire EA, Tobin JD, et al: Aging and ethanol metabolism. Clin Pharmacol Ther 1975;21:343–353. 43. Wacker WE, Haynes H, Druyan R, et al: Treatment of ethylene glycol poisoning with ethyl alcohol. JAMA 1965;194:173–175. 44. Whitfield JB: ADH and ALDH genotypes in relation to alcohol metabolic rate and sensitivity. Alcohol Alcohol 1994;2:59–65. 45. Wilkinson P: Pharmacokinetics of ethanol: A review. Alcohol Clin Exp Res 1980;4:6–21. 46. Williams CS, Woodcock KR: Do ethanol and metronidazole interact to produce a disulfiram-like reaction? Ann Pharmacother 2000; 34: 255–257.

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ANTIDOTES IN DEPTH

Fomepizole Mary Ann Howland

Fomepizole is a competitive inhibitor of alcohol dehydrogenase (ADH) that is useful in preventing the formation of toxic metabolites from ethylene glycol and methanol. It may also have a role in halting the disulfiram-ethanol reaction, and in limiting the toxicity from a variety of xenobiotics that rely on alcohol dehydrogenase for metabolism to toxic metabolites. In addition, as an inducerinhibitor of certain cytochrome P450 isoenzymes it may lead to desirable or undesirable drug interactions.

HISTORY In 1963, Theorell and associates described the inhibiting effect of pyrazole on the horse ADH-NAD+ (nicotinamide adenine dinucleotide) enzyme-coenzyme system.56 Pyrazole appeared to block ADH by complexation. Administration to rats and dogs previously poisoned with methanol and ethylene glycol improved survival.58 However, pyrazole also inhibited other liver enzymes, including catalase and the microsomal ethanol-oxidizing system.39 Additional adverse effects of pyrazole administration resulted in bone marrow, liver, and renal toxicity, and these effects were increased in the presence of ethanol and methanol.48 These factors led to the search for less toxic compounds with comparable mechanisms of action. In 1969, Li and Theorell found that pyrazole and 4-methylpyrazole (fomepizole) inhibited ADH found in human liver preparations.38 Studies in rats and mice using fomepizole found the agent to be relatively nontoxic whether used alone or with ethanol.6 Subsequent studies in monkeys and humans with methanol and ethylene glycol poisoning have demonstrated the inhibitory effect and relative safety of fomepizole.10,11,48

PHARMACOLOGY Fomepizole has a molecular weight of 82 daltons and a pKa of 2.91 at low concentrations and 3.0 at high concentrations. The freebase is chemically equivalent to the chloride and sulfate salts at physiologic pH.14 The freebase is used in the United States, while the salts have been used in Europe. Values for Km have been estimated for the toxic alcohols along with the value for Ki with fomepizole. The smaller the Km the

higher the affinity of the substrate for the enzyme and the lower the concentration of the substrate (ie, alcohol) that is needed to half saturate the enzyme. Studies in monkey liver and human liver demonstrate that fomepizole is a competitive inhibitor of alcohol dehydrogenase.42,54 In monkey liver, fomepizole demonstrated very similar Kis for both ethanol and methanol at 7.5 and 9.1 µmol, respectively.42 In this same model, the Km was 3.2 for ethanol and 20.1 mmol for methanol, demonstrating a 6 times higher affinity of ethanol for alcohol dehydrogenase than methanol,42 while the ratio was 15 times higher when human liver was used.53 Studies in monkeys demonstrate that a concentration of fomepizole of about 9–10 µmol/L (74–82 µg/dL, 0.74–0.8 µg/mL) is needed to inhibit the metabolism of methanol to formate.6,48 In human liver, the level needed to achieve inhibition is about 0.09–1 µmol.38,53 The most recent trial that used intravenous fomepizole in the approved dosing regimen for patients poisoned with methanol, attempted to maintain a serum fomepizole concentration ≥0.8 µg/mL. CYP2E1 isoenzyme oxidizes ethanol and a number of xenobiotics to toxic metabolites including acetaminophen, carbon tetrachloride, nitrosamines, and benzene. Fomepizole, like ethanol and isoniazid, has dual effects on this isozyme. Fomepizole induces this isoenzyme in rats in the liver and kidney but not in the lung through a posttranscriptional mechanism not involving increased mRNA. However, while fomepizole is present the isozyme is inhibited. After fomepizole is eliminated, the consequences of induction would be manifest.8,60,61 In hepatocyte culture, fomepizole appears to stabilize and maintain the induced metabolic activity of the isoenzyme for about a week.62

PHARMACOKINETICS Fomepizole has a volume of distribution of about 0.6–1 L/kg and is metabolized to 4-carboxpyrazole, an inactive metabolite that accounts for 80–85% of the administered dose. In a healthy human volunteer study, oral doses of fomepizole were rapidly absorbed and demonstrated saturation and nonlinear kinetics.27 The Km (concentration at which the maximum elimination rate is 50%) was estimated to be 75 µmol/L, as compared to 6 µmol/L in a dog model.27,44 First-order kinetics were exhibited at concentrations below the Km, while zero order elimination occured at concentrations 100–200% of the Km.27 The elimination of fomepizole at 10 mg/kg, 20 mg/kg, 50 mg/kg, and 100 mg/kg was 3.66, 5.05, 10.3, and 14.9 µmol/L/h, respectively.27 Classical Michaelis-Menten kinetics predicts that the elimination rate is the same at the two higher doses, but this was not the case. The authors speculate that multiple metabolic pathways with different affinities exist and predominate at different fomepizole concentrations. After 20 mg/kg, the half-life of fomepizole calculated from the linear portion of the curve was 5.2 hours and occurred when serum concentrations were less than 100 µmol/L. Peak concentrations after oral administration were achieved within 2 hours and were 132, 326, 759, and 1425 µmol following 10, 20, 50, and 100 mg/kg doses, respectively. Every mg/kg oral dose of fomepizole raised the serum con-

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centration 13–16 µmol.27 The renal clearance was low (0.016 mL/min/kg), and only 3% of the administered dose was excreted unchanged in the urine.27 The pharmacokinetics of intravenous fomepizole were studied in 14 patients being treated for ethylene glycol toxicity.45 A mean peak concentration of 342 µmol (200–400 µmol) was achieved following a loading dose of 15 mg/kg (183 µmol/kg). Supplemental doses of fomepizole of 10 mg/kg every 12 hours for 48 hours followed by 15 mg/kg every 12 hours until ethylene glycol levels were less than 20 mg/dL and every 4 hours during hemodialysis were administered.45,55 The effect of simultaneous plasma ethanol concentrations was not analyzed. The lowest fomepizole plasma concentration of 105 µmol was present at 8 hours after the loading dose. The rate of elimination was determined to be zero order at 16 µmol/L/h as compared with a first-order elimination half-life of 3 hours during hemodialysis. Other authors have reported similar fomepizole clearances (12.99 µmol/L/h).12 The plasma clearance of fomepizole during hemodialysis was 230 mL/min. Previous analysis using determinations of dialysis fluid revealed an extraction ratio of about 75% and a dialysance of 117 mL/min, which was very similar to a simultaneous ethylene glycol determination.17 The Vd was 0.69 L/kg.45 The dialysance of fomepizole was similar to urea in a pig model and suggests no significant protein binding of fomepizole.28 The pharmacokinetic interactions between fomepizole and ethanol were studied in a double-blind crossover design in healthy human volunteers.32 Fomepizole was given orally in doses of 10, 15, and 20 mg/kg 1 hour prior to oral ethanol at 0.5–0.7 g/kg as a 20% solution in orange juice. Fomepizole decreased the elimination rate of ethanol by about 40% from 12–16 mg/dL/h to about 7–9.5 mg/dL/h. When intravenous fomepizole was administered at 5 mg/kg over 30 minutes and ethanol in doses to achieve 50–150 mg/dL for 6 hours were administered orally beginning at the end of the fomepizole infusion, the elimination of fomepizole was decreased by about 50%.32 This occurred without a change in the amount or fraction of unchanged fomepizole appearing in the urine. The authors suggested that the ethanol probably inhibited the metabolism of fomepizole to 4-carboxypyrazole by the cytochrome P450 system. A single low dose of fomepizole given to humans had a maximal effect on ethanol metabolism at 1.5–2 hours.5 Therefore ethanol and fomepizole mutually inhibit the elimination of each other prolonging their respective plasma concentrations. Methanol also decreases the elimination of fomepizole by about 25% in the monkey.48

METHANOL In Vitro and Animal Studies Studies using human livers demonstrate the inhibitory effect of fomepizole on alcohol dehydrogenase.53 Studies in monkeys, the animal species that most closely resembles humans in metabolizing methanol, also clearly demonstrates the inhibitory effect of fomepizole in preventing the accumulation of formate.4,48,49

Human Experience The largest case series to date involved 11 patients given IV fomepizole in the approved US dosing regimen.11 The formate levels in all patients administered fomepizole fell and the arterial pH increased.11 Case reports demonstrate similar findings.12,23,19

Effect of Fomepizole on Methanol and Formate Concentrations Methanol exhibits dose-dependent kinetics.31 At low doses (0.08 g/kg), which achieve serum concentrations of about 10 mg/dL, methanol elimination is first order with a half-life of about 2.5–3 hours.35,37 In concentrations of about 100–200 mg/dL, methanol exhibits zero-order kinetics and is eliminated at about 8.5–9 mg/dL/h in untreated humans33 and 4.4–7 mg/dL/h in untreated monkeys.16,51 At very high methanol doses in monkeys (3 g/kg), achieving serum concentrations of about 500 mg/dL, the elimination of methanol again exhibits apparent first-order kinetics. This alteration is likely caused by the greater contribution of other firstorder pathways, such as pulmonary and urinary elimination, which may account for a greater fraction of the total body clearance under these circumstances.33 Once fomepizole is administered in doses sufficient to achieve a minimum effective concentration to inhibit alcohol dehydrogenase the elimination of methanol becomes first order in humans and the half-life of methanol is about 54 hours.11 When the metabolism of methanol to formate by alcohol dehydrogenase is blocked, formate is eliminated with a halflife dependent on dose and the uncertain effect of folate and bicarbonate therapies. In monkeys administered formate without the presence of methanol, the formate half-life is 30–50 minutes.15 In monkeys given methanol followed by fomepizole, the formate levels decreased by more than 80% in 2 hours.4

ETHYLENE GLYCOL In Vitro and Animal Studies Monkeys given 3 g/kg of ethylene glycol intraperitoneally recovered without treatment, whereas those given 4 g/kg died without therapy and those given 4 g/kg with fomepizole all survived.15

Human Experience The first 3 patients treated in France with oral fomepizole improved clinically and tolerated the therapy.1 Subsequent case reports and case series utilizing fomepizole orally or IV with or without hemodialysis have also demonstrated its effectiveness in preventing glycolate accumulation.2,7,10,22,24,34,50,55

Effect of Fomepizole on Ethylene Glycol and Glycolate Concentrations in Humans Kidney function is essential in the elimination of ethylene glycol. The half-life of ethylene glycol at low concentrations is about 8.6 hours.55 Based on pooled human data, the half-life of ethylene glycol after alcohol dehydrogenase is blocked with fomepizole is about 14–17 hours in those patients with normal renal function, and about 49 hours in patients with impaired renal function.1,24,55 Based on a limited number of determinations, the renal clearance of ethylene glycol averaged 31.5 mL/min during the first 2 days; the corresponding creatinine clearance was 112 mL/min and estimated total body clearance during fomepizole therapy was 57 mL/min.2 These calculations suggest that the renal clearance of ethylene glycol accounted for only 55% of estimated total body clearance. Glycolate (MW 76 daltons) had a mean half-life of 10 ± 8 hours in patients treated with fomepizole before hemodialysis, and a mean half-life of less than 3 hours during hemodialysis,50 although in this study, patient renal function is not defined

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nor is the amount of glycolate excreted unchanged by the kidneys described.

SAFETY AND ADVERSE EFFECTS Because retinol dehydrogenase is an isozyme of ADH, and because it is responsible for converting retinol to retinal in the eye, it was essential to study whether fomepizole would inhibit this enzyme and subsequently produce retinal damage.48 Studies in several species of monkeys and other animals demonstrate that fomepizole is relatively nontoxic, with no demonstrated signs of ocular toxicity.4 An oral placebo-controlled, double-blind, single-dose randomized sequential ascending-dose study was performed in healthy volunteers to determine fomepizole tolerance at 10–100 mg/kg.31 There were no adverse effects in the 10 and 20 mg/kg groups, while at 50 mg/kg 3 of 4 subjects experienced slight to moderate nausea and dizziness within 2.5 hours of medication administration. All subjects reported comparable symptoms at 100 mg/kg. These symptoms lasted for 30 hours in 1 individual. There were no concomitant changes in any vital sign or laboratory parameter measured. Divided daily doses of fomepizole up to 20 mg/kg for 5 days have been administered without any demonstrable toxicity.47 A transient elevation of aminotransferase levels was reported in 6 of 15 healthy volunteer subjects who received fomepizole.30 The most common adverse effects reported by the manufacturer in a total of 76 patients and 63 volunteers were headache 12%, nausea 11%, and dizziness 7%. Other less commonly observed adverse effects include phlebitis, rash, fever, and eosinophilia. In the two largest cases series of fomepizole treatment for ethylene glycol toxicity and for methanol toxicity, there were no adverse events classified as definitely or probably related to fomepizole.10,11 The LD50 of fomepizole in mice and rats is 3.8 mmol/kg after IV administration and 7.9 mmol/kg following oral administration.41

DISULFIRAM AND OTHER TOXINS Fomepizole was successfully used to terminate the reactions (a) resulting from the use of an acetaldehyde inhibitor administered to volunteers pretreated with a small dose of ethanol and (b) occurring in a chronic alcoholic surreptitiously given disulfiram by his wife.40 The intravenous administration of fomepizole prevented the accumulation of acetaldehyde by inhibiting its formation and allowing elimination to predominate thereby lessening the typical symptoms of facial flushing and tachycardia.40 Pretreatment with oral fomepizole was successful in preventing the facial flushing and tachycardia typically associated with ethanol administration in ethanol sensitive Japanese subjects.25,26 Limited animal studies and a few case reports suggest that fomepizole may be effective in limiting the toxicity secondary to diethylene glycol, triethylene glycol and 1,3-difluoro-2-propanol.7,18,57

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to that of the methanol or ethylene glycol; dosing difficulties as a result of its rapid and often unpredictable rate of metabolism; the development of tolerance; the lack of ready availability of an intravenous formulation; the necessity of closely monitoring serum concentrations; the hyperosmolarity of a 5% or 10% intravenous preparation;63 and the potential for hypoglycemia or other ethanolrelated adverse effects such as pancreatitis and hepatitis. Fomepizole has the advantage of being a very potent inhibitor of alcohol dehydrogenase without producing central nervous system (CNS) depression, having an easier dosing schedule without the need for serum concentration monitoring which allows every 12-hour dosing except during hemodialysis, when dosing should occur every 4 hours. Limited adverse effects include local reactions at the site of infusion when concentrations >25 mg/mL are employed, and nausea, dizziness, anxiety, headache, rash, transiently elevated aminotransferases, and eosinophilia.

DOSING The loading dose is 15 mg/kg followed in 12 hours by 10 mg/kg every 12 hours for 4 doses, and then increased to 15 mg/kg every 12 hours for as long as necessary. The increase in the maintenance dose from 10 mg/kg to 15 mg/kg is recommended because fomepizole causes autoinduction, stimulating its own metabolism. Patients undergoing hemodialysis require additional doses of fomepizole to replace the amount removed during hemodialysis. The dose must be diluted in 100 mL of normal saline (NS) or D5W prior to IV administration and then infused over 30 minutes to avoid local reactions.

AVAILABILITY Fomepizole has received FDA approval and is now marketed as Antizol injection by Orphan Medical. Fomepizole is available in a tray pack containing 4 vials (1.5 mL vials of 1 g/mL) that can be diluted in 100 mL of D5W or NS for adults to be administered intravenously over 30 minutes. Temperatures of mescaline Sold as impregnated paper, like LSD Delayed onset of action, peak 3–4 h Fantasy, mood altering, for 10 h, resolution 12–24 h Agitation, sympathetic excess

4-Bromo-2,5-methoxyphenyl-ethylamine (2CB, MFT)

Relaxation Sensory distortion Agitation Hallucinations Potency > mescaline

Methcathinone (cat, Jeff, Khat, ephedrone)

Comparable to hallucinogenic and sympathetic effects of methamphetamine

3,4-Methylenedioxyamphetamine (MDA, love drug)

Empathy, euphoria Agitation, delirium, hallucinations, death associated with sympathetic excess

4-Methyl-2,5-dimethoxyamphetamine (DOM/STP) (serenity, tranquility, peace)

Narrow therapeutic index Euphoria, perceptual distortion Hallucinations, sympathetic stimulation

3,4-Methylenedioxyethamphetamine (MDEA, Eve)

Comparable to MDMA Sympathetic excess

3.4-Methylenedioxymethamphetamine (MDMA, Adam, ecstasy, XTC)

Psychotherapy “facilitator” Euphoria, empathy Nausea, anorexia Anxiety, insomnia Sympathetic excess

Para-methoxyamphetamine (PMA)

Potent hallucinogen Marked stimulant effect

2,4,5-Trimethoxyamphetamine

Similar to mescaline

Structure

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PHARMACOLOGY The pharmacologic effects of amphetamines are complex but the primary mechanism of action is the release of catecholamines, particularly dopamine and norepinephrine, from the presynaptic terminals. Although there are conflicting mechanistic models of the amphetamines induction of catecholamine release, the variable results may be directly correlated with the different concentrations of amphetamines used in the studies. The best models to study the mechanism of action of amphetamines are based on dopaminergic neurons; similar mechanisms are invoked for norepinephrine and serotonin. Two storage pools exist for dopamine in the presynaptic terminals: the vesicular pool and the cytoplasmic pool. The vesicular storage of dopamine and other biogenic amines is maintained by the acidic environment inside the vesicles and the persistence of a stabilizing electrical gradient with respect to the cytoplasm. This environment is preserved by an ATP-dependent active proton transport system.225 At low doses, amphetamines cause release of dopamine from the cytoplasmic pool by exchange diffusion at the dopamine uptake transporter site in the membrane. At moderate doses, amphetamines can also diffuse through the presynaptic terminal membrane and interact with the neurotransmitter transporter on the vesicular membrane to cause exchange release of dopamine into the cytoplasm. Dopamine is subsequently released into the synapse by reverse transport at the dopamine uptake site.225,239 At high doses, an additional mechanism is invoked, as amphetamine diffuses through the cellular and vesicular membranes, alkalinizing the vesicles, permitting dopamine release from the vesicles and delivery into the synapse by reverse transport.240,241 Amphetamines may also block the reuptake of catecholamines similarly to other catecholamine-releasing agents by competitive inhibition.95,110 However, the effects of this mechanism are considered to be minor. At higher doses, amphetamines can cause the release of serotonin (5-hydroxytryptamine, 5-HT) and affect central serotonin receptors. Certain amphetamines, such as MDMA and 4-bromo-2,5-dimethoxyamphetamine (DOB), have more significant serotonergic effects.86,110 Amphetamines are structurally similar to nonhydrazine amine-derivative monoamine oxidase inhibitors such as phenelzine and tranylcypromine, and most also have weak monoamine oxidase inhibiting activities, but the significance of this inhibition is unknown.195 The most identifiable effects of amphetamines are those caused by catecholamine release and the resultant stimulation of peripheral - and
-adrenergic receptors. The increased norepinephrine at the locus ceruleus mediates the anorectic and alerting effects, and some of the locomotor-stimulating effects as well.95 The increase in central dopamine (particular at the neostriatum) mediates stereotypical behavior and some of the other locomotor activities.47,86,95,126 The activity of dopamine in the neostriatum appears to be linked to glutamate release and inhibition of GABAergic efferent neurons.86,125,126 Stimulation of the glutamatergic system contributes significantly to the stereotypical behavior, locomotor activities, and neurotoxicity of amphetamines.18,23,125,126,236,237 The effects of serotonin and dopamine on the mesolimbic system alter perception and cause psychotic behavior.86,109,172 Because amphetamines directly interact with neurotransmitter transporters, minor modification of the molecule may significantly alter its pharmacologic profile.114 The -methyl group in amphetamines introduces chirality to the molecule. Except for MDMA

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and certain MDMA analogues, the d-enantiomers are much more potent (typically 4–10 times) than l forms of amphetamines. Substitution at different positions of the phenylethylamine molecule alters general clinical effects of amphetamines, as demonstrated by animal discrimination studies and human observations. Compounds with methyl substitution at the  carbon, such as amphetamine and methamphetamine, possess strong stimulant, cardiovascular, and anorectic properties.83,181 Large group substitution at the  carbon reduces the stimulant and cardiovascular effects, but retains the anorectic properties (such as in phentermine).12 Substitution at the para position of the phenyl ring enhances the hallucinogenic or serotonergic effects of amphetamines (such as in p-chloroamphetamine and MDMA).12,83,181 Although some of these generalizations enable scientists to understand the effects of amphetamines, there are many exceptions, and such generalization may not apply when large doses of a particular molecule are employed.67 In terms of the spectrum of activities, methamphetamine has the most potent cardiovascular effects, and DOB has the most potent hallucinogenic or serotonergic effects.83,181

Methamphetamine Methamphetamine abuse in the United States is not new. From the 1950s to the 1970s, there were multiple epidemics of methamphetamine abuse.17 Methamphetamine was and sometimes still is referred to as “crack,” “speed,” “yaba,” and “go.” The pharmacologic profile of methamphetamine is quite similar to amphetamine, although the effects on the central nervous system are more substantial.38 “Ice,” the most recent common name for methamphetamine, does not differ pharmacologically from other forms of methamphetamine. Methamphetamine is readily absorbed by the oral, parenteral, and inhalational routes. Because of a prolonged half-life of 19–34 hours, the duration of its acute effects can be greater than 24 hours.38,59,60 Since the 1990s, the activity and purity of methamphetamine available on the street is substantially higher than previous epidemics because of the method of synthesis.146 Methamphetamine is now typically greater than 80–90% pure and almost exclusively in the dextroisomer form, which is most active on the central nervous system (CNS). The ephedrine method, using pharmaceutical grade L-ephedrine, produces a product with few contaminants that is stereochemically pure.59,197 The production of the large crystal is possible by creating a supersaturated solution of methamphetamine hydrochloride.59 Methamphetamine can be easily synthesized with the proper chemicals and minimal equipment.79 The primary ingredient of methamphetamine synthesis is ephedrine, which can be hydrogenated into methamphetamine. Phenyl-2-propanone (P2P), as an alternative ingredient, can be methylated into ephedrine and then into methamphetamine.26 Because of the strict control of ephedrine and P2P, illicit chemists use phenylacetic acid to synthesize P2P.26,51 Lead acetate, which is used as a substrate for the reaction, resulted in an epidemic of lead poisoning associated with methamphetamine abuse in Oregon.3,36 Lead levels reported in drug users were as high as 513 µg/dL, and some samples of illicit manufactured methamphetamine had lead contents as high as 60% by weight.36 Mercury contamination was also documented, although clinical mercury toxicity has not been reported.26 The number of potential chemicals involved in the methamphetamine

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manufacturing process is significant, and without any legal monitoring, contamination of the product and the environment is inevitable.4,26,113,139 In fact, 30% of the illicit methamphetamine manufacturing sites discovered in Oregon were discovered because of laboratory explosion. In California’s San Bernadino County alone in 1995, 360 methamphetamine laboratories were identified and closed by drug enforcement agents.72 Currently, sale of other potential amphetamine synthesis ingredients such as hydrochloric acid, hydrogen chloride gas, red phosphorous, and iodine are also monitored and restricted in the United States.

3,4-Methylenedioxymethamphetamine (MDMA) MDMA was first synthesized in 1912, and was rediscovered in 1965 by Shulgin.25 It is currently one of the most widely abused amphetamines by college students and teenagers.43,191,249,253 It is commonly known as “ecstasy,” “E,” “Adam,” “XTC,” “M&M,” and “MDM.” Other structural relatives of MDMA, MDEA (“Eve”) and MDA (“love drug”), are also used or distributed as MDMA in areas of MDMA use. These agents have similar clinical effects and acute and chronic toxicity. Recently, other MDMA-related substances are also found in “rave” scenes, 2CB, 2,4-dimethoxy-4-(n)-propylthiophenylethylamine (2C-T7), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB).32,70,82,132 The term, “ecstasy” may also be used for all of these substances. Typically, MDMA is available in colorful and branded tablets, vary from 50 mg to 200 mg. MDMA and similar analogues are so-call entactogens (meaning touching within), capable of producing euphoria, inner peace, and a desire to socialize.163,235 In addition, some psychologists used MDMA to enhance psychotherapy until the Controlled Substances Act of 1986.182 People who use MDMA report that it enhances pleasure, heightens sexuality, and expands consciousness without the loss of control.25,93,163 Negative effects reported with acute use included ataxia, restlessness, confusion, poor concentration, and memory problem.235 MDMA has about one-tenth the CNS stimulant effect of amphetamine. Unlike amphetamine and methamphetamine, MDMA is a potent stimulus for the release of serotonin.28,61,95,171 The concentration of MDMA required to stimulate the release of serotonin is 10 times less than that required for the release of dopamine or norepinephrine. In animal models, the stereotypic and the discriminatory effects of MDMA and its congeners can be distinguished from those of other amphetamines.29,182 The sympathetic effects of MDMA are mild in low doses. However, when a large amount of MDMA is taken, the clinical presentation is similar to that of other amphetamines and deaths can result from abuse.66,104,105,177,253 Those patients at greatest risk developed dysrhythmias, hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation.66,105,230 Significant hyponatremia has been reported with MDMA use.2,160,183 The increase in serotonin results in the excessive release of vasopressin (ADH).103 Furthermore, large free-water intake combined with sodium loss from physical exertion (in dance clubs) may be crucial to the development of hyponatremia. A major concern with MDMA usage is its long-term effects on the brain. In numerous animal models, acute administration of MDMA leads to serotonin transporter dysfunction, and repetitive administration of MDMA ultimately leads to permanent damage to serotonergic neurons.161,164,166,173,184,203,205 Animal data suggest that MDMA induces hydroxyl free-radical generation and de-

creases antioxidants in serotonergic neurons.207,227 When sufficient antioxidants are depleted, neuronal damage may occur. The evidence for these potential neurotoxic effects in humans is less clear. Indirect evidence of serotonergic effects in humans includes lower levels of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebral spinal fluid (CSF) of MDMA users than in controls.204 Case reports and studies of MDMA users demonstrate alteration in mood, sleep, anxiety, cognition, memory, and impulse control—all functions that are believed to be affected by serotonin.5,162,165,167,171 Either single photon emission tomography (SPECT) or positron emission tomography (PET) demonstrates decreased serotonin transporter function in MDMA users.185,201 Memory deficits appeared to persist even in abstinent MDMA users.90,176 A major deficit in human studies is finding comparable control groups; it is possible that people with psychiatric problems are more likely to be MDMA users.168 Another confounding variable is that MDMA users are more likely to use other drugs. Further studies are required to address the long-term neuropsychiatric effects of MDMA.

Propylhexedrine Smith, Kline and French introduced propylhexedrine in 1949 as the primary active ingredient in Benzedrex nasal inhaler, to replace the widespread abuse of amphetamine in nasal inhalers.7,77 Propylhexedrine is an alicyclic aliphatic sympathomimetic amine that is structurally similar to amphetamine, with a local vasoconstrictive effect and approximately 10% of the CNS stimulatory effect of amphetamine.7 Propylhexedrine abuse became prevalent after the removal of amphetamine from nasal inhalers. The abusers disassembled the inhaler and ingested the cotton pledget vehicle of propylhexedrine itself, diluted it in beverages, or reconstituted the drug for intravenous injection. Numerous effects were reported with propylhexedrine abuse, including sudden death, myocardial infarction, cardiomyopathy, pulmonary hypertension, and acute psychosis.6,7,49,63,77,147,156,157,251 Although propylhexedrine in nasal inhalers has largely been replaced by safer sympathomimetic agents (Chap. 35), the drug is still readily available and is abused as an inexpensive, legal “high.”

Khat, Cathinone, and Methcathinone Khat (also known as quat and gat), the fresh leaves and stems from the Catha edulis shrub, is one of the most commonly used drugs in eastern and central Africa, and in parts of the Arabian peninsula. Attention to khat was highlighted in the early 1990s by the media coverage of war in Somalia and Ethiopia. Khat is sold in small bundles of leaves in the local markets of these countries. The leaves and the tender stems are chewed or occasionally concocted into tea. Khat chewing has a significant role at social gatherings in these countries.154 When the dried leaves and stems were studied, the primary active ingredient was thought to be cathine (norpseudoephedrine), present as 0.1–0.2% of the dried material. Cathine has about one-tenth the stimulant effects of D-amphetamine. Numerous other amphetaminelike compounds are also isolated, but occur in minute quantities.122 When the fresh leaves are analyzed, however, cathinone (benzylketoamphetamine), a more potent psychoactive compound, was demonstrated to be the primary active agent.84,98,122 As the leaves age, cathinone is degraded into cathine, which also explains why dried khat is neither popular nor widely distributed. Imported fresh khat must be consumed within a week before losing much of its potency. The primary effects of khat are

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increased alertness, insomnia, euphoria, anxiety, and hyperactivity. Significant adrenergic complications are much less frequent than those associated with amphetamine abuse. Methcathinone, the methyl-derivative of cathinone, chemically synthesized from ephedrine, has been abused in the Soviet Union for many years. The potency of methcathinone is comparable to that of methamphetamine.85,257 Methcathinone—also termed ephedrone, or sold under the street names of “cat” or “Jeff”—currently remains widely abused in Russia. Methcathinone abuse was first reported in Michigan in the early 1990s and is now reported in other states as well.69

Ephedrine or Ma-Huang Herbal Products

Ephedrine is commonly found in over-the-counter cold preparations. Ephedrine is also the active substance in the Chinese plant ma-huang, which has been used for centuries for the treatment of asthma. Although ephedrine is much less potent than amphetamine, when combined with other catecholamine-stimulating agents or when taken in large quantities, significant toxicity may occur.24,30,192,221 In the United States, numerous ephedrine products, such as “go,” “ultimate xphoria,” “up your gas,” and “herbal ecstasy,” are marketed primarily to teenagers. Some of these products contain more than 500 mg of ephedrine, and this may be combined with pseudoephedrine, phenylpropanolamine, and caffeine; other products contain the plant extract ma-huang.143,192,194 Many of these products are marketed as legal stimulants or safe herbal stimulants for a natural “high.” Similarly, ma-huang is also widely marketed as a “safe” herbal weight-reducing product, especially when phenylpropanolamine was recently demonstrated to associate with brain hemorrhage in women.130 Unfortunately, these products are linked to numerous deaths and adverse reactions.98a,178,194,242a,254,259 Because these products are sold as food supplements, they are not regulated by the FDA. Only when the FDA can demonstrate a product’s hazards, can the federal authority restrict these products (Chap. 77).

Sibutramine Sibutramine (Meridia) is an amphetamine analogue (
-phenylethylamine analogue) with properties distinct from most amphetamines. Although originally investigated as an antidepressant, the FDA approved sibutramine in 1997 as a weight-reducing agent. Pharmacologically, sibutramine blocks the reuptake of serotonin, norepinephrine, and, to a lesser extent, dopamine, which are similar action those of many antidepressants.155 Sibutramine has no direct affect or binding to - or
-adrenergic, dopaminergic, and muscarinic receptors. Although sibutramine may increase the blood pressure of patients with hypertension, significant sympathomimetic effects are unexpected.145 Sibutramine is extensively metabolized in the liver, especially by CYP3A4 into 2 active components.145 Currently, overdose data are quite limited. Based on its

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pharmacologic profile, altered mental status, seizures, and some serotonin symptoms may be expected with significant overdoses.

PHARMACOKINETICS AND TOXICOKINETICS In general, amphetamines are relatively lipophilic and hence they can cross the blood-brain barrier readily. They have large volumes of distribution, varying from 3–5 L/kg for amphetamine and 3–4 L/kg for methamphetamine and phentermine, to 11–33 L/kg for methylphenidate. Pemoline is the exception as it has a small volume of distribution (0.2–0.6 L/kg).11 Amphetamines differ from catecholamines in that they lack the catechol structure (hydroxyl groups at the 3 and 4 positions of the phenyl ring) and are resistant to metabolism by catechol-O-methyl transferase (COMT).110 The -methyl group in amphetamines makes them resistant to metabolism by monoamine oxidase. These characteristics permit better oral bioavailability and longer duration of effects.181 Amphetamine elimination may occur through multiple pathways, including diverse hepatic transformations and renal elimination. For MDMA and its analogues, N-dealkylation, hydroxylation, and demethylation are the dominant hepatic pathways.39,40,159 Depending on the particular substance, active metabolites of secondary amphetamines and ephedrine derivatives may be formed.11,39 N-Demethylation of methamphetamine and MDMA result in the formation of amphetamine and MDA, respectively.39 Dealkylation and demethylation are mainly performed by cytochrome P450 isoenzymes, including CYP1A2, CYP2D6, and CYP3A4, but they are also performed by flavin monooxygenase (FMO).159 Polymorphism of CYP2D6 in humans was discovered as a result of decreased p-hydroxylation of amphetamine in certain populations. Since its discovery, CYP2D6 polymorphism has been implicated in drug toxicity, substance use and abuse, and lack of drug efficacy in susceptible populations.226 Increased amphetamine toxicity is a potential concern in patients with decreased CYP2D6 activity. Animal models with CYP2D6 deficiency are demonstrated to be more susceptible to MDMA toxicity; this has not been studied in human.45 In general, because multiple enzymes and pathways (including renal) are involved in amphetamine elimination, it is less likely that CYP2D6 polymorphism or drug interaction with CYP3A4 alone will increase toxicity significantly. However, it is unclear if toxicity is enhanced when multiple mechanisms for altering drug metabolism and renal dysfunction are present simultaneously. Renal elimination is substantial for amphetamine (30%), methamphetamine (40–50%), MDMA (65%), and phentermine (80%). Amphetamines are relatively strong bases with a typical pKa range from 9–10, and renal elimination varies depending on the urine pH.11 The half-life of amphetamines varies significantly: amphetamine, 8–30 hours; methamphetamine, 12–34 hours; MDMA, 5–10 hours; methylphenidate, 2.5–4 hours; and phentermine, 19–24 hours.11,39 Repetitive administration, which occurs typically during binge use, may lead to drug accumulation and prolongation of the drug’s half-life and duration of effect.118

CLINICAL MANIFESTATIONS The clinical effects of amphetamines are largely related to the stimulation of central and peripheral adrenergic receptors. These clinical manifestations and complications are similar to those from

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cocaine use and may be indistinguishable except for the duration of effect of amphetamines, which tends to be longer (up to 24 hours).59,74 Compared to cocaine, amphetamines are less likely to cause seizures, dysrhythmias, and myocardial ischemia. This may be related to the sodium channel blocking effects and to the thrombogenic effect of cocaine that do not result from amphetamine use.87 Psychosis appears to be more likely with amphetamines than cocaine, which may be related to the more prominent dopaminergic effects of amphetamines.8,86 Tachycardia and hypertension are the most common manifestations of cardiovascular toxicity. Most patients present to the emergency department, however, because of the CNS manifestations.59,115,253 These patients are anxious, volatile, aggressive, and may have life-threatening agitation. Visual and tactile hallucinations, as well as psychoses, are common.20,60,62,101,150,209,220 Other sympathetic findings include mydriasis, diaphoresis, and hyperthermia (Table 68–2).60,66 Death from amphetamine toxicity most commonly results from hyperthermia, dysrhythmias, and intracerebral hemorrhage.35,55,73,121,128,149,189,210 Direct CNS effects may result in seizures. Tachycardia, hypertension, and vasospasm may lead to cerebral infarction,89,138,213 intraparenchymal and subarachnoid hemorrhage,52,100,112,127,238,258 myocardial ischemia or infarction,76,190,246 aortic dissection,52,65 pulmonary edema,27,179,180 obstetrical complications, fetal death,148 and ischemic colitis.16,107,119 Dysrhythmias vary from premature ventricular complexes to ventricular tachycardia and ventricular fibrillation.121,151 Agitation, increased muscular activity, and hyperthermia can result in metabolic acidosis, rhabdomyolysis,50 acute tubular necrosis (acute renal failure), and coagulopathy.66,81,120,129 Unless these systemic signs and symptoms are rapidly reversed, multiorgan failure and death ensue. Amphetamine users seeking intense “highs” may go on “speed runs” for days to weeks. Because of the development of acute tolerance, they use increasing amounts of amphetamines during these periods, usually without much sustenance or sleep, attempting to achieve their desired euphoria.17,48,140,232,242 Acute psychosis resembling paranoid schizophrenia may occur during these binges and has contributed to both amphetamine-related suicides and homicides.68,136 Return to a normal sensorium occurs within a few days after discontinuation of the drug. Once an amphetamine user experiences psychosis, it is likely to be recurrent even after prolonged abstinence, which may be related to a kindling phenomenon.17,74,186,242 Amphetamine-induced psychosis has contributed to the understanding of dopamine’s function in schizophrenia. Typically after such binges, patients may sleep for prolonged periods, feeling hungry and depressed when awake. During this period of depression or withdrawal, the patient has continued craving for amphetamines.101,137,143 There are some direct neurologic effects of amphetamines. Compulsive repetitive behavior patterns are reported in humans and animals. Individuals may constantly pick at their skin, grind their teeth (bruxism), or perform repetitive tasks, such as constantly cleaning their house or car.17 Choreoathetoid movements, although uncommon, are reported with acute and chronic amphetamine usage.134,153,158,202,219,231 The etiology of the choreoathetoid movements may be related to increased dopaminergic activity at the striatal area. Necrotizing vasculitis is associated with amphetamine abuse.19,42 Angiography typically demonstrates beading and narrowing of the small and medium-sized arteries (see Fig. 8–23).215,238 Progressive necrotizing arteritis52 can involve multiple organ systems, including the central nervous, cardiovascular, gastrointestinal, and renal

TABLE 68–2.

Amphetamine Toxicity Acute toxicity Cardiovascular System Hypertension Tachycardia Dysrhythmias Myocardial ischemia Aortic dissection Vasospasm Central Nervous System Hyperthermia Agitation Seizures Intracerebral hemorrhage Headache Euphoria Anorexia Bruxism Choreoathetoid movements Hyperreflexia Paranoid psychosis Other Sympathetic Symptoms Diaphoresis Tachypnea Mydriasis Tremor Nausea Other Organ Systems Rhabdomyolysis Muscle rigidity Acute lung injury Ischemic colitis Chronic toxicity Vasculitis Cardiomyopathy Pulmonary hypertenion Aortic and mitral regurgitation Permanent damage to dopaminergic and serotonergic neurons Laboratory abnormalities Leukocytosis Hyperglycemia Hyponatremia Elevated CPK Elevated liver enzymes Myoglobinuria

systems. Complications include cerebral infarction and hemorrhage, coronary artery disease, pancreatitis, and renal failure.42,99,152,215,218,238,258 The etiology of the arteritis remains unclear. Although various contaminants associated with parenteral drug use were postulated as potential etiologies, oral and IV amphetamine use in animal models is also associated with vasculitis, suggesting that this is a direct amphetamine effect.216,217,243 Cardiomyopathy is also reported with acute and chronic amphetamine abuse.19,111,188,234 Excessive catecholamine exposure in patients with pheochromocytomas and chronic cocaine use may be responsible for their associated cardiomyopathies; amphetamine-induced cardiomyopathy may be produced by similar mechanisms.87,124,252 Primary pulmonary hypertension, a rare and potentially fatal disease, is reported with chronic methamphetamine and propylhexedrine use.6,63,141,222 However, substantial epidemiologic risk

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for primary pulmonary hypertension is demonstrated only with fenfluramine and aminorex (2-amino-5-phenyl-2-oxazoline).22,96,229 Pulmonary hypertension was associated with the use of aminorex as an anorectic agent in Europe from 1965–1968.97 In 1996, a case-controlled study substantiated the increased risk of pulmonary hypertension with the use of amphetamine appetite-suppressant drugs, particularly with fenfluramine.1 The risk of pulmonary hypertension was increased 23-fold when the cumulative use of anorectic agents totaled more than 3 months.1 Pulmonary hypertension may develop following exposure to anorectic agents that may be as brief as 3 weeks.96 The exact cause of the pulmonary hypertension is unclear. Increased serotonin in the pulmonary vasculature is postulated to result in pulmonary vasoconstriction and endothelial proliferation.108,179,212 Pulmonary hypertension is not currently reported with sibutramine. Pulmonary hypertension that develops following the use of anorectic drugs may be partially reversible after withdrawal of the agent, however, the median survival of patients studied during the European aminorex epidemic was 3.5 years from the time of diagnosis.96 With current advances in therapy, improved survival is expected.214 Valvular heart disease is also associated with the use of the appetite-suppressants fenfluramine, dexfenfluramine, and phentermine, particularly if the duration of therapy is greater than 4 months.46,78,117,131,250 The initial reports, in 1997, implicated significant aortic and mitral regurgitation with the use of these agents, and the prevalence was as high as 32%.31 These reports resulted in the withdrawal of fenfluramine and dexfenfluramine. Subsequent studies demonstrated mostly mild aortic regurgitation and possible mitral regurgitation; the overall prevalence varies from study to study, ranging from 0.14% to 22.7%.78,117,131,248 The highest risks appear to be in patients taking combination therapy with fenfluramine and phentermine, and those who utilized the agent for more prolonged periods (>4 months).117 The dramatic differences in the overall prevalence rate in these studies may be related to differences in patient population, duration of therapy, and the timing of echocardiography (ie, during therapy or after the cessation of therapy). The echocardiographic findings usually improve following cessation of these agents.106 The exact etiology of the valvular disease is unclear, but postulated to be related to the presence of increased serotonin levels. Similar valvular disorders are recognized in patients exposed to persistently increased serotonin levels with conditions such as malignant carcinoid syndrome.211 Although the chronic administration of MDMA and its analogues are better publicized and were discussed earlier, chronic administration of various amphetamines, including amphetamine and methamphetamine, to animals, depletes dopamine and serotonin in the neuronal synapses and produces irreversible destruction of those neurons.15,80,205,206,208,224,255 The etiology of neuronal toxicity may be related to the generation of free oxygen radicals, resulting in the generation of toxic dopamine and serotonin metabolites and neuronal destruction.80,142,223,255,256 Although not as well studied as MDMA, recent studies in former methamphetamine users demonstrated impaired memory and psychomotor functions, as well as corresponding dopamine transporter dysfunction and abnormal glucose metabolisms on PET scans.244,245 The potential for permanent neurologic effects associated with chronic amphetamines use requires further study. Finally, multiple medical complications can result from parenteral drug use and from the associated contaminants. Contami-

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nation with infectious agents may result in HIV infection, hepatitis, and malaria. Bacterial and foreign body contamination may result in endocarditis, tetanus, wound botulism, osteomyelitis, and pulmonary and soft tissue abscesses37 (Chaps. 8 and 109).

DIAGNOSTIC TESTING Diagnosis by history is rarely reliable, and there is no readily available drug-specific serum analysis. The prevalence of amphetamine abuse in the local geographic region should heighten the suspicion of amphetamine toxicity. The physical and psychological assessment is nonspecific, and polydrug abuse is quite common. Qualitative urine immunoassay testing for amphetamines is available, but it is not valuable in the acute setting. Typically, the turnaround time for the test result is at least several hours, which is far too long to be clinically useful. Both false-positive and false-negative results are common. Many cold preparations contain structurally similar substances (pseudoephedrine, ephedrine, phenylpropanolamine, l-methamphetamine) that may cross-react with the available immunoassays.44,64,75,196 In addition some immunoassays may not react with all amphetamines, resulting in false-negative results. MDMA frequently goes unrecognized on standardized testing.16,44 Selegiline, a selective MAO-B inhibitor used for the treatment of parkinsonism, is metabolized to amphetamine and methamphetamine; patients taking selegiline will react positively with most amphetamine-testing techniques.123 Even a true-positive result only means the patient has used an amphetamine analogue within the last several days. Management decisions must be determined by the clinical manifestations and impressions. Although newer, rapid, serum qualitative drug screens are available, false-positive and false-negative results remain common and may be misleading. The gold standard for drug testing, gas chromatography/mass spectrometry analysis, can misidentify isomeric substances such as l-methamphetamine, which is present in nasal inhalers, with d-methamphetamine if performed by inexperienced personnel.233 In summary, the suspicion of amphetamine toxicity cannot be confirmed rapidly with a high level of reliability by the laboratory.

MANAGEMENT Table 68–3 summarizes the therapeutic approach to a patient with amphetamine toxicity. The initial medical assessment of the agitated patient must include the vital signs and a rapid complete physical examination. An often-neglected vital sign is the rectal temperature. Hyperthermia, a frequent and rapidly fatal manifestation in patients with drug-induced delirium, requires immediate interventions to achieve cooling.81,120,129 Some patients will require physical restraint to gain clinical control and prevent personal harm to themselves or others. Because agitation and resistance against physical restraint may lead to rhabdomyolysis and continued heat generation, intravenous chemical sedation should be instituted immediately. Blood specimens should be sent for glucose, BUN, and electrolyte assays. Hyponatremia should be considered for patient with altered sensorium and suspected MDMA usage (see Chap. 24). Intravenous (IV) glucose (D50W, 0.5–1 g/kg) and thiamine 100 mg should be given as indicated. An ECG should be obtained to exclude ischemia, hyperkalemia, and drug toxicity (cyclic antidepressant), and cardiac monitoring should be initiated.

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TABLE 68–3. Management of Patients with Amphetamine Toxicity Agitation Benzodiazepines (usually adequate for the cardiovascular manifestations) Diazepam 10 mg (or equivalent) IV, repeat rapidly until the patient is calm (cumulative dose may be >100 mg of diazepam) Seizures Benzodiazepines Barbiturates Propofol Hyperthermia External cooling Control agitation rapidly Gastric decontamination and elimination Activated charcoal for oral ingestions Hypertension Control agitation first α-Adrenergic receptor antagonist (phentolamine) Vasodilator (nitroprusside, nitroglycerin) Delirium or hallucinations with abnormal vital signs If agitated: benzodiazepines Delirium or hallucinations with normal vital signs Consider haloperidol or droperidol

A complete blood count, urinalysis, coagulation profile, chest radiograph, CT of the head, and lumbar puncture may be necessary, depending on the clinical presentation. Because the clinician cannot accurately distinguish the diverse etiologies of drug-induced delirium, the choice of chemical sedation should be safe and effective regardless of the etiology. The most appropriate choice of sedation is a benzodiazepine because these agents have a high therapeutic index and good anticonvulsant activity. They are effective for the treatment of delirium induced by acute overdose of cocaine, amphetamines, and other agents, and the delirium associated with ethanol and sedative-hypnotic withdrawal.57,60,87,187 The dose of benzodiazepine should be titrated rapidly intravenously until the patient is calm. In our clinical experience, cumulative benzodiazepine dosages required in the initial 30 minutes to achieve adequate sedation frequently exceeds 100 mg of diazepam or its equivalent. Antipsychotic agents, particularly potent dopamine antagonists such as haloperidol and droperidol, are frequently recommended by others for amphetamine-induced delirium. Antipsychotic agents may actually antagonize some of the effects of amphetamines via dopamine blockade.57,58,71 In animal models, haloperidol may be superior to diazepam in preventing mortality from amphetamine toxicity.33,54,57,58 In clinical experience, however, the benzodiazepines appear to be as efficacious as the antipsychotic agents in the management of amphetamine toxicity.60 Antipsychotic agents may lower the seizure threshold, alter temperature regulation, may cause acute dystonia and cardiac dysrhythmias, and do not interact with the benzodiazepine–γ-aminobutyric acid (GABA)–chloride channel receptor complex. All of these effects may worsen the

clinical outcomes related to occult or concomitant cocaine toxicity and ethanol withdrawal.87,91,187 Rhabdomyolysis from amphetamine toxicity usually results from agitation and hyperthermia.77,129 Sedation prevents further muscle contraction and heat production. External cooling should be instituted for significant hyperthermia. Adequate IV hydration and cardiovascular support should maintain urine output of 1–2 mL/kg/min. Although urinary acidification can significantly increase the elimination and decrease the half-lives of amphetamine or methamphetamine,11,13,14,53 this pH manipulation does not decrease toxicity, and, in fact, may increase the risk of renal compromise and acute tubular necrosis from rhabdomyolysis. Acidification of the urine should not be considered because of the precipitation of ferrihemate in the renal tubules and increased risk of acute renal failure.50 Patients with acute renal failure, acidemia, and hyperkalemia will likely require urgent hemodialysis. Amphetamine body packers should be treated similarly to those who transport cocaine (Chap. 67). Any sympathomimetic symptoms suggesting leakage of the packets require surgical intervention.247 Fluids, benzodiazepines, intubation, and external cooling may be necessary to stabilize these patients.

SUMMARY Amphetamine usage is increasing dramatically throughout the United States. Similarly, ED visits, and morbidity and mortality related to amphetamines, parallel amphetamine usage. Many of these complications are similar to those of cocaine, such as agitation, hyperthermia, rhabdomyolysis, myocardial ischemia, and cerebral infarction. Physicians, more than ever, must understand the pathophysiology of amphetamines and be ready to diagnosis and treat its toxicity. The chronic effects of amphetamines as demonstrated in animal models pose serious concerns for humans, particularly as amphetamine usage becomes more prevalent; further studies are required to achieve prevention and management.

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237. Sonsalla PK, Nicklas WJ, Heikkila RE: Role for excitatory amino acids in methamphetamine-induced nigrostriatal dopaminergic toxicity. Science 1989;243:398–400. 238. Stoessl AJ, Young GB, Feasby TE: Intracerebral haemorrhage and angiographic beading following ingestion of catecholaminergics. Stroke 1985;16:734–736. 239. Sudilovsky A: Disruption of behavior in cats by chronic amphetamine intoxication. Int J Neurol 1975;10:259–275. 240. Sulzer D, Chen TK, Lau YY, et al: Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 1995;15:4105–4108. 241. Sulzer D, Pothos E, Sung HM, et al: Weak base model of amphetamine action. Ann N Y Acad Sci 1992;654:525–528. 242. Tadokoro S, Kuribara H: Reverse tolerance to the ambulationincreasing effect of methamphetamine in mice as an animal model of amphetamine-psychosis. Psychopharmacol Bull 1986;22:757–762. 242a. Traub SJ, Hoyek W, Hoffman RS: Dietary supplements containing ephedra alkaloids. N Engl J Med 2001;344:1095–1097. 243. Trugman JM: Cerebral arteritis and oral methylphenidate. Lancet 1988;1:584–585. 244. Volkow ND, Chang L, Wang G, et al: Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 2001;158:377–382. 245. Volkow ND, Chang L, Wang G, et al: Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers. Am J Psychiatry 2001;158:383–389. 246. Waksman J, Taylor RN Jr, Bodor GS, et al: Acute myocardial infarction associated with amphetamine use. Mayo Clin Proc 2001;76: 323–326. 247. Watson CJ, Thomson HJ, Johnston PS: Body-packing with amphetamines—An indication for surgery. J R Soc Med 1991;84: 311–312. 248. Wee CC, Phillips RS, Aurigemma G: Risk for valvular heart disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication. Ann Intern Med 1998;129:870–874. 249. Weir E: Raves: A review of the culture, the drugs and the prevention of harm. CMAJ 2000;162:1829–1830. 250. Weissman NJ, Tighe JF Jr, Gottdiener JS, et al: An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. N Engl J Med 1998; 339:725–732. 251. White L, DiMaio VJM: Intravenous propylhexedrine and sudden death [letter]. N Engl J Med 1977;297:1071. 252. Wiener RS, Lockhart JT, Schwartz RG: Dilated cardiomyopathy and cocaine abuse. Report of two cases. Am J Med 1986;81:699–701. 253. William H, Dratcu L, Taylor R, et al: “Saturday night fever”: Ecstasy-related problems in a London accident and emergency department. J Accid Emerg Med 1998;15:322–326. 254. Wooten MR, Khangure MS, Murphy MJ: Intracerebral hemorrhage and vasculitis related to ephedrine use. Ann Neurol 1983;13: 337–340. 255. Wrona MZ, Yang Z, Zhang F, et al: Potential new insights into the molecular mechanism of methamphetamine-induced neurodegeneration. NIDA Res Monogr 1997;173:146–174. 256. Yamamoto BK, Zhu W: The effects of methamphetamine on the production of free radical and oxidative stress. J Pharmacol Exp Ther 1988;287:107–114. 257. Young R, Glennon RA: Cocaine-stimulus generalization to two new designer drugs: Methcathinone and 4-methylaminorex. Pharmacol Biochem Behavior 1993;45:229–231. 258. Yu YJ, Cooper DR, Wellenstein DE, et al: Cerebral angiitis and intracerebral hemorrhage associated with methamphetamine abuse. J Neurosurg 1983;58:109–111. 259. Zhinger KY, Dovensky W, Crossman A, et al: Ephedrone: 2-Methylamino-1-phenylpropan-1-one (Jeff). J Forensic Sci 1991;36: 915–920.

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PHENCYCLIDINE AND KETAMINE Rueben Olmedo

A 17-year-old male was brought to the Emergency Department (ED) by his school supervisor and two police officers. The boy was extremely agitated, with transient periods of blank staring and myoclonic movements of both arms. It took several members of the ED staff to keep him on a stretcher. Initially, no history was obtainable from the patient, who responded to verbal stimuli with inappropriate physical gestures and a few nonsensical words. The school supervisor reported that the boy had become suddenly agitated and had created a disturbance in the lunchroom, throwing chairs about the room. His vital signs were: blood pressure, 130/90 mm Hg; pulse, 110 beats/min; respiratory rate, 18 breaths/min; and temperature, 99.9°F (37.2°C). He was well developed and well nourished, anicteric, and acyanotic. The examination was normal except for a few pertinent findings. The skin was cool and diaphoretic. Conjunctivae were normal; extraocular movements were intact, but there was persistent vertical and horizontal nystagmus; pupils were equal at 4 mm and reactive to light; fundi were normal. The patient moved all extremities, had good strength and normal, symmetric deep-tendon reflexes; muscle tone seemed increased and there were periodic myoclonic jerks; plantar flexion was elicited; sensory examination could not be performed because of the patient’s lack of response and agitation. Blood was drawn for initial laboratory tests and an intravenous infusion of 5% dextrose in 0.45% sodium chloride solution was started at 200 mL/h. Fifty milliliters of 50% dextrose and 100 mg of thiamine were given IV. He was placed on 6 L of oxygen via nasal cannula. Fifty grams of activated charcoal with 50 g of sorbitol were administered by mouth. The initial laboratory data, including complete blood count (CBC), electrolytes, arterial blood gas analysis, and urinalysis, were all normal. An electrocardiogram (ECG) revealed a sinus tachycardia at 110 beats/min and was otherwise normal. By the time the physical examination and laboratory tests were completed, the patient had become calm and cooperative. He related that while at lunch, one of his friends had put mustard on his sandwich and that it tasted “terrific.” He recalled finishing the sandwich and then slowly “freaking out,” losing control of his mind and body.

The patient’s clinical condition had significantly improved by the time his mother arrived in the ED. Within 3 hours after his arrival, he was cooperative and his neuropsychiatric examination was entirely normal. He was discharged home and arrangements were made for a followup examination with his pediatrician.

HISTORY AND EPIDEMIOLOGY Phencyclidine (PCP) was discovered in 1926, but it was not until the 1950s, when Parke Davis, while searching for an ideal intravenous anesthetic that would rapidly achieve analgesia and anesthesia with minimal cardiovascular and respiratory depression, rediscovered PCP as a general anesthetic.37 It was marketed under the name Sernyl because it rendered an apparent state of serenity when administered to laboratory monkeys. Its surgical use began in 1963, but was rapidly discontinued when a 10–30% incidence of postoperative psychoses and dysphoria was documented over the next 2-year period.80 By 1967, the use of PCP was limited exclusively to veterinary medicine as a tranquilizer under the name Sernylan. Simultaneously in the 1960s, PCP was evolving as a San Francisco street drug called “the PeaCe Pill.”63 The names subsequently applied to phencyclidine have been numerous and geographically diverse: on the West Coast it was “Angel Dust, PCP, crystal, crystal joints (CJs);” Chicago called it “THC” or “TAC;” and the East Coast opted for “the sheets” or “Hog” and “elephant tranquilizer.”107 The drug was initially unpopular with drug users because of its dysphoric effects and unpredictable oral absorption.156 With time, though, its use spread in a similar geographic pattern to that of marijuana and LSD, from the coastal United States to the Midwest region.63 Phencyclidine abuse first became widespread during the 1970s.26 The relatively easy and inexpensive synthesis coupled with the common masking of PCP as LSD, mescaline, psylocybin, cocaine, amphetamine, and/or “synthetic THC” (tetrahydrocannabinol), added to its allure and consumption.107 By the late 1970s, PCP use had reached epidemic proportions.7 The Drug Abuse Warning Network (DAWN) reported that the number of

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PCP-related emergencies and deaths more than doubled in the 2 years from 1975 to 1977. In 1978, the National Institute of Drug Abuse (NIDA) reported that of young adults (18–25-years-old), 13.9% had used PCP.50 The manufacture of phencyclidine was ultimately prohibited in 1978, when the drug was added to the Federal Controlled Substance Act of 1970. Classifying PCP as a Schedule II substance led to its decrease in availability and, therefore, use. The 1980s brought about a cocaine epidemic that eclipsed PCP; however, PCP has remained consistently available on the streets, primarily regionalized to large cities in the northeastern United States and Los Angeles,96 where PCP use continues to rise and fall with various societal trends. Because many of PCP congeners made during the manufacturing process were being abused in place of PCP, the Controlled Substance Analogue Enforcement Act of 1986 made these derivatives illegal and established that the use of PCP’s precursor, piperidine, necessitated mandatory reporting. With this new law in place, those possessing similar but not identical illegal substances could be prosecuted, leading to a further decline in the popularity of phencyclidine. Laboratory investigation of phencyclidine derivatives led to the discovery of ketamine, a chloroketone analogue. Ketamine was introduced for general clinical practice in 1970 and marketed as Ketalar and Ketaject, and for veterinary use, as Ketavet. Ketamine has approximately one-tenth to one-twentieth the potency of PCP and a much shorter duration of action, it therefore provides greater control in clinical use. Thirty years of clinical experience have established that ketamine provides adequate surgical anesthesia, a rapid recovery, and less prominent emergence reactions than noted with PCP use.54,77,139,169 Because of the simplicity and efficacy of its use, it is regularly employed in operating rooms, emergency departments, and throughout the developing world where little clinical monitoring is available during surgical and emergency procedures.52,74,75,76,77,78,79,139,169 Abuse of ketamine was first noted on the West Coast in 1971.146 During the 1980s, there were reports of its abuse internationally, as well as among physicians.3,65 The nonmedical use of dissociative anesthetics has continued to increase in the 1990s, in spite of the common complications associated with their use.159 Presently ketamine, methylenedioxyamphetamine (MDA), and methylenedioxymethamphetamine (MDMA) are popular with today’s youth. The same pharmacologic qualities that made ketamine more clinically popular than PCP are also responsible for its nonmedical popularity. Ketamine is regularly consumed at allnight “rave parties” and in nightclubs because of its reportedly “hallucinatory” and “out-of-body” effects, relatively inexpensive price, and short duration of effect (single snort lasting 15–20 minutes).11,44,87,91,170 The use of ketamine is not limited to the inner-city population. In the past 5 years, the media reports police arrests in affluent suburban communities for possession and sale of ketamine, as well as more in-depth and frequent reporting of the effects of its toxicity among users.44,87,136,170 In contrast to PCP, ketamine is not manufactured illegally, but rather, obtained illicitly from medical, dental, and veterinary sources. Additionally, with the advent of the Internet, it is available nationwide; a sham “biotech” Internet company was seized by New York City police for selling so-called “date-rape drugs,” including ketamine.116 Adverse reactions do occur, although, there are few reports of fatalities secondary to ketamine during this period of increased use.71,102,122 Because of its abuse potential, ketamine was also placed in Schedule III of the Controlled Substance Act in 1999.138

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PHARMACOLOGY General Chemistry Phencyclidine’s chemical name 1-(1-phenylcyclohexyl) piperidine provided the basis for its street acronym PCP. During its unlawful chemical synthesis, numerous analogues are made which have similar effects on the central nervous system (CNS) and which have been used as PCP substitutes. The “designer” arylcyclohexylamines are aliphatic or aromatic substituted amines, ketones, or halides, and appear similar to the parent compound. More than 60 psychoactive analogues are mentioned in the medical literature and the following salient points about the 5 most prevalent compounds are worth mentioning. TCP and PCC are piperidine derivatives. Piperidine, the synthetic precursor, was easily bought prior to 1986 for manufacturing PCP and its derivatives. TCP, a thiophene analog, (1-[1-(2-thienyl)cyclohexyl] piperidine), produces even more intense effects than PCP. An intermediate of PCP synthesis, PCC (1-piperidino-cyclohexanecarbonitrile) was a constituent of up to 20–22% of illicit drug preparations analyzed for phencyclidine; this is likely a result of a poor manufacturing process.14,145 PCC degrades to piperidine, which may be recognized by its strong fishy odor. The presence of its carbonitrile group adds to its toxicity by generating cyanide on smoking.12,14,152,153 The pyrrolidine derivative, PHP (phencycloclohexylpyrrolidine), is comparable clinically to PCP and is not detected by the many drug screening methods available.28,85 More potent than PCP, PCE (1-phenyl-cyclohexylethylamine) was commonly available on the street as a white powder indistinguishable from PCP.145 Ketamine and tiletamine, two legal congeners of PCP, are used clinically for sedation and anesthesia. In large quantities, both are also used in veterinary medicine for animal sedation. Ketamine is the only dissociative anesthetic product manufactured for use on humans for the purpose of anesthesia, conscious sedation, and the treatment of bronchospasm. The molecular structure of ketamine, [2-(ortho-chlorophenyl)2-methylaminocyclohexanone], contains a chiral center, producing a racemic mixture of two resolvable optical isomers or enantiomers, the D(+)-isomer and L(
)-isomer. Commercially available preparations of ketamine contain equal concentrations of the two enantiomers. These two molecules differ in their pharmacodynamic effects. In a randomized double-blind evaluation of these two enantiomers on patients undergoing surgery, the D(+)isomer of ketamine was a more effective anesthetic, but manifested a higher incidence of psychotic emergence reactions than the L(
)-isomer. Other studies have also found differences in their effects on catecholamine reuptake.139,169 The D(+)-isomer causes a greater increase in both blood pressure and pulse than the D(
)-isomer, as well as more bronchodilating effects.

Pharmacokinetics and Toxicokinetics Phencyclidine is a white, stable solid that is readily soluble in both water and ethanol. It is a weak base with a pKa between 8.6 and 9.4 and a high lipid to water partition coefficient. It is rapidly absorbed from the respiratory and the gastrointestinal tracts; as such, it is typically self-administered by oral ingestion, nasal insufflation, smoking, or intravenous and subcutaneous injection. The effects of PCP are dependent on routes of delivery and dose. Its onset of action is most rapid from the intravenous and in-

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halational routes (2–5 minutes) and slowest (30–60 minutes) following gastrointestinal absorption.42,43 Sedation is commonly produced by doses of 0.25 mg intravenously, whereas oral ingestion typically requires 1–5 mg to produce similar sedation. Signs and symptoms of abuse toxicity usually last 4–6 hours, and after large overdoses generally resolve within 24–48 hours, but may persist in a chronic user.16,53,55,106,124,135 However, in the PCP-intoxicated patient, the relationships between dosage, clinical effects, and serum levels are not reliable or predictable. There are several explanations for PCP’s protracted CNS effects. It has a large volume of distribution of 6.2 L/kg.42,174 Its high lipid solubility accounts for its entry and storage in the adipose and brain tissue. Also, upon reaching the acidic CSF, PCP becomes ionized. It is because of this ion-trapping that CSF levels are approximately 6–9 times higher than those of plasma.118 PCP undergoes first-order elimination over a wide range of doses. It has an apparent terminal half-life of 21 ± 3 hours under both controlled and overdose settings.42,90 Prolonged signs or symptoms are demonstrated in those patients who “body-stuff” PCP in plastic bags.90,176 Ninety percent of PCP is metabolized in the liver and 10% is excreted in the urine unchanged. Evidence indicates that PCP undergoes hepatic oxidative hydroxylation into 2 monohydroxylated and 1 dihydroxylated metabolites. All three of these compounds are conjugated to the more water-soluble glucuronide derivatives and are then excreted in the urine. Urine pH is an important determinant of renal elimination of PCP. In acidic urine, the PCP molecule becomes ionized and reabsorption is blocked. Acidification of the urine thereby increases renal clearance of PCP from 1.98 ± 0.48 L/h to 2.4 ± 0.78 L/h.42 Additional studies have found a much higher renal clearance (8.04 ± 1.56 L/h) if the urine pH was decreased to 38.8°C/101.8°F).114 In an experimental animal model, PCP failed to increase body temperature.37,55 When hyperthermia does occur from severe psychomotor agitation, all the known complications including encephalopathy, rhabdomyolysis, myoglobinuria, electrolyte abnormalities and liver failure occur8,19,39,133 (Chap. 18). Both cholinergic and anticholinergic clinical manifestations occur in the PCP- or ketamine-intoxicated patient. Miosis, mydriasis, blurred vision, profuse diaphoresis, hypersalivation, bronchospasm, bronchorrhea, and urinary retention occur.12,18,103,113,114 Clinically, ketamine stimulates salivary and tracheobronchial secretions; both of which are equally and effectively inhibited by atropine and glycopyrolate.123 Furthermore, in a randomized double-blind trial, after infusion of 1.5 mg/kg of ketamine in healthy volunteers, physostigmine decreased nystagmus, blurred vision, and the time to recovery.160 Ironically, the very characteristics that were thought to make phencyclidine ideal for anesthesia—the preservation of muscle tone and cardiopulmonary function—magnify the difficulties in managing an individual who manifests dysphoria after an overdose. The course of delirium, stupor, and coma associated with PCP and ketamine is extremely variable, although the manifestations are much milder following ketamine use.

DIAGNOSTIC TESTING Most hospital laboratories do not perform quantitative analysis of PCP, but many can do a qualitative test for the presence of the drug. The use of qualitative test for PCP is almost always more important than a quantitative determination, as the precise serum concentration does not correlate closely with the clinical effects. PCP may not be part of a routine toxicologic screening and it may therefore be necessary to request a specific analysis. When a routine toxicologic screen is reported as negative this result should not lead to the erroneous conclusion that PCP exposure has been excluded. If it is necessary to confirm the suspicion that PCP is the offending agent, urine is most commonly utilized for analysis, although serum and possibly gastric contents can be employed. Rarely is it essential to make this determination. PCP is qualitatively detected by an enzyme immunoassay at a sensitivity of 10 ng/mL. High-affinity antibodies were once studied as specific PCP antagonists to reverse PCP toxicity.131,162 The detection of PCP is thus dependant on the concentration of PCP in

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the body fluid tested and the affinity of the antibody for the PCP molecule. As such, nonspecific antibody binding to a molecule similar in structure to PCP can produce analytic false-positive reactions. Metabolites of PCP, such as PCE, PHP, TCP, and its pyrrolidine derivative, TCPy, cross-react with the immunoassay at concentrations 30 times higher than those used to detect PCP. Because of its similar structure to PCP, dextromethorphan and its metabolite, dextrorphan, also cross-react with Syva EMIT (enzyme-multiplied immunoassay technique) and TDx PCP assays167 (Chap. 7; Fig. 69–2). Although nonspecific, laboratory findings resulting from PCP use may include leukocytosis, hypoglycemia, and elevation of muscle enzymes, myoglobin, BUN, and creatinine.114 The EEG reveals diffuse slowing with theta and delta waves, which may return to normal before the patient improves clinically. There is no commercially available immunoassay for ketamine. When necessary, ketamine is detected by gas chromatography and mass spectroscopy. There is anecdotal evidence that ketamine also cross-reacts with the urine PCP immunoassay because of their structural similarity.143 Other authors, including the manufacturer who tests the reactivity of the commercially available PCP immunoassay with ketamine, do not confirm such results.33,163

MANAGEMENT Agitation Conservative management is indicated for PCP and ketamine intoxication and includes maintaining adequate respiration, circulation, and thermoregulation. The psychobehavioral symptoms observed during acute dissociative intoxication and during the emergence reaction are similar. To treat the symptoms of agitation and alteration of mental status of acutely intoxicated PCP patients, it is helpful to recognize that both pharmacologic1,34,38,41,61,77,78,110,112 and behavioral40,41,77,101 modalities have been employed to diminish agitation and emergence phenomena during conscious sedation with ketamine. To prevent self-injury, a common form of PCPinduced morbidity and mortality, the patient must be safely restrained, initially physically and then chemically. An intravenous line must be established and blood drawn for electrolytes, glucose, BUN, and creatinine determinations. The use of 0.5–1.0 g/kg (body weight) of dextrose and 100 mg of thiamine HCl intravenously should be considered following an immediate bedside determination of glucose.

Figure 69–2.

Dextromethorphan.

In the pharmacologic treatment of emergence reactions, antipsychotics and benzodiazepines are utilized, with benzodiazepines having the most success. A benzodiazepine such as diazepam, administered in titrated doses of up to 10 mg intravenously every 5–10 minutes until agitation is controlled, is usually safe and effective. Numerous studies demonstrate the benefits of benzodiazepines, although under certain conditions,38,77 they may prolong recovery time. Midazolam may be more effective than diazepam under certain circumstances.34,112 In contrast, phenothiazines may lower the seizure threshold, and both phenothiazines and butyrophenones may cause acute dystonic reactions. Phenothiazines may also cause significant hypotension, worsen hyperthermia, and exacerbate any anticholinergic effects from the drug. Some behavioral modalities have also been implemented in the treatment. Early studies demonstrated that the psychotomimetic effects of PCP were diminished when external stimulation was reduced by environmental sensory deprivation.40 The practice of placing patients in a quiet room with minimal sensory stimulation is recommended by many but has never been formally studied in a double-blind controlled trial. Conversely, it is observed in patients undergoing ketamine anesthesia that emergence reactions are less violent when patients are talked to or when music is played.101,149 Although it is always important to ask the patient the names, quantities, times, and route of all drugs taken, the information obtained from such a patient is notoriously unreliable. Even when the patient is trying to cooperate and give an accurate history, many street psychoactive agents are drug mixtures whose contents are unknown to the patient. Therefore pharmacologic management is complex and often sign or symptom dependent. Although some authors have attempted to define the appropriate therapy for specific PCP congeners,70 we have not found such an approach to be beneficial.

Decontamination Patients with a history of recent oral use of PCP are candidates for gastrointestinal decontamination, but they should be considered too unstable for the use of ipecac, as uncontrolled agitation or respiratory compromise may rapidly develop. Gastric lavage may be initiated with a nasogastric tube, but the patient may need to be sedated and the risk: benefit ratio considered. Activated charcoal, 1 g/kg, may be administered and repeated every 4 hours for several doses in the most symptomatic patients. Activated charcoal effectively adsorbs PCP and increases its nonrenal clearance; even without prior gastric evacuation this approach is usually adequate.134 A single dose of a cathartic, such as sorbitol, may be given but its role is questionable. Theoretically, toxic substances that are weak bases, such as PCP, can be eliminated more rapidly if the urine is acidified. Although urinary acidification with ammonium chloride was previously recommended,9 we do not recommend this approach. The risks associated with acidifying the urine—simultaneously inducing a systemic acidosis, thereby potentially increasing urinary myoglobin precipitation—outweigh any perceived benefits (Chap. 6). As opposed to the problems in applying ion-trapping to renal excretion, ion-trapping results in the active mobilization of PCP into gastric secretions. Phencyclidine is in a substantially ionized (and therefore nonlipid-soluble) form in the acid of the stomach and can be absorbed only when it reaches the more alkaline intes-

CHAPTER 69

tine. Gastric suction, therefore, can remove a significant amount of the drug and also interrupts the gastroenteric circulation (by which the drug is secreted into the acid environment of the stomach only to be reabsorbed again in the small intestine).9 Continuous gastric suction, however, may also be dangerous and unnecessary. It should be reserved only for stuporous or comatose patients. Continuous suction may result in trauma to the patient as well as in fluid and electrolyte loss, which can further complicate management and possibly interfere with drug clearance by inhibiting the efficacy of activated charcoal. For these reasons the administration of multiple-dose activated charcoal rather than continuous nasogastric suction appears to be the safest and most effective way of removing ion-trapped drug from the stomach. Most patients rapidly regain normal CNS function anywhere from 45 minutes to several hours after using the drug. However, those who have taken exceedingly high doses or who have an underlying psychiatric disorder may remain comatose or exhibit bizarre behavior for days or even weeks before returning to normal. Those who regain normal function rapidly should be monitored for several hours and then, after a psychiatric consultation, should receive drug counseling and any additional social support available. Patients whose recovery is delayed should be treated supportively and monitored carefully in an intensive care unit. Many patients become depressed and anxious during the “posthigh” period, and chronic users may manifest a variety of psychiatric disturbances.175 These individuals typically present with repeated drug use, hospitalizations, and poor psychosocial functioning in the long-term. The major toxicity of PCP appears to be behaviorally related: self-inflicted injuries, injuries resulting from exceptional physical exertion, and injuries sustained as a result of resisting the application of physical restraints are frequent. Patients appear to be unaware of their surroundings and are sometimes even oblivious to pain because of the agent’s dissociative anesthetic effects. In addition to major trauma, rhabdomyolysis and resultant myoglobinuric renal failure account in large measure for the high morbidity and mortality associated with PCP intoxication. (Chapter 115 discusses indications and techniques of restraint application.) If significant rhabdomyolysis39,133 has occurred, myoglobinuria may be present. Early fluid therapy should be used to avoid deposition of pigment into the kidneys, leading to renal failure. Urinary alkalinization as part of the treatment regimen for rhabdomyolysis would potentially increase PCP reabsorption and deposition in fat stores, but this is only theoretical. The clinical experience with recreational use of ketamine is limited, however, their manifestations appear to be similar yet milder and shorter-lived when compared to PCP. In a recent study of 20 patients who presented with acute ketamine intoxication, all were treated conservatively and successfully with intravenous hydration, and sedation with benzodiazepines.163

SUMMARY As “dissociative” anesthetics became clinically available their abuse potential was also discovered. The popularity of PCP and ketamine results from their ability to produce an “out-of-body experience” with seemingly hallucinatory effects. The action of these agents is mediated by the NMDA receptor. Their toxicity, in great part neuropsychiatric in nature, is managed by supportive

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care. The popularity of ketamine may be related to its lesser toxicity and milder distortion of the personality.

ACKNOWLEDGMENT Harold Osborn, MD, contributed to this chapter in a previous edition.

REFERENCES 1. Abajian JC, Page P, Morgan M: Effects of droperidol and nitrazepam on emergence reactions following ketamine anesthesia. Anesth Analg 1973;52:385–389. 2. Adams JD, Baillie TA, Trevor AJ, et al: Studies on the biotransformation of ketamine—Identification of metabolites produced in vitro from rat microsomal preparations. Biomed Mass Spec 1981;8: 527–538. 3. Ahmed SN, Petchkovsky L: Abuse of ketamine. Br J Psychiatry 1980;137:303. 4. Akunne HC, Reid AA, Thurkuf A, et al: [3H]1-[2-(2-thienyl) cyclohexyl]piperidine-labeled two high-affinity binding sites associated with the biogenic amine reuptake complex. Synapse 1991;8: 289–300. 5. Altura BT, Altura BM: Phencyclidine, lysergic acid diethylamide and mescaline: Cerebral artery spasm and hallucinogenic activity. Science 1981;212:1051–1052. 6. Anis NA, Berry SC, Burton NR, et al: The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharm 1983;79: 565–575. 7. Anonymous: Phencyclidine: The new American street drug. 1980; 281:1511–1512. 8. Armen R, Kanel G, Reynolds T: Phencyclidine-induced malignant hyperthermia causing submassive liver necrosis. Am J Med 1984;77: 167–172. 9. Aronow R, Done AK: Phencyclidine overdose: An emerging concept of management. JACEP 1978;7:56–59. 10. Aronow R, Miceli JN, Done AK: Clinical observations during phencyclidine intoxication and treatment based on ion-trapping. Res Monogr Ser 1978;21:218–228. 11. Awuonda M: Swedes alarmed at ketamine misuse. Lancet 1996; 348:122. 12. Bailey DN: Clinical findings and concentrations in biological fluids after non-fatal intoxication. Am J Clin Pathol 1979;72:795–799. 13. Bakker CB, Amini FB: Observations on the psychotomimetic effects of Sernyl. Compr Psychiatry 1961;2:269–280. 14. Ballinger JR, Chow AYK, Downie RH, et al: GLC quantitation of 1piperidinocyclohexanecarbonitrile (PCC) in illicit phencyclidine (PCP). J Anal Tox 1979;3:158–161. 15. Balster RL, Woolverton WL: Continuous access phencyclidine selfadministration by rhesus monkeys leading to physical dependence. Psychopharmacology 1980;70:5–10. 16. Ban TA, Lohrenz JJ, Lehmann HE: Observations on the action of Sernyl—A new psychotropic drug. Can Psychiat Assoc J 1961;6: 150–156. 17. Barone FC, Price WJ, Jakobsen S, et al: Pharmacological profile of a novel neuronal calcium channel blocker includes cerebral damage and neurological deficits in rat focal ischemia. Pharmacol Biochem Behav 1994;48:77–85. 18. Barton CH, Sterling ML, Vaziri ND: Phencyclidine intoxication: Clinical experience with 27 cases confirmed by urine assay. Ann Emerg Med 1981;10:243–246. 19. Barton CH, Sterling ML, Vaziri ND: Rhabdomyolysis and acute renal failure associated with phencyclidine intoxication. Arch Intern Med 1980;140:568–569.

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LYSERGIC ACID DIETHYLAMIDE AND OTHER HALLUCINOGENS Jeffrey R. Tucker / Robert P. Ferm

Lysergic acid diethylamide

A 17-year-old male was brought to the Emergency Department (ED) by his friends because he was acting bizarrely on the way home from school. He told a friend that he had done “acid” after school and now could not stop staring at the bright lights. He kept telling his friends to join with him to enjoy the “peace of the lights.” Physical examination in the ED revealed an agitated male staring at the overhead lights. Vital signs were: blood pressure, 150/100 mm Hg; pulse, 112 beats/min; respiratory rate, 28 breaths/min; and oral temperature, 100.4°F (38°C). His skin was moist and pale. Examination of the eyes revealed slowly reactive 6-mm pupils without nystagmus. He had occasional faint, scattered end-expiratory wheezes. Cardiac auscultation was normal. The abdomen was soft and nontender, with hyperactive bowel sounds. There was no clubbing, cyanosis, or edema. The neurologic examination initially revealed an agitated, frightened, but oriented young male. He was frightened by the visual hallucinations and was “hearing purple and blue” from the overhead lights. The remainder of the neurologic examination was intact with the exception of a fine tremor. The patient admitted that he had taken LSD. He had previously used LSD at concerts with others, but this was the first time that he had used it alone. Although he knew where he was and that he was experiencing drug effects, he was frightened and extremely anxious of losing his mind. He was placed in a quiet location with minimal stimuli and an intravenous line was established. He received 10 mg diazepam by slow IV push. A rapid bedside blood glucose was 120 mg/dL. Pulse oximetry was 97%. After approximately 8 hours observation, the patient was fully alert and oriented and was at his baseline functional status. His primary care provider was notified about this exposure, a referral was made for drug counseling, and he was discharged with family members.

Hallucinogens are a diverse group of drugs that alter and distort perception, thought, and mood without clouding the sensorium. To understand the effects of these drugs, an understanding of the concepts and definitions of altered perception, thought and mood is important. A hallucination is a false perception that has no basis in the external environment. The term is derived from the Latin “to wander in mind.” An illusion is a mental impression that is derived from misinterpretation of an actual experience. The classic hallucinogens are also illusiogenic. Although many terms are used to describe the effects, the term “hallucinogens” often refers to the medical-legal context of these toxins, whereas psychedelic is used to describe the nonmedical and recreational use of these compounds. Other terms are used to describe the effects of these compounds, including entheogen (generating religious experience), oneirogen (producing dreams), psychotomimetic (producing psychosis), and phanerothyme (making feeling visible).80

EPIDEMIOLOGY Hallucinogens have been used for thousands of years by different cultures, largely for religious experiences. Early hallucinogens were derived from fungi and plants. The ancient Indian holy book, Rig-Veda, written over 3500 years ago, describes a sacramental substance called Soma both as a god and as an intoxicating substance. The source of Soma is believed to be the juice of the mushroom Amanita muscaria.65,71 The Aztecs used the psilocybincontaining teonanacatl (flesh of the gods), and ololiuqui (morning glory seeds) in their religious ceremonies. In AD 994, an epidemic of ergotism caused by the ingestion of contaminated rye and wheat product, which was produced by the fungus Claviceps purpurea,

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led to the deaths of 40,000 people in Europe. Ergotism has also been implicated as a cause of the behavior of the alleged witches of Salem, Massachusetts.23 Synthetic hallucinogen use is often said to have begun with the discovery and ingestion of LSD-25, commonly known as LSD. The synthesis of LSD was the result of extensive research at Sandoz laboratories with the ergot alkaloids from Claviceps purpurea. In 1938, while searching for a new analeptic agent, the Swiss chemist Albert Hofmann synthesized LSD-25. (The number 25 denotes that it was the 25th substance synthesized within the series.) LSD is the abbreviation of the German name Lysergsäurediäthylamide. LSD-25 was “tested” 5 years later when Hofmann unintentionally became exposed to the agent by the topical route and subsequently developed hallucinations.41,77 In 1947, Sandoz began marketing LSD under the trademark Delysid. In the 1950s, psychiatrists used LSD as an adjunct for analytic psychotherapy and as an experimental model for schizophrenia.83 It was thought that the administration of LSD could aid the patient in releasing repressed material. The Central Intelligence Agency experimented with the use of LSD as a tool for interrogating suspected communists and as a mind-control agent.17,77 In the 1960s, LSD became popular as a recreational drug with the concept of “fifth freedom”: the right of all individuals to alter their consciousness as they saw fit. Timothy Leary popularized LSD as a way to “Tune in, Turn on, Drop out.”77 In 1966, because of concerns about the public health, a federal law banned LSD.62 Initial reports of LSD-induced chromosomal breakage also appeared in the 1960s.24,43,50 Further studies of pregnant women who had taken LSD did not show an increase risk of abortions or birth defects.30,49 Hallucinogen use diminished in the late 1970s and early 1980s, but over the last decade, there has been resurgence in hallucinogen use.4 An annual survey of high school students showed a steady rise in use with a peak in 1996. In 1999, 14.2% of high school seniors claimed to have used LSD at least once in their life as compared to 9.9% in 1989.44 LSD use is more prevalent in the suburbs than the in the inner city.63,73 Hallucinogenic drugs were a regular experience at Grateful Dead Concerts for almost 30 years, are used at rave parties, and in the Acid House Movement.28,61 In the late 1980s, the Acid House Movement appeared in Britain where LSD and methylenedioxymethamphetamine (MDMA) and “acid music” were used at all-night dance parties.52 Myths have been perpetuated regarding LSD toxicity. In an effort to reduce the use of LSD, it was reported that psychotic reactions occured in children after LSD blotter paper was stuck to their skin. In 1999, there was a rumor spread across the Internet that gang members were spreading a deadly mixture of LSD and strychnine on pay phone buttons. This combination was ironic because LSD and strychnine have long been associated with each other, as a result of unfounded concerns that strychnine was a byproduct or contaminant in the production of LSD. Neither myth has credible evidence to support it. LSD is classified as a Schedule I agent with high abuse potential, lack of established safety even under medical supervision, and no known use in medical treatment. However, after little research in the 1970s and 1980s, there was a revival of scientific interest in the 1990s. There are now several studies involving human subjects intended to clarify the mechanism of action and the basic physiologic and central nervous system effects of hallucinogens.37,79 Although hallucinogens have been suggested as potential treatment

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alternatives for patients with obsessive-compulsive disorder, controlled trials have not been conducted.25

CLASSIC HALLUCINOGENS The major structural classes of hallucinogens are the lysergamides, indolealkyamines, phenylethylamines, and tetrahydrocannabinoids (Table 70–1). Lysergamides include LSD and lysergic acid hydroxyethylamide (olloliuqi) (Fig. 70–1). Psilocybin, N,N-dimethyltryptamine, and bufotenine are the major indolealkylamines (Fig. 70–2). The most significant phenylethylamines include mescaline and amphetamine derivatives such as MDMA (Chap. 68). Tetrahydrocannabinoids are discussed in Chap. 71.

Lysergamides Lysergic acid diethylamide is the synthetic derivative of an ergot alkaloid. Although four LSD isomers exist, only the D(
) is active. Lysergic acid diethylamide is a water-soluble, colorless, tasteless, and odorless powder. Currently, most LSD is synthesized and typically sold as liquid-impregnated blotter paper, microdots, tiny tablets, “window pane” gelatin squares, liquid, powder, or tablets.73 The minimum effective dose is 25 µg.47 The Drug Enforcement Administration reports that the current street dose of LSD ranges from 20–80 µg which is lower than the 100–200 µg reported during the 1960s and early 1970s.26

TABLE 70–1.

Agents Classified as Hallucinogens

Lysergamides D-Lysergic acid diethylamide (LSD) Lysergic acid hydroxyethylamide Ipomoea violacea Ololiuqui (South American morning glories) Ergine Argyreia (Wood rose) Indolealkylamines/Tryptamine 5-Methoxy-N,N-dimethyltryptamine Ibogaine N,N-Dimethyltryptamine Psilocin Psilocybin Phenylethylamines Mescaline MDMA (3,4-methylenedioxymethamphetamine) DOB (4-bromo-2,5-dimethoxyamphetamine) PMA (paramethoxyamphetamine) Tetrahydrocannabinoids (THC) Marijuana Hashish Anticholinergics Belladonna alkaloids Jimsonweed (Datura stramonium) Mandrake (Mandragora officinarum) Henbane (Hyoscyamus niger) Deadly nightshade (Atropa belladonna)

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Figure 70–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Hallucinogens of the lysergamide chemical class and their chemical similarity to serotonin.

Lysergamides are also found naturally in several species of morning glory (Rivea corymbosa) or Hawaiian baby woodrose (Ipomoea violacea).72 Morning glory seeds contain the toxin lysergic acid hydroxyethylamide, which has one-tenth the potency of LSD. Hallucinogenic effects require about 200–300 seeds. The seeds must be pulverized, because the intact seed coat prevents drug absorption.

Phenylethylamines Peyote (Lophophora williamsii) is a small blue-green spineless cactus that grows in dry and rocky slopes throughout the southwestern United States and northern Mexico. Mescaline is the active hallucinogenic alkaloid found in the peyote cactus. Peyote buttons are the round fleshy tops of the cactus that have been sliced off and dried. The buttons are bitter tasting and nausea, vomiting, and diaphoresis often precedes the psychological effects. Six to 12 buttons (270–540 mg) are the common dose to produce hallucinogenic effects.72 The legal use of peyote in the United States is restricted to the Native American Church where peyote buttons are used in religious ceremonies and as a medical treatment for physical and psychological ailments.19,22

MDMA MDMA is an amphetamine analogue with stimulant and hallucinogenic properties. MDMA has one-tenth the central nervous system (CNS) stimulant effects of amphetamine, but unlike amphetamine and methamphetamine, it can cause release of serotonin. Proponents of MDMA believe it enhances pleasures, heightens sexuality and expands consciousness without loss of control.74 It has a reputation as a safe drug. As its use has increased, there is an increasing recognition of significant toxicity: hyperthermia, dysrhythmias, hypertensive crisis, and disseminated intravascular coagulation (Chap. 68).

Indoles

Figure 70–2. Hallucinogens of the indolealkylamine chemical class and their chemical similarity to serotonin.

Psilocybin is found in three major genera of mushrooms: Psilocyba, Panaelous, and Conocybe (Chap. 76).71 Psilocybin-containing mushrooms are found in the southern United States, usually in cow pastures. The mushroom may be recognized by a greenish blue color that it assumes after bruising, but misidentification is

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common.10 The active toxin, psilocybin, was first isolated in 1958 by Albert Hofmann. The effects are similar to LSD, but with a shorter duration of action of about 4 hours. N,N-Dimethyltryptamine (DMT) is a potent short-acting hallucinogen. It is found naturally in the bark of the Yakee plant (Virola calophylla), which grows in the Amazon basin and is used by shamans as a hallucinogenic snuff to communicate with the spirits.71 DMT is not absorbed from the gastrointestinal tract and is typically smoked, snorted, or injected. Because DMT is smoked or injected, it peaks in 5–20 minutes, with a duration of 30–60 minutes. This has earned it the name “businessman’s trip.” Current human hallucinogenic research involving DMT is being conducted to determine safety, specific receptor binding, and potential treatments.80,81 Bufotenine (5-hydroxydimethyltryptamine) is present in the secretions and skin of toads of the genus Bufo.16 Although it is believed that bufotenine is a hallucinogen, there is controversy about its ability to cause altered perception.51,66 Bufotenine does have peripheral effects on the heart rate and blood pressure, but does not cross the blood-brain barrier. In contrast, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent hallucinogen. The only species that produces 5-MeO-DMT is the Bufo alvarius (Colorado river toad).66,85 Severe toxicity and death have occurred from the practice of toad licking in an attempt to experience the hallucinogen effects.40,57,75 Ibogaine is an indole alkaloid derived from the African shrub Tabernanthe iboga. It was initially used as a hallucinogen in religious ceremonies by indigenous people. In 1970, it was classified by the FDA as a Schedule I substance because of its illicit use.35 The hallucinogenic effects have been divided into two phases. An acute phase of intense hallucinations develops 4–8 hours after ingestion, followed by a second stage lasting approximately 8–20 hours after ingestion. Ibogaine’s unique mechanism of action may allow a more complete understanding of the neurobiology of addiction. Ibogaine has a complex interaction with multiple receptors as opposed to simple replacement therapy, such as methadone.6,42 Currently, Ibogaine is under investigation for the treatment of drug addiction involving opioids, ethanol, and nicotine, but significant side effects have limited its clinical benefit.35,42 This has led to the development of safer and effective congeners such as 18-methoxycoronaridine to be tested as an antiaddictive medication.

PHARMACOKINETICS Although the effects of the hallucinogens are similar, the onset of action, peak effect, and duration can be variable. The hallucinogens can be characterized by duration of action: ultrashort acting, short acting, intermediate acting, and long acting80 (Table 70–2).

TABLE 70–2.

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LSD has been the most studied hallucinogen and there is extensive information about its pharmacokinetics. Ingestion is the most common route of exposure. The gastrointestinal tract rapidly absorbs LSD. Other routes of administration include intranasal, parenteral, sublingual, smoking, and conjunctival instillation. Plasma protein binding is over 80% and volume of distribution is 0.28 L/kg. It is concentrated within the visual cortex and the limbic and reticular activating systems. It is metabolized in the liver via hydroxylation and glucuronidation, excreted predominately as a pharmacologically inactive compound, and has an elimination half-life of about 2.5 hours. Only small amounts are eliminated unchanged in the urine. Tolerance to the psychological effects of LSD occurs within 2–3 days with daily dosing but rapidly dissipates if the drug is withheld for 2 or more days. Cross-tolerance among mescaline, psilocybin, and LSD has been reported in humans.12 There is no evidence for physiologic tolerance, physiologic dependence, or a withdrawal syndrome with the classic hallucinogens. Cross-tolerance has not been documented between any members of that group and the amphetamines.66 Limited tolerance is also demonstrated between psilocybin and cannabinoids such as marijuana.18,64

PHYSIOLOGY Although the mechanism of action of the classic hallucinogens is incompletely understood, recent studies support a common site of action, on central serotonin receptors.5,20,39,67 Serotonin, or 5-hydroxytryptamine (5-HT), is involved in the modulation of smooth muscle function in the gastrointestinal tract and cardiovascular system, in the regulation of platelet function, and as a neurotransmitter in the brain. Serotonin modulates many psychological and physiologic processes, including mood, personality, affect, appetite, motor function, sexual activity, temperature regulation, pain perception, sleep induction and ADH release. The 5-HT2A receptor is implicated in the modulation of hallucinations.5,33,54,82,87 5-HT2 receptors are located postsynaptically on certain subpopulations of neurons, predominately in the cerebral cortex. There is very good correlation between the affinity of both indolealkylamine and phenylethylamine hallucinogens for 5-HT2 receptors and hallucinogenic potency in humans.34 Cortical involvement correlates with the substantial effect that hallucinogens cause on cognition, mood and perception, because this is the area of the brain that would mediate these effects. In the cerebral cortex, 5-HT2A receptors are expressed in many areas with the highest density in the neocortex (layer Va) and the piriform cortex.5 Also involved is the locus coeruleus, a subcortical area located bilaterally in the upper pons at the lateral border of the 4th ventricle that, projects throughout the entire neocortex and receives sensory

Pharmacokinetic Classification of Hallucinogens

Classification

Toxin

Onset

Peak effect

Duration of effect

Ultrashort acting Short acting Intermediate acting Long acting Ultralong acting

DMT IV DMT IM Psilocybin LSD; Mescaline Ibogaine

1 min 5–15 min 15–30 min 30–90 min 2–4 h

5 min 15–60 min 1–3 h 3–5 h 4–8 h

30 min 1–2 h 6h 8–12 h 18–24 h

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input from all parts of the brain. This area is important in sympathetic nervous system regulation. Hallucinogens do not directly stimulate the locus coeruleus, but their actions are mediated through the 5-HT2A receptors. LSD is also an agonist at 5HT2C.11,56,88 Although the majority of investigation has focused on the role of serotonin for drug-induced hallucinations, other neurotransmitters are involved. Stimulation of 5-HT2A receptors enhances release of glutamate in the cortical layer V pyramidal cells.5,9 Recent work indicates that LSD and other lysergamides stimulate both D1 and D2 dopamine receptors.8,32,84 The psychological aspect of hallucinogens seems to represent a complex interaction between different neurotransmitters with the exact relationship of the serotonergic and dopaminergic systems still elusive.

CLINICAL EFFECTS Physiologic changes accompany and often precede the perceptual changes. The physical effects may be caused by either direct drug effect or by a response to the disturbing or enjoyable subjective experience. Sympathetic effects mediated by the locus ceruleus include mydriasis, tachycardia, hypertension, tachypnea, hyperthermia, and diaphoresis. They occur shortly after ingestion and often precede the hallucinogenic effects. The sympathetic manifestations are mild in nature as compared to the effects of cocaine and amphetamines. Other clinical findings that are reported include piloerection, dizziness, hyperactivity, muscle weakness, ataxia, altered mental status, coma, and hippus, a spasmodic, rhythmical, pupillary dilation and constriction.48 Nausea and vomiting often precede the psychedelic effects produced by psilocybin and mescaline. Potential life-threatening complications such as hyperthermia, coma, respiratory arrest, hypertension, tachcardia, and coagulopathy were described in a report of 8 patients with a massive LSD overdose.45 The psychological effects of LSD are dose related and affect changes in arousal, emotion, perception, thought process, and selfimage. The response to the drug is related to the person’s mindset, emotions, or expectations at the time and can be altered by the group or setting.2 The person experiencing the effects of a hallucinogen is usually fully awake, alert, and oriented but confronted with diverse perceptual anomalies and varied sensations. The person may experience euphoria or dysphoria, can be emotionally labile, but generally realizes that he or she is under the influence of a drug. Perceptual distortions are common, typically involve loss of body image (people’s faces and body parts appear distorted) and alteration in visual perceptions (objects undulate, their boundaries are lost and merge). There is acute attention to details with excessive attachment of meaning to ordinary objects and events. Usual thoughts seem novel and profound. Many people report an intensification of their sensory perceptions such as sound magnification and distortion; colors seem brighter with halolike lights around objects. Frequently, the person relates a sense of depersonalization and separation from the environment. The hallucinating person may perceive that he or she is observing an “out-of-body experience.” Synesthesias, or sensory misperceptions, are frequent and include “hearing” color or “seeing” sounds. True hallucinations may occur and can be visual, auditory, tactile, or olfactory, although those of a visual nature are the most common.86 Acute adverse psychiatric effects of hallucinogens include panic reactions, true hallucinations, psychosis, and major depres-

sive dysphoric reactions. Acute panic reactions, the most common adverse effect, present with frightening illusions, tremendous anxiety, apprehension, and a terrifying sense of loss of self-control. The acute depersonalization and perceptual alterations associated with hallucinogen use may be the stimulus for the decompensation.46

DIFFERENTIAL DIAGNOSIS Hallucinosis is the abnormal organic mental condition of persistent hallucinations. The major causes of hallucinosis can be divided into structural, infectious, functional, and toxic-metabolic origins. The diagnosis of hallucinogen exposure often must be established on the basis of history and physical examination alone. Sympathomimetic effects such as mydriasis, tachycardia, hypertension, diaphoresis, and hyperactivity are generally less prominent in LSD ingestion than in phenylethylamine intoxication. The person who has ingested hallucinogens typically is oriented and will often give a history of drug use. This stands in stark contrast to patients with drug-induced delirium, in whom orientation is, by definition, altered. Drugs such as amphetamine, cocaine, phencyclidine (PCP), and anticholinergics produce delirium or psychosis at doses capable of producing hallucinations. Patients with amphetamine toxicity typically present with elaborate and paranoid delusions as well as visual hallucinations. Psychiatric or “functional” causes of perceptual changes such schizophrenia typically present with auditory hallucinations. Patients with central anticholinergic toxicity usually present with disorientation, combative behavior, and incoherent mumbling, and may be unaware that the hallucinations are drug induced.47 The presence of marked hyperthermia, uncontrollable behavior, or extreme agitation should suggest an alternative exposure such as cocaine, PCP, or amphetamines.

LABORATORY The routine drug-of-abuse screens do not detect the classic hallucinogens such as LSD or DMT, but may detect MDMA or PCP. Although LSD exposure can be detected by radioimmunoassay, confirmation by high-performance liquid chromatography or gas chromatography is necessary. These tests are rarely used in the clinical setting, but are much more common for forsenic matters.12,27

TREATMENT Most patients with hallucinogenic experiences are never brought to medical attention because they experience only the desired effect of the drug. In any patient who presents to the emergency department with disturbing hallucinations or psychosis, even if an ingestion of a hallucinogen is suspected, the basic approach for altered mental status should include consideration of the administration of dextrose, thiamine, and oxygen as indicated, and the vigorous search for other etiologies. The patient with a dysphoric reaction can be placed in a quiet location with minimal stimuli. A nonjudgmental advocate should attempt to reduce the patient’s anxiety, provide reality testing, and remind the individual that a drug was ingested and the effect will

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wear off in a couple of hours.78 Significant agitation, dysphoria, or a “bad trip,” combined with signs of autonomic instability, can usually be treated by the administration of a benzodiazepine.1,73 Benzodiazepines remain the cornerstone of therapy, as the sedating effect will diminish both endogenous and exogenous sympathetic effects.60 Phenothiazines have been used to treat acute psychotic reactions; however, there may be an increased incidence of hallucinogen persisting perception disorder, previously known as flashbacks, in those patients treated with phenothiazines.3 Prolonged psychosis may require treatment with long-term antipsychotic therapy. Gastrointestinal decontamination with activated charcoal may be considered for asymptomatic patients with recent ingestions, but is probably not helpful after clinical symptoms appear, and attempts may lead to further agitation. Excessive physical restraint should be avoided because of concerns for hyperthermia and rhabdomyolysis. Hallucinogens rarely produce life-threatening problems. Sedation with benzodiazepines is usually sufficient to treat autonomic instability and hyperthermia. In rare cases, hyperthermia may require more aggressive therapy with hydration, active external cooling, and muscle relaxants ranging from benzodiazepines to paralytic agents depending upon the severity of the individual’s condition.15 Morbidity and mortality typically result from the complications of hyperthermia including rhabdomyolysis and myoglobinuric renal failure, hepatic necrosis, and disseminated intravascular coagulopathy. For the most part, however, hydration, sedation, a supportive environment, and meticulous supportive care will prove adequate.21 Atypical antipsychotics such as clozapine and risperidone are antagonist at the 5-HT2 receptors.29 In animal model systems 5HT2 antagonists such as risperidone and ritanserin are effective in blocking the electrophysiologic and behavioral effects of hallucinogenic drugs. These agents may be a potential treatment for adverse reactions to hallucinogens, but require further before study they are used routinely.58,59,68

LONG-TERM EFFECTS Long-term consequences of LSD use include prolonged psychotic reactions, severe depression, and exacerbation of preexisting psychiatric illness.38,70 When LSD was initially popularized, some patients were noted to behave in a manner similar to schizophrenia and required admission to psychiatric facilities. In volunteer studies, panic reactions, hallucinogen persisting perception disorder, and extended psychoses were noted. When the drug was used for alleviation of anxiety and personality abnormalities, flashbacks and extended psychosis were reported.31 It has been suggested that these individuals had preexisting compensated psychological disturbances.5,53,76 Hallucinogen persisting perception disorder (HPPD), previously known as flashbacks, is a chronic problem associated with LSD abuse and is characterized by transient recurrence of perceptual disturbances that were experienced in a previous hallucinogen experience.7 These perceptions can be triggered during times of stress, illness, and exercise, and are often a virtual recurrence of the initial hallucinations. Common perceptual and visual disturbances in HPPD include geometric forms; false, fleeting perceptions in the peripheral fields; flashes of color; intensified color; and halos around objects.53 hallucinogen persisting perception disorder may only last for several months, but some patients have re-

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ported perceptual abnormalities up to 5 years. Reality testing is intact in patients with HPPD as opposed to patients with psychosis. The etiology of HPPD is unknown. Although, many drugs have been tried to treat patients with HPPD, most have not proven beneficial. Haloperidol and risperidone are associated with an exacerbation of panic and visual symptoms.3 Clonidine may be an option. Patients who are on therapeutic doses of lithium are at risk for seizures or HPPD, whereas patients being treated with tricyclic antidepressants or a selective serotonin reuptake have an inconsistent altered response to the pyschotropic effects.13,14,55 Although there are no reported case of serotonin syndrome reported with classic hallucinogens, there are cases associated with MDMA.

SUMMARY Hallucinogens are a diverse group of drugs that alter and distort perception, thought, and mood without clouding the sensorium. Acute adverse psychiatric effects of hallucinogens include panic reactions, true hallucinations, psychosis, and major depressive dysphoric reactions. Hallucinogens rarely produce life-threatening problems. Long-term consequence of LSD use may include prolonged psychotic reactions, severe depression, exacerbation of preexisting psychiatric illness, and hallucinogen persisting perception disorder.

ACKNOWLEDGMENT Cynthia K. Aaron, MD, contributed to this chapter in a previous edition.

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13. Bonson KR, Murphy DL: Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium. Neurosci Biobehav Rev 1996;73:229–233. 14. Bonson KR, Buckholtz JW, Murphy DL: Chronic administration of the serotonergic antidepressants attenuates the subjective effects of LSD in humans. Neuropsychopharmacology 1998:14:425–436. 15. Borowiak KS, Ciechanowski K, Waloszczyk P: Psilocybin mushroom intoxication with myocardial infarction. J Toxicol Clin Toxicol 1998; 36:47–49. 16. Brubacher JR, Lachmanen D, Ravikumar PR, Hoffman RS: Efficacy of digoxin-specific Fab fragments (Digibind) in the treatment of toad venom poisoning. Toxicon 1999;37:931–942. 17. Buchman J: Brainwashing, LSD, and CIA: Historical and ethical perspective. Int J Soc Psychiatry 1977;23:8–19. 18. Buckholtz NS, Zhou D, Freedman DX: Serotonin 2 agonist administration down-regulates rat brain serotonin 2 receptors. Life Sci 1988; 42:2439–2445. 19. Bullis RK: Swallowing the scroll: Legal implications of the recent Supreme Court peyote cases. J Psychoactive Drugs 1990;22:325–332. 20. Burris KD, Sanders-Bush E: Unsurmountable antagonism of brain 5-hydroxytryptamine-2 receptors by (+)-lysergic acid diethylamide and bromo-lysergic acid diethylamide. Mol Pharmacol 1992;42: 826–830. 21. Callaway CW, Clark RF: Hyperthermia in psychostimulant overdose. Ann Emerg Med 1994;24:68–76. 22. Calabrese JD: Spiritual healing and human development in the Native American Church: Toward a cultural psychiatry of peyote. Psychoanal Rev 1997;84:237–255. 23. Caporeal LR: Ergotism: The satan loosed in Salem? Science 1976; 192:21–26. 24. Cohen MM, Hirshhorn K, Frosch W: In vivo and in vitro chromosomal damage induced by LSD-25. N Engl J Med 1967;277:1043–1049. 25. Delgado PL, Moreno FA: Hallucinogens, serotonin and obsessivecompulsive disorder. J Psychoactive Drugs 1998;30:359–365. 26. Drug Enforcement Agency. Lysergic acid diethylamide (LSD). Department of Justice. [On-line] Available: www.usdoj.gov/dea/concern/lsd.htm (accessed 07/20/00). 27. Dupont RL, Verebey K: The role of the laboratory in the diagnosis of LSD and ecstasy psychosis. Psychiatr Ann 1994;24:142–144. 28. Erickson TB, Aks SE, Koenigsberg M, Bunney EB: Drug use patterns at major rock concerts events. Ann Emerg Med 1996;28:22–26. 29. Fink H, Morgenstern R, Oelssner W: Clozapine-A serotonin antagonist? Pharmacol Biochem Behav 1984;20:513–517. 30. Fody RP, Walker EM: Effects of drugs on the male and female reproductive systems. Ann Clin Lab Sci 1985;15:451–458. 31. Frankel FH: The concepts of flashbacks in historical perspective. Int J Clin Exp Hypn 1994;152:321–326. 32. Giacomelli S, Palmery M, Romanelli L, et al: Lysergic acid diethylamide (LSD) is partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactrotrophs in vitro. Life Sci 1998;63;215–222. 33. Glennon RA: Do classical hallucinogens act as 5-HT2 agonists or antagonists? Neuropsychopharmacology 1990;3:509–517. 34. Glennon RA, Titeler M, McKenney JD: Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 1984;35:2505–2511. 35. Glick SD, Maisonneuve IM: Mechanism of antiaddictive actions of ibogaine. Ann N Y Acad Sci 1998;844:214–226. 36. Glick SD, Maisonneuve IM: Development of novel medications for drug addiction: The legacy of an African shrub. Ann N Y Acad Sci 2000;909:88–103. 37. Gouzoulis-Mayfrank E, Hermle L, Thelen B, et al: History, rationale and potential of human experimental hallucinogenic drug research in psychiatry. Pharmacopsychiatry 1998;31:63S–68S. 38. Halpern JH, Pope HG: Do hallucinogens cause residual neuropsychological toxicity. Drug Alcohol Depend 1999;53:247–256.

39. Harrington MA, Zhong P, Garlow SJ, Ciarnello RD: Molecular biology of serotonin receptors. J Clin Psychiatry 1992;53(Suppl):8–27. 40. Hitt M, Ettinter DD: Toad toxicity. N Engl J Med 1986;314:517. 41. Hofmann A: History of the discovery of LSD. In: Pletscher A, Ladewig D, eds: 50 Years of LSD: Current Status and Perspective of Hallucinogens, New York, Parthenon, 1994, pp. 7–16. 42. House RV, Thomas PT, Bhargava HN: Comparison of the hallucinogenic indole alkaloids ibogaine and harmaline for potential immunomodulatory activity. Pharmacology 1995:51:56–65. 43. Jacobson CB, Berlin CM: Possible reproductive detriment in LSD users. JAMA 1972;222:1367–1373. 44. Johnston LD, O’Malley PM, Bachman: Drug trends in 1999 are mixed. University of Michigan and Information Services. Ann Arbor, MI. [On-line] Available: www.monitoringthefuture.org (accessed 02/15/00). 45. Klock JC, Boerner U, Becker CE: Coma, hyperthermia and bleeding associated with massive LSD overdose. West J Med 1973;120: 183–188. 46. Kulick AR, Ahmed I: Substance-induced organic mental disorders: A clinical and conceptual approach. Gen Hosp Psychiatry 1986;8: 168–172. 47. Kulig K: LSD. Emerg Med Clin North Am 1990;8:551–558. 48. Leikin JB, Krantz AJ, Zell-Kanter M, et al: Clinical features and management of intoxication due to hallucinogenic drugs. Med Toxicol Adverse Drug Exp 1989;4:324–350. 49. Li JH, Lin LF: Genetic toxicology of abused drugs: A brief review. Mutagenesis 1998;13:557–565. 50. Louria DB: Current concepts: Lysergic acid diethylamide. N Engl J Med 1968;278:435–438. 51. Lyttle T, Goldstein D, Gartz J: Bufo toads and bufotenine: Fact and fiction surrounding an alleged psychedelic. J Psychoactive Drugs 1996;28:267–290. 52. Lyttle T, Monagne M: Drugs, music and ideology: A social pharmacological interpretation of the acid house movement. Int J Addict 1992;27:1159–1177. 53. Madden JS: LSD and post-hallucinogen perceptual disorder. Addiction 1994;89:762–763. 54. Marek GJ, Aghajanian GK: Indoleamine and the phenethylamine hallucinogens: Mechanism of psychotomimetic action. Drug Alcohol Depend 1998:51:189–198. 55. Markek H, Lee A, Holmes RD, et al: Flashback syndrome exacerbated by selective serotonin reuptake inhibitor antidepressant in adolescents. J Pediatr 1994;125:817–819. 56. McClue SJ, Brazell C, Stahl SM: Hallucinogenic drugs are partial agonists of the human platelet shape change response: A physiological model of the 5-HT2 receptors. Biol Psychiatry 1989;26:297–302. 57. McLeod WR, Sitaram BR: Bufotenine reconsidered. Acta Psychiatr Scand 1985;72:447–450. 58. Meert T, Clincke G: Evidence for a possible role of the 5-HT2 antagonist ritanserin in drug abuse. Ann N Y Acad Sci 1992;654:483–486. 59. Meert TF, de Haes P, Janssen PAJ: Risperidone (R 64 766), a potent and complete LSD antagonist in drug discrimination by rats. Psychopharmacology 1989;97:206–212. 60. Miller PL, Gay GR, Ferris KC, Anderson S: Treatment of acute adverse psychedelic reactions: “I’ve tripped and I can’t get down.” J Psychoactive Drugs 1992;24:277–279. 61. Millman RB, Beeder AB: The new psychedelic culture: LSD, ectasy, “rave parties” and the Grateful Dead. Psychiatr Ann 1994;24: 145–147. 62. Neill JR: “More than medical significance”: LSD and American Psychiatry 1953–1966. J Psychoactive Drugs 1979;19:39–45. 63. O’Malley PM, Johnston LD, Bachman JG: Adolescent substance use: Epidemiology and implications for public policy. Pediatr Clin North Am 1995;42:241–260. 64. Owens MJ, Knight DL, Ritchie JC, Nemeroff CB: The 5-hydroxytryptamine 2 agonist, (-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis: II.

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65. 66.

67.

68.

69.

70.

71. 72. 73. 74. 75.

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Biochemical and psychological evidence for the development of tolerance after chronic administration. J Pharmacol Exp Ther 1991;256: 795–800. Riedlinger TJ: Wasson’s alternative candidates for soma. J Psychoactive Drugs 1993;25:149–156. Rivier L: Ethnopharmacology of LSD and related compounds. In: Pletscher A, Ladewig D, eds: 50 Years of LSD: Current Status and Perspective of Hallucinogens. New York, Parthenon 1994, pp. 43–55. Roth BL, Willins DL, Kristiansen K, et al. 5-Hydroxytryptamine 2— Family receptors: Where structure meets function. Pharmacol Ther 1998;79:231–257. Sadzot B, Baraban JM, Glennon RA, et al: Hallucinogenic drug interactions at human brain 5-HT2 receptors: Implications for treating LSD-induced hallucinogenesis. Psychopharmacology 1989;98: 495–499. Schechter M, Rosecrans J: Lysergic acid diethylamide (LSD) as a discriminative cue: Drugs with similar stimulus properties. Psychopharmacologia 1972;26:313–316. Schneier FR, Siris SG: A review of psychoactive substance use and abuse in schizophrenia: Patterns of drug choice. J Nerv Ment Dis 1987;175:641–652. Schultes RE: Hallucinogens of plant origin. Science 1969;163: 245–254. Schultes RE, Hofmann A: Plants of the Gods. Rochester, VT: Healing Arts Press, 1992. Schwartz RH: LSD. Its rise, fall and renewed popularity among high school students. Pediatr Clin North Am 1995;42:403–413. Shannon M: Methylenedioxymethamphetamine (MDMA “Ecstacy”). Pediatr Emerg Care 2000:16:337–380. Siegel DM, McDaniel SH: The frog prince: Tale and toxicology. Am J Orthopsychiatry 1991;61:558–562.

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76. Smith DE, Seymour RB: LSD: History and toxicity. Psychiatr Ann 1994;24:145–147. 77. Stevens J: Storming Heaven. New York, Harper and Row, 1987. 78. Strassman RJ: Adverse reactions to psychedelic drugs: A review of the literature. J Nerv Ment Dis 1984;172:577–595. 79. Strassman RJ: Human hallucinogenic drug research: Regulatory, clinical, and scientific issues. NIDA Res Monogr 1994;146:92–123. 80. Strassman RJ: Hallucinogenic drugs in psychiatric research and treatment. J Nerv Ment Dis 1995;183:127–138. 81. Strassman RJ: Human psychopharmacology of N,N-dimethyltryptamine. Behav Brain Res 1996;73:121–124. 82. Titeler M, Lyon RA, Glennon RA: Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology 1988;94: 213–216. 83. Ulrich RF, Patten BM: The rise, decline and fall of LSD. Perspect Biol Med 1991;34:561–578. 84. Watts VJ, Lawler CP, Fox DR, et al: LSD and structural analogs: Pharmacological evaluation at D1 receptors. Psychopharmacology 1995;118:401–409. 85. Weil AT, Davis W: Bufo alvarius: A potent hallucinogen of animal origin. J Ethnopharmacol 1995;41:1–8. 86. Weller M, Wiedmann P: Visual hallucinations. Int Ophthalmol 1989; 13:193–199. 87. Wing LL, Tapson GS, Geyer MA: 5-HT2 mediation of acute behavioral effects of hallucinogens in rats. Psychopharmacology 1990; 100:417–425. 88. Winter JC, Fiorella DJ, Timineri DM, et al: Serotonergic receptor subtypes and hallucinogen-induced stimulus control. Pharmacol Biochem Behav 1999;64:283–293.

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71

MARIJUANA Edward J. Otten

A 20-year-old male was brought to the Emergency Department (ED) by the police after they had stopped him for driving his automobile recklessly. The patient’s car was weaving along the highway and had crossed the centerline several times. The police initially thought that the patient was intoxicated with alcohol, but breath analysis was negligible for ethanol. Because they felt that he might have some medical problem, he was taken to the emergency department. Upon arrival the patient was drowsy but easily arousable to verbal stimuli. He stated that he had been to a party earlier that evening and thought that someone may have put something in his nonalcoholic drink. He insisted that he had not been drinking alcohol and did not use drugs in any form. He complained of a slight headache and inability to focus, but had no other complaints. His past medical history was negative. He had no known allergies and took no medications regularly. The patient’s vital signs were: blood pressure, 138/84 mm Hg; pulse, 112 beats/min; respiratory rate, 18 breaths/min; and temperature, 99.0°F (37.2°C). He was drowsy but arousable, oriented to person, place, time, and situation. Pupils were 5 mm, equal and reacted to light; conjunctivae were injected, and extraocular movements were normal without nystagmus. Lungs were clear to auscultation, and heart examination revealed a rapid, regular rhythm without murmur or rub. Neurologic examination was normal except for difficulty maintaining a normal erect posture. The patient’s gait was normal as was his “finger-to-nose” examination. The patient remained difficult to arouse. Oxygen saturation was 95% on room air and a fingerstick blood glucose was 120 mg/dL. A urine screen was positive for tetrahydrocannabinol. Upon further questioning the patient admitted to smoking several “joints” of marijuana prior to attempting to drive home. After 6 hours in the ED the patient was completely arousable and neurologic examination was completely normal. The patient was referred to outpatient drug counseling and discharged in the custody of his brother.

psychoactive substance
9-tetrahydrocannabinol (THC). THC is found in both the male and female plants. Cannabis has been cultivated for thousands of years for numerous purposes including medical, religious, and “recreational” use as well as for fiber. Cannabis sativa is the only species belonging to the genus Cannabis. Cultivated varieties of Cannabis sativa are used in the manufacture of fiber for rope and clothing, which have erroneously been thought to be separate species. Cannabis sativa contains a number of active compounds known collectively as cannabinoids, including cannabidiol, cannabinol, cannabidiolic acid, cannibicyclol, and cannabigrol. In all, approximately 60 cannabinoids and 200 other chemical compounds have been identified in Cannabis plant material. Most of these constituents are found in small concentrations and have little or no psychoactive effects when compared to THC. These constituents do have chemical activity and may contribute to the acute and chronic medical problems resulting from marijuana use. Thus, THC is the primary constituent of marijuana, but not the only one; and THC is not pharmacologically equivalent to marijuana. The percentage of the THC found in plants depends on ecotypic variables, including amount of light, moisture, soil type, trace elements, pH, and nutrients. Common misconceptions associated with potency of various types of marijuana that are based on origin, sex of the plant, and color are probably related to the phenotypic plasticity of the plants. The amount of active THC found in a sample deteriorates with time. Hashish and hashish oil are derivatives of the Cannabis plant that contain higher concentrations of THC; they are smoked either alone in pipes (hashish) or mixed with tobacco and smoked (hashish oil). Marijuana may also be ingested in food and is commonly used in conjunction with other drugs such as opium, alcohols, cocaine, heroin, phencyclidine, ketamine, and formaldehyde.4,21,27

EPIDEMIOLOGY Marijuana is a common name for material obtained from the leaves and flowers of the Indian hemp plant, Cannabis sativa. Marijuana is one of many names for cannabis, which contains the

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Nicotine, alcohol, caffeine, and marijuana are the most commonly used psychoactive substance in the world. In the United States, marijuana is the most frequently utilized illegal substance involv-

CHAPTER 71

ing an estimated 20 million people.45 Marijuana is thought by many to be a “gateway” drug, leading to use of other more dangerous substances such as heroin, cocaine, or amphetamines. Marijuana was shown to be a gateway drug in a study of 1265 New Zealand children over a 21-year period. In that study, those children using marijuana more than 50 times a year abused other drugs 140 times more often than did nonmarijuana users.15 The United States Drug Enforcement Agency (DEA) has classified marijuana as a Schedule I substance. Both the latest Centers for Disease Control and Prevention (CDC) statistics and National Institute on Drug Abuse (NIDA) data suggest a rise in the use of marijuana in the general population, particularly among teenagers. The NIDA survey on drug use showed an increase in the prevalence of reported marijuana usage in all groups of teenagers in 1994. Eighth grader use increased by 13%, 10th grader use increased by 25%, and 12th grader use increased by 31% as compared with 1993 estimates. From a historical peak of reported marijuana use in 1978, use decreased from 1979 to 1991. This trend was reversed in 1992, and the prevalence rate has increased annually since then. The Substance Abuse and Mental Health Services Administration (SAMHSA) National Household Survey on Drug Abuse, SAMHSA’s Drug Abuse Warning Network (DAWN), and the National Institute of Justice Drug Use Forecasting (DUF) system data all suggest increases in marijuana use in 1998. National drug-related ED visits for marijuana increased 43%, from 152,433 in 1996 to 172,014 in 1998. The Youth Risk behavior Surveillance–National Alternative High School Youth Risk Behavior Survey, United States 1998 reported that 85% of students used marijuana once during their lifetime. Male students (88%) were more likely than female students (82%) to use marijuana and white students (89%) were more likely than African American students (77%) to use marijuana.19 The Monitoring the Future Study for 1999 shows a trend of increasing marijuana use among high school students over a 20-year period. Not surprisingly, the higher the baseline use of marijuana in adolescents, the higher the probability of continued use.18,24,25,28,41,45 The number of motor vehicle or work-related injuries that are caused by marijuana use is unknown. Studies have implicated marijuana in motor vehicle fatalities, especially in the 15–30-yearold age group. After alcohol, marijuana was the most common drug found, being detected in 11–33% of the motor vehicle fatalities.7,33,49 The federal government requires drug testing of the crew of any commercial carrier (planes, trains, buses) involved in major crashes.

PHARMACOLOGY AND PATHOPHYSIOLOGY The onset of marijuana effects depend on the route of administration and the concentration of THC in the product used. Smoking marijuana usually leads to nearly immediate effects, whereas oral ingestion has a slow and unpredictable effect because of the instability of THC in the acidic environment of the stomach.38 The smoking dynamics or manner in which the marijuana is smoked is the most important factor in determining the absorption of THC.5,10 Depending on the initial concentration of THC, pyrolysis of THC, loss in sidestream smoke, and mucosal concentration, on average about half of the THC in the marijuana is delivered to the lungs. It takes about 15 seconds for the lungs to absorb the THC and to transport it to the brain.40 A family of specific cannabinoid

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receptors in the cerebral cortex may be responsible for the pharmacologic effects of marijuana. The endocannabinoids, or naturally occurring ligands, 2arachidonolyl-glycerol (Ara-G1) and anandamide, bind these same cannabinoid receptors.3,8 These ligands produce effects similar to plant-derived THC with significant pharmacologic differences. Ara-G1 produces vasodilation and hypotension. Anandamide is 10-fold less potent and has a shorter duration of action.36 Although the mechanisms for the synthesis and metabolism of anandamide are known, the physiologic role and the reason for the differences are unknown.22,34,39 The CB1 receptors, found in the pain-processing areas of the brain and spinal cord, and the CB2 receptors located in the peripheral nerves, suggest a potential analgesic effect of THC. For these reasons it is suggested that the endogenous ligands may be important in pain modulation. After smoking, the effects of marijuana peak in 10–30 minutes and may last for 1–4 hours, depending on the dose actually inhaled.9 THC is lipophilic and therefore accumulated in lipid tissue; it is highly protein bound (97–99%), has a an apparent Vd of 10 L/kg, and it is enterohepatically recirculated. All of these characteristics result in slow elimination from the body. THC is oxidatively metabolized to the active compound 11-hydroxy-
9tetrahydrocannabinol, which is further oxidized to the inactive 11nor-9-carboxy-
9-THC.10 THC also has a dose-dependent effect in diminishing the cytolytic activity of large granular lymphocytes against K562 tumor cells, while decreasing the synthesis of tumor necrosis factor by macrophages. Both B- and T-cell activity are depressed by THC; however, cell-mediated immunity is more readily affected. Both CB1 and CB2 receptors have been identified in immune cells and modulate the effect of THC on the immune response. The CB2 receptor mediates the activation of mitogen-activated protein kinase, which may be the mechanism for the immunosuppressive effect.30,39,46,54

CLINICAL EFFECTS Acute The clinical effects of marijuana may be both physiologic and psychological, based partly on previous experience of the user.9 The usual psychological effects are fairly predictable and include alterations in sensation, perception, cognition, and psychomotor functions.29 Although users report enhanced perception and sensation, this enhancement is not observed experimentally. A sense of euphoria, relaxation, and various sensory alterations are generally the effects that are sought with marijuana use.9 The true danger of acute marijuana toxicity results from the loss of motor skills and judgment. Airline pilots using a flight simulator were impaired for as long as 24 hours after a single dose of marijuana; the impairment was compounded by the pilot’s age and the difficulty of the required flying tasks.32 Perhaps as expected, the National Highway Traffic Safety Administration (NHTSA) study showed that a combination of marijuana and alcohol, even at low levels, impaired drivers more than either higher levels of marijuana or alcohol alone.37 Marijuana affects performance of neuropsychiatric tests, especially digit recall and mathematical skills, and this appears to correlate with serum THC levels.13,42 An acute psychosis is associated with marijuana use; it is not clear whether preexisting psychopathology is responsible or

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PART D

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

whether this behavioral alteration is related to the dose of THC or the inexperience of the user. Studies of patients without prior psychopathology who developed acute psychotic reactions following marijuana use have shown that the reactions are usually transient.35 Although the psychological effects of marijuana may or may not be dose dependent, the physiologic effects are. Increase in heart rate is common, but blood pressure response is variable. Endocannabinoids cause vasodilation and hypotension in both humans and laboratory animals via the CB1 receptor. This effect may occur through inhibition of transmitter release or direct effects on smooth muscle cells.22 Acutely, muscle tremors, and weakness, as well as bronchodilation occur. Conjunctival injection, increased appetite, decreased intraocular pressure, decreased testosterone levels, and urinary retention are all common sequelae of acute marijuana usage.5,23,38 Pneumomediastinum and pneumothorax may occur following the alveolar overdistension and rupture from deep inhalation during marijuana smoking.6 Dyspnea and chest pain may result, but are rarely life-threatening.

Chronic Cannabinoids increase the activity of dopaminergic neurons in the mesolimbic pathway, which reinforces the abuse potential. Tolerance is associated with repeated use of marijuana. Similar to many other psychoactive drugs, tolerance can lead to both physiologic and psychological dependence, and a withdrawal syndrome. The withdrawal syndrome resulting from marijuana use can be reproduced experimentally and includes sleep disturbances, irritability, decreased appetite, nausea, and restlessness, all of which can be reversed by small doses of THC. Persistent consequential marijuana use produces residual neuropsychological effects that do not occur in light infrequent users.1,20,42 Smoking marijuana is implicated in chronic lung disease and carcinogenesis unrelated to tobacco smoking.51 Marijuana smoking causes a 5-fold increase in blood carboxyhemoglobin level and a 3-fold increase in the amount of tar inhaled when compared with tobacco smoking.53 Some studies indicate that because of the smoking dynamics associated with marijuana (ie, deep inhalations), a 4-fold greater respiratory burden of particulates occur compared to tobacco smoking, making marijuana inhalation potentially more dangerous to the lung than tobacco.40 Marijuana seems to have a greater impact on central airway function, while the predominant effect of tobacco is on peripheral airways. Significantly worse values for specific airway conductance and airway resistance were found with marijuana smoking when compared with nonsmokers or tobacco smokers.51 Bronchoalveolar lavage fluid from the lungs of marijuana smokers demonstrates an increase in macrophages and other inflammatory cells that is independent of, and additive to, that of tobacco.44,51,53 Base fractions of marijuana are more mutagenic than tobacco, and high-dose base fractions were 7-fold more mutagenic than either tobacco or lowdose marijuana base fractions.50 Studies in pregnant female marijuana smokers demonstrate that there are a number of neonatal neurobehavioral disturbances that correlate with marijuana use during pregnancy; the effects seem to disappear during infancy and reappear later in early childhood.2,12,16,43 Prenatal marijuana use by the mother significantly correlated with subsequent increased hyperactivity, impulsivity, increased delinquency, and inattention symptoms in the child.17 Another study of subjects who started using marijuana before age

17 had smaller whole-brain and gray matter volumes and smaller stature.52 THC interferes with testicular function by a number of mechanisms causing a decrease in sperm motility and numbers as well as an increase in abnormal morphology.24

MEDICAL USES Marijuana may be used to treat symptoms, but not specific diseases. The Institute of Medicine evaluated a number of clinical studies of marijauna use.26 As an antiemetic, although marijuana is useful in treating the nausea and vomiting associated with cancer chemotherapy, neither THC nor its analogues, nabilone and levonantradol, are as effective as standard antiemetics. Marijuana is useful in stimulating the appetite of HIV/AIDS patients and others, but was less effective than megestrol acetate. Some authors recommend the use of THC in the treatment of glaucoma, muscle spasticity, movement disorders, multiple sclerosis, and asthma, but there are no scientific studies supporting these recommendations. The dose of THC in marijuana that is smoked cannot be controlled, making scientific studies difficult to interpret as to efficacy and therapeutic drug levels. Currently, one prescription product, dronabinol (Marinol), contains synthetic THC. This drug has a standardized concentration of THC and therefore the amount that the patient receives can be controlled. Dronabinol is a Schedule II drug and can be prescribed for nausea and vomiting or anorexia. Animal studies show some promise for the use of THC as an analgesic, and clinical studies based on these findings are ongoing.26 In November 1996, California and Arizona passed propositions legalizing marijuana for medical purposes. The US Senate Judiciary Committee and the DEA have not supported these laws, and in 1997, the Arizona Senate passed a law nullifying a physician’s right to prescribe Schedule I substances without federal approval. The DEA continues to prosecute in California, marijuana traffickers, and those arrested for criminal activities in the possession of marijuana under federal law.4,31,47

LABORATORY All of the 20 metabolites of THC may cross-react with THC in the standard immunoassay used for the screening urine for marijuana. The screening test is designed to detect THC at either levels of 20, 50, or 100 ng/mL, depending on the purpose for which the test is performed. The gas chromatography-mass spectrometry (GC-MS) confirmation test for nor-9-carboxy-
9-THC uses a cutoff level of 15 ng/mL.23,48 The pattern of excretion is similar for most users of marijuana. The individual differences result from variable lengths of each phase of excretion, which depend on the individual pattern of usage. These variations result in screening and confirmation test results that may be positive for up to 70 or more days, depending on the cutoff levels used and the individual’s lipid stores of THC. In general, THC can be detected for 1–3 days after a single acute use, and for 10 days to 4 weeks after daily use.14 Passive exposure to marijuana smoke, depending on room air concentration, may give positive screening results for several days, even after a single exposure.11 Rarely, false-positive results may occur after therapeutic use of naproxen, ibuprofen, and fenoprofen. False-negative results may occur from urine dilution, diuretic use, and the addition of table salt, or other contaminants to the urine. Concomitant test-

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ing of urine specific gravity, pH, temperature, and creatinine have eliminated most of these confounding variables.23,48 14.

MANAGEMENT

15.

The acute psychotic reaction involving paranoid delusions and hallucinations that may occur with marijuana usage can be managed effectively with benzodiazepines.35 Patients presenting with dyspnea, chest pain, decreased breath sounds and or a low oxygen saturation may have a pneumothorax or pneumomediastinum and should be evaluated and managed accordingly. Patients with marijuana ingestions and overdoses of dronabinol should be treated with activated charcoal. Coingestants, such as PCP or cocaine, should be managed as indicated. There are no known cases of lethal marijuana intoxication.

16.

17.

18.

19.

SUMMARY Patients with psychological manifestations can usually be treated supportively. Marijuana is a commonly used agent, often used with other toxins, but rarely associated with consequential overdoses. The role that marijuana plays in an individual’s subsequent drug use remains highly debated, as does its role as a medicinal agent. Recent studies of marijuana’s role in motor vehicle crashes and occupational injuries have initiated an increased focus on these substantial toxicologic complications.

20.

21.

22. 23.

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ed: Neurobiology of Drug Abuse: Learning and Memory. NIDA research monograph 97. Washington, DC, USDHHS, 1990, pp. 79–93. Ellis GM, Mann MA, Judson BA, et al: Excretion patterns of cannabinoid metabolites after last use in a group of chronic users. Clin Pharmacol Ther 1985;38:572–578. Ferguson DM, Horwood LJ: Does cannabis use encourage other forms of illicit drug use? Addiction 2000;95:505–520. Fried PA: Behavioral outcome in preschool and school-age children exposed prenatally to marijuana: A review and speculative interpretation. In: Wetherington CL, Smeriglio VL, Finnegan LP, eds: Behavioral Studies of Drug-Exposed Offspring: Methodological Issues in Human and Animal Research. NIDA research monograph 164. Washington, DC, USDHHS, 1996, pp. 242–260. Goldschmidt L, Day NL, Richardson GA: Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol Teratol 2000;22:325–336. Golub A, Johnson BD: The shifting importance of alcohol and marijuana as gateway substances among serious drug abusers. J Stud Alcohol 1994;55:607–614. Grunbaum JA, Kann L, Kinchen SA, et al: Youth risk behavior Surveillance-National Alternative High School Youth Risk Behavior Survey, United States 1998. MMWR Morb Mortal Wkly Rep 1999; 48(SS-7):18–19. Haney M, Ward AS, Comer SD, et al: Abstinence symptoms following smoked marijuana in humans. Psychopharmacology 1999;141: 395–404. Hawks, RL: The constituents of Cannabis and the disposition and metabolism of cannabinoids. In: Hawks RL: The Analysis of Cannabinoids in Biological Fluids, NIDA research monograph 42. Washington, DC, USDHHS, 1982, pp. 125–317. Hillard CJ: Endocannabinoids and vascular function. J Pharmacol Exp Ther 2000;294:27–32. Huestis M: Pharmacology and toxicology of marijuana. Ther Drug Monit 1993;14:131–138. Husain S: Marijuana abuse: Its pharmacology and effects on testicular function. In: Redda KK, Walker CA, Barnett G, eds: Cocaine, Marijuana, Designer Drugs: Chemistry, Pharmacology and Behavior. Boca Raton, FL, CRC Press, 1989, pp. 127–143. Johnston LD, O’Malley PM, Bachman JG: National Survey Results on Drug Use from Monitoring the Future Study, 1975–1994. Washington, DC, USDHHS, 1996. Joy JE, Watson SJ, Benson JA: The medical value of marijuana and related substances in marijuana and medicine: Assessing the science base. Washington DC, National Academy Press, 1999, pp. 137–192. Joyce CRB, Curry SH: The Botany and Chemistry of Cannabis. London, J&A Churchill, 1970, pp. 1–60. Kann L, Warren CW, Harris WA, et al: Youth risk behavior surveillance—United States, 1995. MMWR Morb Mortal Wkly Rep 1996; 45(SS4):1–83. Kurzthaler I, Hummer M, Miller C, et al: Effects of cannabis on cognitive functions and driving ability. J Clin Psychiatry 1999;60: 395–399. Kusher DI, Dawson LO, Taylor AC, Djeu, JY: Effect of the psychoactive metabolite of marijuana, delta-9-tetrahydrocannabinol (THC), on the synthesis of tumor necrosis factor by human large granular lymphocytes. Cell Immunol 1994;154:99–108. Lane M, Vogel CL, Ferguson J, et al: Dronabinol and prochlorperazine in combination for the treatment of cancer chemotherapyinduced nausea and vomiting. J Pain Symptom Manage 1991;6: 352–359. Leirer VO, Yesavage JA, Morrow DG: Marijuana, aging and task difficulty effects on pilot performance. Aviat Space Environ Med 1989;60:1145–1152. Logan BK, Schwilke EW: Drug and alcohol use in fatally injured drivers in Washington State. J Forensic Sci 1996; 41:505–510. Martin BR, Mechoulam R, Razdan RK: Discovery and characterization of endogenous cannabinoids. Life Sci 1999;65:573–595.

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35. Mathers DC, Ghodse AH: Cannabis and psychotic illness. Br J Psychiatry 1992;161:648–653. 36. Matsuda LA, Lolait SJ, Brownstein MJ, Bonner TI: The THC receptor and its implications. In: Korenman SG, Barchas JD, eds: Biological Basis of Substance Abuse. Oxford, Oxford University Press, 1993, pp. 95–106. 37. National Highway Traffic Safety Administration: Marijuana and alcohol combined severely impede driving performance. Ann Emerg Med 2000;35:398–399. 38. Ohlsson A, Lingren JE, Wahlen A, et al: Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther 1980;28: 409–416. 39. Parolaro D: Presence and functional regulation of cannabinoids receptors in immune cells. Life Sci 1999;65:637–644. 40. Perez-Reyes M: Marijuana smoking: Factors that influence the bioavailability of tetrahydrocannabinol. In: Chiang CN, Hawks RL, eds: Research Findings on Smoking of Abused Substances. NIDA research monograph 99. Washington, DC, USDHHS, 1990, pp. 42–62. 41. Perkonigg A, Lieb R, Hofler M, et al: Patterns of cannabis use, abuse and dependence over time: Incidence, progression and stability in a sample of 1228 adolescents. Addiction 1999;94:1663–1678. 42. Pope HG, Yurgelun-Todd D: The residual cognitive effects of heavy marijuana use in college students. JAMA 1996;275:521–527. 43. Richardson GA, Day NL, McGauhey PJ: The impact of prenatal marijuana and cocaine use on the infant and child. Clin Obstet Gynecol 1993;36:302–318. 44. Roth MD, Arora A, Barsky SH, et al: Airway inflammation in young marijuana and tobacco smokers. Am J Resp Crit Care Med 1998; 157:928–937. 45. Rouse BA: Epidemiology of illicit and abused drugs in the general population, emergency department drug-related episodes, and arrestees. Clin Chem 1996;42:1330–1336.

46. Sarafian RA, Magallanes JA, ShauH, et al: Oxidative stress produced by marijuana smoke. An adverse effect produced by cannabinoids. Am J Respir Cell Mol Biol 1999;20:1286–1293. 47. Schwartz RH, Beveridge RA: Marijuana as an antiemetic drug: How useful is it today? Opinions from clinical oncologists. J Addict Dis 1994;13:53–65. 48. Schwartz RH, Hawks RL: Laboratory detection of marijuana use. JAMA 1985;254:788–792. 49. Soderstrom EA, Trifillis AL, Shankar BS, et al: Marijuana and alcohol use among 1023 trauma patients. Arch Surg 1988;123:733–737. 50. Sparacino CM, Hyldburg PA, Hughes TJ: Chemical and biological analysis of marijuana smoke condensate. In: Chiang CN, Hawks RL, eds: Research Findings on Smoking of Abused Substances. NIDA research monograph 99. Washington, DC, USDHHS, 1990, pp. 121–140. 51. Tashkin DP, Coulson AH, Clark VA, et al: Respiratory symptoms and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone and nonsmokers. Am Rev Resp Dis 1987;135:209–216. 52 Wilson W, Mathew R, Turkington T, et al: Brain morphological changes and early marijuana use: A magnetic resonance and positron emission tomography study. J Addict Dis 2000;19:1–22. 53. Wu TC, Tashkin DP, Djahed B, Rose JE: Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med 1988; 318:347–351. 54. Zheng ZM, Specter S, Friedman H: Inhibition by delta-9-tetrahydrocannabinol of tumor necrosis factor alpha production by mouse and human macrophages. Int J Immunopharmacol 1992;14:1145–1152.

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SUBSTANCE WITHDRAWAL Richard J. Hamilton

Case 1. A 46-year-old male arrived in the Emergency Department (ED). He had been in police custody for 18 hours and requested evaluation by a physician because he had a seizure disorder and needed his daily dose of phenytoin. He stated that he was a frequent drinker but denied drug use. His seizures began 10 years ago, and he had been taking phenytoin ever since. He had been noncompliant with his phenytoin, possibly for 2 months. He denied any physical complaints and wanted to be seen and discharged. His vital signs were: blood pressure, 130/80 mm Hg; respiratory rate, 12 breaths/min; pulse, 105 beats/min without orthostatic changes; and rectal temperature, 99.9°F (37.2°C). The man was well developed, poorly nourished, and appeared older than his stated age. He was garrulous and somewhat anxious. He was alert and oriented to time, place, and person. The pertinent positives on physical examination included a fine hand and tongue tremor, scattered spider hemangiomata, and hepatomegaly of 14 cm. The history and initial physical examination appeared consistent with the diagnosis of alcoholism and suspected alcohol withdrawal. Blood was drawn for a complete blood count, serum chemistries, liver function tests, and serum alcohol and phenytoin levels. The patient was to be observed while serum laboratory test results returned. A rapid reagent blood sugar was 70 mg/dL. One liter 0.9% sodium chloride was administered at 500 mL/h with multivitamins and 100 mg of thiamine. In addition, 25 mL of 50% dextrose solution was administered over 2 minutes. One hour later, the patient began to shout at nursing staff that he was being held against his will and that he must leave. Repeat vital signs were blood pressure, 130/80 mm Hg; respiratory rate, 12 breaths/min; pulse, 130 beats/min; room air pulse oximetry, 98% saturation; and rectal temperature, 100.3°F (37.9°C). The patient was diaphoretic. The pupils were 5 mm, equal and briskly reactive. The tremor was now coarse. The patient demanded to be released and could not remember why he asked to be evaluated or who brought him to the hospital. The patient’s clinical condition was unchanged after 20 mg of diazepam was given as two 10-mg IV boluses 15 minutes apart. A portable chest radiograph was within normal limits. The electrocardiogram demonstrated a sinus tachycardia. A room air arterial blood gas analysis was reported as pH, 7.41; PCO2, 37.4 mm Hg; PO2, 73 mm Hg; HCO−3 , 24 mEq; oxygen saturation, 95%. Diazepam was repeated as 10-mg IV boluses to a total of 100 mg, and the patient was placed in 4-point soft restraints after he began to remove his intravenous line and climb off the stretcher. His diaphoresis and tachycardia continued. He picked at the restraints, scratched his skin, and shouted nonsensical words occasionally.

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Diazepam administered to a total dose of 220 mg did not improve the patient’s agitation; the pulse was 110 beats/min; respiratory rate, 12 breaths/min; and temperature, 101.0°F (38.3°C). Toxicology consultation recommended phenobarbital intravenously. This was administered as 130-mg boluses over 3 minutes and repeated 4 times (520 mg total); the patient was sleeping, and the heart rate was 100 beats/min. The patient was electively intubated using thiopental and placed on a mechanical ventilator for airway protection. The patient remained sedate and required an additional 40 mg of diazepam over the next 24 hours. He developed a right lower lobe infiltrate on day 2 of his hospitalization and was treated with ampicillin/sulbactam. He recovered uneventfully and was extubated 48 hours later.

The central nervous system must balance excitation and inhibition to control physiologic function. The most intuitive way to balance this might be to increase excitatory nerve impulses for a physiologic action, and to increase inhibitory impulses whenever a physiologic action must be stopped. The central nervous system (CNS) uses a more efficient method: Excitatory neurons fire regularly, and inhibitory neurons inhibit the transmission of these impulses. Whenever action is required, the inhibitory neurons decrease their firing and permit the excitatory nerve impulses to travel to their end organs. Thus, all action in human neurophysiology is disinhibition.101,185,204 When administered chronically, many drugs and toxins affect the transmission of all classes of inhibitory neurons. Some act to increase the inhibitory effect with subsequent adaptive modulation (such as benzodiazepines and the GABAA receptor, opioids on the opioid receptor, or clonidine on the central
2 receptor). Others act to block the inhibitory effect with subsequent adaptive modulation (caffeine on the adenosine receptor). Still others appear to increase the inhibitory effect with subsequent adaptive modulation of both inhibitory and excitatory neurons (ethanol and the GABAA and NMDA receptors respectively).70,172 A withdrawal syndrome occurs when the drug or toxin is removed or reduced and the adaptive changes persist, producing dysfunction instead. Thus, every withdrawal syndrome has two characteristics: (a) a preexisting physiologic adaptation to a drug or toxin, the continuous presence of which prevents withdrawal; and (b) decreasing concentrations of that substance. In contrast, simple tolerance to a drug is characterized as a physiologic adaptation that shifts the dose-response curve to the right. Patients with withdrawal syndromes have often developed tolerance, but toler-

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ance does not require the continued presence of the drug to prevent withdrawal. Finally, drugs and toxins that stimulate the excitatory neuronal pathways, such as cocaine, can produce a postintoxication syndrome that often results in lethargy, hypersomnolence, movement disorders, and irritability. Despite this syndrome meeting DSM-IV (Diagnostic and Statistical Manual of Mental Disorders 4th Edition) criteria for a withdrawal syndrome, it does not meet a toxicologic definition because the continuous use of this drug does not prevent withdrawal. This postintoxication syndrome, so called “crack crash” or “washed-out syndrome,” is caused by prolonged use of the drug, and patients return to their premorbid function without intervention.151,173,186,202 Withdrawal syndromes are best described and treated based on the class of receptors that are mostly affected. This concept organizes the approach to patient care as well.

HISTORY Physicians have been faced with difficulties in treating ethanol withdrawal since Pliny the Elder in the 1st century BC. In his work Naturalis Historia, the alcoholic and alcohol withdrawal are described, “. . . drunkenness brings pallor and sagging cheeks, sore eyes, and trembling hands that spill a full cup, of which the immediate punishment is a haunted sleep and unrestful nights. . .”.147 An understanding of the relationship between alcohol and deterioration in health was obvious in that day. The appropriate treatment of ethanol withdrawal evolved over the course of the last century. The era of modern medicine begins with Osler, and so it is fitting that we start with his remedies. His recommended treatment included confinement to bed, no restraints, withdrawal of alcohol, and judicious use of potassium bromide, chloral hydrate, hyoscine, and, possibly, opium.140 He suggested that cold douches or baths be used to reduce fever and thereby produce sedation. He also emphasized the importance of feeding milk or broth. By using these methods, mortality was 14% according to several studies at the time. In 1927, Cecil wrote that there were “no specific treatments,” but that it was essential to produce sleep, stimulate the neurologic and circulatory systems, and feed the patient.34 Paraldehyde, chloral hydrate, and hyoscyamine were considered acceptable hypnotics, but barbiturates were not recommended and morphine use was avoided. Strychnine and ergot were recommended for the treatment of tremor. Sheet restraints were suggested as humane replacements for “old-fashioned” canvas jackets. Sodium bicarbonate and cathartics were given hourly to patients with gastritis. Despite Cecil’s innovations, mortality for uncomplicated cases approached that found in studies following Osler’s recommendations. When severe alcohol withdrawal was associated with infections such as pneumonia, mortality was even higher; if associated with trauma, mortality reached 50%. In 1929, the link between agitation, alcohol withdrawal, and hyperthermia was recognized.23 Physical manifestations and complications of agitation were noted to be common to all markedly disturbed patients, regardless of the type of mental illness (alcohol or organic delirium, manic-depressive psychosis, schizophrenia, or dementia paralytica). Because of the severity of the agitation, febrile patients often received inadequate fluid replacement, resulting in dehydration. Further studies supported the benefits of

administration of carbohydrates, sodium chloride, and fluids were essential for a good outcome. By the mid-1930s at Boston City Hospital the fatality rate for all cases declined; an improvement largely attributed to improved nursing care.130 In the early 1950s, Victor and Adams, Mendelson and LaDou, and Isbell and coworkers correctly identified the etiology of delirium tremens (DTs) as alcohol withdrawal in a chronically (usually at least 2–3 weeks) dependent individual.88,129,211 They determined that delirium tremens was not caused by alcohol intoxication, electrolyte or fluid disturbances, shock, infection, or trauma, as previously postulated, but only by withdrawal. All of these investigators noted the similarity of alcoholic DTs and barbiturate and paraldehyde withdrawal. Delirium tremens in its full-blown form is the most dramatic and gravest of all the alcoholic complications. It develops in a variety of settings. The patient, an excessive and steady drinker . . . may have been admitted for an unrelated illness, accident, operation, or infection . . . He may have suffered through several days of tremulousness, hallucinosis or seizures. The patient is restless and agitated, requiring restraints, . . . constantly pulling at his bed clothes, . . . swept over by a wave of apprehension and tremulousness, . . . conversation being garbled and unintelligible. Autonomic overactivity is manifested by dilated pupils, tachycardia, and an elevated temperature, attributable occasionally to no cause other than delirium. Drenching sweats may result in severe dehydration.211 The keen observations and classifications of the symptoms associated with withdrawal make worthwhile reading and can still contribute to the clinician’s understanding of the natural history of this disorder. Much of the terminology used in these reports continues to this day and, unfortunately, adds to a confusing assortment of terms. The term “rum fit” appears to have originated as a description of the convulsions and/or behavior of sailors who were denied their daily rum rations. The term is used to describe a typical alcohol withdrawal seizure—brief, generalized, and occasionally recurrent. “Delirium tremens” was originally described as the “distinct clinical condition characterized by psychomotor, speech, and autonomic overactivity, disorientation, confusion, disordered sense perception, and frequently fatal outcome.”211 In the late 1950s and early 1960s, clinicians examined the link between pharmacologic treatment choices and the impact on outcome. At the time, phenothiazines, paraldehyde and chloral hydrate were often employed in the treatment of DTs.65 The phenothiazines were associated with slower control of fever and greater morbidity and mortality. A controlled study in 1964 demonstrated a 35% mortality rate with promazine and a 4.5% mortality rate with paraldehyde.198 Causes of death were similar: fever, tachycardia, stupor, cyanosis, and cardiovascular collapse without defined pathology. These early studies established a clear improvement in outcome when sedative-hypnotics were compared to antipsychotics. Phenothiazines and butyrophenones are now generally considered inappropriate for any form of withdrawal, because they increase the incidence of hypotension, hyperthermia, seizures, and mortality.20,71,75,76,140 A comprehensive review of 39 fatal cases of DTs found dehydration in all cases in which volume status was noted.197 The

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review included psychotic patients displaying mania or hyperactivity, and patients with DTs who also exhibited increased somatic activity (tremor, seizures) associated with dehydration. Approximately 50% of patients had temperatures greater than 40°C (104°F), including 9 of 12 patients with seizures; in 11 cases, hyperthermia was attributed solely to the delirium. Thus, regardless of etiology, hyperthermia, increased motor activity, and fluid depletion in the setting of DTs carried a grave prognosis. However, recognition and treatment of complications along with better fluid replacement and supportive care seemed to be the most important determinants of survival. Mortality at Philadelphia General Hospital decreased to 5.4% in the late 1950s (as compared to 18.5% in the early 1950s) using this approach.196 Finally, the benefits of benzodiazepines as the sedativehypnotic of choice were first realized after controlled trial of diazepam and paraldehyde for severe DTs.200 There was no mortality in diazepam-treated patients and sedation was achieved more rapidly. Adverse reactions and mortality, however, were significant with paraldehyde. The suggested diazepam regimen was 10 mg IV followed by 5 mg IV every 5 minutes until calm. A quarter century later, our understanding of neurotransmitters and neurologic function makes a more precise understanding of this disorder possible. Alcohol withdrawal is a neurologic disorder with a continuum of progressively worsening symptoms caused by the effects of chronic ethanol on the central nervous system, and is often exacerbated by the clinical manifestations of alcoholism (nutritional depletion, impaired immunity, anemia, cirrhosis, head trauma).108 The morbidity and mortality from this condition largely arise from inappropriate resuscitative efforts (failure to correct hypovolemia and lower temperature), inappropriate treatments (antipsychotics), and failure to identify concurrent illness (infection, CNS trauma). The 15% mortality observed by Victor and Adams largely occurred in the patients with concurrent illness. Half of all patients with delirium tremens and two-thirds of the patients with fatal delirium tremens had concurrent illness. This mortality was reduced to below 5% within a decade of their work when aggressive fluid resuscitation, cooling, and supportive care became the goal of therapy.196,197 Finally, the development of the benzodiazepine class of sedative-hypnotics has lead to safe control of CNS manifestations without exacerbating concurrent illness or morbidity. Now, we only expect a fatal outcome if the underlying illness overcomes the patient.176

EPIDEMIOLOGY Alcohol is the leading drug of abuse in the world. The National Institute for Alcohol Abuse and Alcoholism reports that roughly 5% of the US population has engaged in recent heavy drinking (5 or more drinks on 5 or more occasions within the past 30 days) and 15% of the population has engaged in recent binge drinking (5 or more drinks on at least 1 occasion within the past 30 days).170 Alcohol-withdrawal patients present to emergency departments for numerous reasons, but acute withdrawal is rarely the chief complaint. Many patients arrive at the hospital seeking care for the illness or circumstance that prevented them from drinking, such as an upper respiratory infection, trauma, or imprisonment.69 Although we often consider alcoholism when we are confronted with patients with chronic diseases of the liver and pancreas, in fact, a greater percentage of patients admitted to the hospital with surgi-

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cal diagnoses are likely to have a history of alcohol misuse and suffer from withdrawal.132 In one Australian study of 2046 admitted patients of all types, 8% were at risk for alcohol withdrawal.61 However, 16% of all postoperative patients and 31% of all trauma patients suffered some actual form of alcohol withdrawal during their admission. Half of all trauma patients are under the acute influence of alcohol at the time of the event. In general, alcoholwithdrawal patients are typically males in their third or fourth decade of life and patients who drink continuously, as opposed to “binge drinkers,” are theoretically at highest risk for withdrawal.149 However, characterizing alcohol withdrawal patients by age, sex, or otherwise will lead to a missed diagnosis more often than not. In fact, the severity of alcohol withdrawal does not diminish or increase with age, although patients over the age of 60 years are more likely to experience cognitive and functional impairments.97 In addition, benzodiazepine requirements in the elderly relate to the severity of the withdrawal and do not diminish, and physicians should dose patients accordingly.

PATHOPHYSIOLOGY OF ALCOHOL AND OTHER GABAMINERGIC WITHDRAWAL SYNDROMES Ethanol, benzodiazepines, and barbiturates enhance GABAminergic tone. This is the mechanism by which they produce sedation. γ-Aminobutyric acid (GABA)A receptors are postsynaptic receptors that, when activated, hyperpolarize the postsynaptic neuron by an inward chloride current without a G protein messenger.101 These receptors have separate binding sites for GABA, barbiturates, benzodiazepines, and picrotoxin. Barbiturates and benzodiazepines bind to their receptor sites and enhance the affinity for GABA at its receptor site.5 Chronic exposure to benzodiazepines appears to decrease GABAA receptor sensitivity.110,195 Only highdose barbiturates can open the GABA chloride channel without concomitant binding of a GABA molecule, and this has been specifically demonstrated with phenobarbital and pentobarbital.64,82 Many drugs (eg, ethanol, etomidate) have GABA-receptor activity without a clearly identified binding site. Ethanol, benzodiazepines, etomidate, and propofol are examples of drugs that merely enhance GABAA chloride channel activity and are classified as indirect GABA agonists. Traditional discussions suggest that acute exposure to ethanol affects membrane fluidity and cross-couples the 5 proteins that construct the GABA receptor, interact with a portion of the receptor, and enhance GABA release.30,99,144,166,167 The result is an enhancement in GABA chloride channel activity, apparently without enhancing GABA binding to its recognition site on the receptor.103 Recent research with chimeric reconstruction of GABA and NMDA channels demonstrates highly specific binding sites for ethanol. Ethanol binding to these sites enhances GABA and inhibits NMDA.129a The adaptation to chronic exposure to ethanol is a modified GABAA receptor function.29,103,104,153,154,158,195 Chronic ethanol exposure first increases, and then ultimately decreases, messenger ribonucleic acid (mRNA) expression of certain GABAA subunit proteins.29,95,103 These subunit proteins (
1,
3,
6, γ2s, γ2l, and γ3) are assembled in multiple combinations to form GABA receptor complexes with slightly different characteristics in different areas of the brain. Ul-

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timately, withdrawal symptoms may represent the clinical manifestation of a change in GABA receptor complex characteristics, and thus cause diminished effectiveness, rather than a simple change in receptor numbers.50 Genetic research using quantitative trait locus mapping and investigations examining GABAA receptor sensitivity suggest that a complex interaction between ethanol, production of GABAA subunits, and receptor modulation will ultimately explain many of the clinical characteristics of ethanol withdrawal.31,93 Although the exact mechanism is not completely known, what is clear is that during withdrawal, GABA synaptic activity is so diminished that inhibitory control of excitatory neurotransmitters and pathways such as glutamate, norepinephrine, and dopamine is lost.60,164 This results in the clinical syndrome of withdrawal: CNS excitation (seizures, tremor, hallucinations) and autonomic stimulation (tachycardia, hypertension, hyperthermia, diaphoresis).71,101 Up-regulation in the excitatory neuronal pathways is also important in ethanol withdrawal, and the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor (especially the MK-801 binding site) appears to be the major contributor.84,206 Enhanced excitatory neurotransmission is a characteristic of ethanol withdrawal that appears to explain the “kindling” hypothesis, in which withdrawal events become progressively more severe.12,17,22,27,210 The activity of an excitatory neuronal pathway increases the more it fires, a phenomenon known as long-term potentiation.70 This may be a result of increased activity of mRNA and receptor protein expression.46 Thus, as NMDA receptors increase in number and function, and GABAA receptor activity diminishes, withdrawal becomes more severe.47,110,126,158 Knowledge of this phenomenon should prompt the clinician toward aggressive treatment of even minor withdrawal symptoms, in the hopes of attenuating the progression to subsequently more severe withdrawal episodes.222

CLINICAL CHARACTERISTICS OF ALCOHOL WITHDRAWAL Alcohol withdrawal is a neurologic disorder with a continuum of progressively worsening symptoms caused by the effects of chronic ethanol on the central nervous system, and is often exacerbated by the clinical manifestations of alcoholism (nutritional depletion, impaired immunity, anemia, cirrhosis, head trauma).108 In keeping with our model of withdrawal physiology, ethanol levels are falling or zero when clinical manifestations of withdrawal begin. For many patients, a brief alcohol withdrawal seizure (AWS) may be the first event. In others, a fine-motor tremor may develop (see Fig. 72–1). AWS, or rum fits, may occur without other signs of withdrawal and are characteristically brief tonicclonic events with a short postictal period. They may recur, but status epilepticus is distinctly unusual in withdrawal (40% single seizures and 3% status epilepticus).211 A rapid recovery and normal mental status belie the seriousness of AWS. For one-third of all patients with alcohol withdrawal characterized by delirium (delirium tremens), the sentinel event is an isolated AWS. This seizure may occur despite the presence of an elevated serum ethanol level. In fact, an AWS that occurs despite an elevated ethanol level is a poor prognostic indicator because the relative protection of an elevated ethanol level will continue to be lost as the level drops.210 They may even have a history of a seizure disorder and be taking anticonvulsant medica-

Figure 72–1. Representation of alcohol withdrawal. As ethanol levels fall, patients may develop alcohol withdrawal seizures (“rum fits”), alcoholic hallucinosis, or alcoholic tremulousness. Following this state, the patient can recover, develop another early manifestation of withdrawal, or progress to delirium tremens.

tions, largely because alcohol withdrawal seizures (AWS) cannot be differentiated from other acquired seizure disorders (eg, posttraumatic). An asymptomatic period after an alcoholic abstinence seizure may last for several hours, or the CNS excitation may progress without recovery. Progressive CNS excitation characterizes the next phase of withdrawal. We suggest that patients with alcohol withdrawal be clinically classified into those with an intact and those with an altered consciousness. The advantage to this simple classification is that it avoids clinical descriptors that are only confusing, such as delirium, DTs, or florid DTs. Tachycardia, fever, and hypertension are identifiable markers for worsening withdrawal. The central nervous system excitation begins as a fine intention tremor that can be detected in the outstretched hands or protruding tongue. This appears to be a variation of physiologic tremor except that patients with alcohol withdrawal have a tremor with a significantly higher amplitude as compared to the tremor normally associated with anxiety or emotional stress. Formication, or the sensation of ants crawling on the skin, often promotes repeated itching and leads to excoriations. Disorders of thought, anxiety, agitation, and lability of mood also manifest to varying degrees. Hallucinations are largely visual and appear to occur especially in patients with inadequate thiamine stores.85 When these CNS manifestations are present with normal vital signs, the patient may be anxious, display a fine tremor, and appear otherwise normal. Because these symptoms will invariably progress, all patients should be treated with sedation. Patients with a history of alcoholism who develop CNS excitation and then manifest abnormal vital signs are experiencing clinical deterioration. Tachycardia, elevated temperature, hypertension, and diaphoresis mark the autonomic manifestations of this worsening withdrawal syndrome. If untreated or undertreated, the central nervous system excitation of these patients progresses to uncontrollable agitation, seizures, involuntary tremor, hyperthermia, rhabdomyolysis, and death.

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MANAGEMENT FOR ALCOHOL AND OTHER GABAERGIC WITHDRAWAL SYNDROMES There are four important principles in the management of the patient in withdrawal. 1. Restore inhibitory tone to the central nervous system by using long-acting benzodiazepines or barbiturates. 2. Identify and correct fluid, electrolyte, and nutritional deficiencies. 3. Evaluate the patient for concurrent illness including infection. 4. Allow the patient to rest peacefully without self-harm, decrease the need for restraints, and decrease the risk of rhabdomyolysis and hyperthermia while undergoing all necessary diagnostic studies. The advantage of a neuropharmacologic approach to withdrawal is that it simplifies the treatment. Patients with alcohol withdrawal are disinhibited. They have amplified excitatory neuronal pathways and impaired inhibitory neuronal pathways that require the continuous presence of ethanol to approximate normal physiology. The goal of therapy is to rapidly restore the inhibitory tone—to reinhibit them. Numerous studies support the “loading” and “symptom-triggered therapy” principles. In the “loading” approach, a benzodiazepine with active metabolites is administered in an escalating bolus fashion until the patient is brought to sedation. In the “symptom triggered” approach a fixed dose of benzodiazepine is repeated after interval reassessment until withdrawal symptoms are controlled.121,168,214 Although the initial doses may be quite high in either approach, withdrawal is ultimately better managed with less total benzodiazepine, shorter duration of treatment, similar efficacy of treatment, and fewer adverse sequelae. This approach is in contradistinction to the fixed interval, fixed-dose technique, which administers benzodiazepine without consideration for the patients symptoms. This gives insufficient quantities of medication when withdrawal is severe and drug and active metabolites accumulates later as the withdrawal symptoms resolve. This causes lingering and excessive sedation. In addition, studies indicate that the hospital can realize a cost savings (50%) by using the loading dose regimen.215 Properly sedated patients also improve staff perceptions of the safety of the environment because of a decrease in patient violence and agitation using the loading technique.83 Even with substantial benzodiazepine doses, respiratory compromise and the need for airway support are unlikely. Concerns about dosing benzodiazepines in patients with liver failure and the elderly are justified, but these patients also benefit from this approach, as the modest prolongation in half-life is not deleterious and patients do not have greater CNS depression but only a potentially more prolonged phase.26,80,144,221 The selection of a benzodiazepine is important to the success of this loading principle. Chlordiazepoxide and lorazepam have been used, but offer no unique benefits over diazepam.92,137,159 In fact, it is precisely because large boluses of diazepam are metabolized to active metabolites (desmethyldiazepam) over the typical period of withdrawal (48–72 hours) that diazepam is the only benzodiazepine needed to treat this disorder.3,223 A retrospective re-

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view reported that the use of a single benzodiazepine rather than multiple benzodiazepines was a marker for treatment success in surgical patients experiencing alcohol withdrawal during surgical admission.134 It is more important to rapidly sedate the patient with adequate doses of a single benzodiazepine, than to use multiple agents in hopes of finding an effective regimen. When a loading dose is administered, and the patient is adequately sedated, minimal additional sedation is required. Diazepam and desmethyldiazepam have long half-lives, thus permitting the primary agent and the metabolite to be endogenously tapered and avoiding drug-induced cyclic variations.2,3,150,176,177 Ultimately, this approach has the added benefit of greatly simplifying management. The typical starting dose for a patient in alcohol withdrawal is 10 mg of diazepam given intravenously repeated every 5–15 minutes until the patient is sedated and the vital signs have improved. Twenty milligrams may be all that is needed for slightly more than one-third of the patients; 25% of all patients in ethanol withdrawal require 200 mg.168 Patients who begin to experience withdrawal with an elevated ethanol level require the initial loading dose therapy and will likely require additional therapy as the ethanol level continues to decrease. An alcoholic can take as long as 6–8 hours to eliminate a serum ethanol level of 150 mg/dL (Chap. 64). A portion of severe withdrawal patients can remain symptomatic despite doses of diazepam that approach 1 g.109,136 In fact, doses can be so high (eg, gram quantities of diazepam) that the excipients such as propylene glycol may approach toxicity, although this has never been reported for a diazepam-loading regimen.18,107,209 One report describes the use of 2335 mg of diazepam intravenously and 21,225 mg of oxazepam orally without control of agitation from alcohol withdrawal. There was no evidence of an abnormal pharmacokinetic profile.220 When this level of benzodiazepine “resistance” is noted, it is more efficacious to add a barbiturate to attain a synergistic effect on the GABAA receptor chloride channel and bypass the ineffectual benzodiazepine receptor.64,89 There are several acceptable approaches to treating benzodiazepine-resistant withdrawal patients: intravenous phenobarbital or pentobarbital. Intravenous phenobarbital, a long-acting barbiturate, can be given as a bolus of 260 mg (phenobarbital is supplied in 130-mg ampules) over 5 minutes. Repeat dosing should be considered in 30 minutes. This is accomplished by giving a bolus of 130 mg of phenobarbital over 3 minutes. Studies and clinical experience with this drug show that most patients will require 8.5 mg/kg to achieve the endpoint of light sedation. Side effects of this drug regimen include hypotension (6%) that is easily reversed with fluid administration and respiratory depression that frequently requires ventilatory support. Phenobarbital levels are unnecessary, as the patient is loaded to a clinical effect and only treated as symptoms occur.122,124 Intravenous pentobarbital, a short-acting barbiturate, given as a 3–5-mg/kg bolus and 100-mg/h infusion should be an effective starting point and is a more aggressive and reliably effective technique for managing severe withdrawal. Symptoms dictate subsequent management and infusion rates. The initial pentobarbital bolus should be used as the induction agent for rapid sequence intubation and mechanical ventilation. Ultimately, very-high-dose anesthetic-type doses of barbiturates never fail to treat withdrawal because they directly open the GABAA chloride channel.55,71 However, such therapy for prolonged periods (24 hrs) alters the

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apparent pharmacokinetics of pentobarbited in such a way that it has a long duration of effect. Propofol is an alternative agent for patients who do not respond to benzodiazepines. It has the advantage of easy titratability as well as a rapid offset of effect when the infusion is terminated. This latter effect uniquely allows periodic assessment of the patients’ mental status. However, respiratory depression remains consequential and most patients require mechanical ventilation.125 Although the mechanism of action is not completely understood, it appears to be both an GABA agonist and an NMDA receptor antagonist.

Seizures Alcohol withdrawal seizures are brief, and recurrent, and rarely progress to status epilepticus. If seizure focality is evident, other CNS pathology is invariably present.175 AWS are often first recognized in patients who are in their third and fourth decades. All other seizures should be considered to have a cause other than alcoholism itself.211 All patients with first-time AWS should receive a thorough evaluation, including computed tomography (CT) scan of the brain, an electroencephalogram (EEG), and consideration for lumbar puncture. These studies have a high yield for identifying useful etiologic information such as evidence of CNS trauma and cortical atrophy, although intervention is uncommon.53,98,105 Cortical atrophy is a common finding on a CT scan of the head in alcoholic patients, but temporal lobe volume deficits may correlate with AWS either as a cause or sequela.193 It is unclear whether these AWS invariably progress to a permanent seizure disorder with chronic neurologic dysfunction or are merely a marker for the problems associated with severe alcoholism, such as recurrent head trauma, infections, and hypoxia, which cause CNS injury.14 Phenytoin does not protect against AWS seizures and is, in fact, no better than placebo.8,36,155 Alcoholics may be on phenytoin for primary epilepsy or a seizure disorder acquired from the manifestations of their disease (CNS infections, trauma, cortical atrophy).

Other Therapies The use of antihypertensive agents, phenothiazines, antipsychotics, and sedative hypnotics other than benzodiazepines and barbiturates is without foundation. A number of studies that use vital signs as surrogate markers for severity of withdrawal support the use of clonidine and -adrenergic antagonists.16,86 However, these patients often experience more of the CNS manifestations of withdrawal, such as anxiety, agitation, and delirium.3,213 The use of these drugs has largely arisen because of a lack of understanding of the pathophysiology of withdrawal. Although these drugs obviously will block the peripheral manifestations of alcohol withdrawal, they fail to treat the primary neurologic derangement responsible for these symptoms. For example, although the use of antipyretic agents are an important adjunct in treating patients with bacterial infection and fever, one would never consider reducing the dose of antibiotics if the fever resolved with acetaminophen. Vital sign abnormalities are the peripheral manifestations or markers for the severity of the neurologic derangement, and should be aggressively treated with drugs (benzodiazepines and barbiturates) that primarily affect the CNS. In addition, other therapies may actually exacerbate toxicity. Alcohol withdrawal treated with neuroleptics has a mortality rate of 6%.11 These drugs lower the seizure threshold, impair heat regulation, and fail to correct the neurologic origin of this disorder.9,14,20,75,76,207 Their use is only justified to treat underlying medical problems other than

withdrawal. Patients with CNS excitation with normal vital signs are candidates for oral benzodiazepines therapy, and can often be managed by an alcohol detoxification service.19,79 Alcohol withdrawal should not be fatal if the patient receives proper supportive care. Sedation (to produce calm, restful sleep), substrate repletion (dextrose, thiamine, folic acid), fluid and electrolyte balance, oxygen, and control of hyperthermia and agitation improve survival, although patients still die from complications such as trauma, CNS hemorrhage, pancreatitis, infection, liver disease, and electrolyte- or alcoholic cardiomyopathy-related dysrhythmias.108,117 Aggressive evaluation for concurrent CNS infection and avoiding the pitfall of attributing fever solely to withdrawal symptoms prevents this morbidity. In general, the more severe the alcohol withdrawal, the more likely a concurrent illness.58 The effects of rapid cooling and hydration in combination with sedation have virtually eliminated mortality.199 A similar approach to all agitated patients significantly reduces mortality and morbidity related to hyperthermia, rhabdomyolysis, and dehydration.48,102 Hyperthermia in the agitated patient carries a particularly high risk. Unlike fevers of infectious etiologies, temperatures may exceed 106°F (41.1°C), with resultant tissue damage. Rapid cooling, titration of sedation with a benzodiazepine, and adequate hydration are essential early steps in the management of the agitated patient, regardless of the etiology. A thorough evaluation of the alcohol withdrawal patient also includes fingerstick glucose, CBC, serum electrolytes, calcium and magnesium, chest radiograph, and urinalysis. The yield on these clinical investigations is extraordinarily high, and often reveals complications or phenomena associated with alcoholism that require treatment (occult infection, remote and/or recent head trauma, anemia, electrolyte abnormalities, and so forth).59 Hypoglycemia is an important problem in alcohol withdrawal because of increased CNS glucose requirements and altered counterregulatory responses.54 Thus, all patients with withdrawal require supplemental glucose and thiamine to assist in its transport and metabolism (Chap. 64).216 Chest radiography often reveals evidence of chronic pulmonary infections, aspiration pneumonia, and cardiomyopathy. Magnesium supplementation continues to be a source of controversy in alcohol withdrawal. Though many reports suggest a beneficial effect and animal models point to a role in NMDA antagonism, prospective trials fail to find a benefit. Because deficiencies of this electrolyte can mimic ethanol withdrawal and alcoholics are often magnesium depleted, measuring magnesium levels and repleting a patient with a magnesium deficiency is important. There appears to be no defined role for its empiric use in this setting.21,62,68,217

CLINICAL CHARACTERISTICS AND TREATMENT OF BENZODIAZEPINE AND BARBITURATE WITHDRAWAL The similarity between alcohol and barbiturate withdrawal was identified by Victor and Adams who noted the work of Isbell on chronic barbiturate intoxication and withdrawal.87 Patients who are dependent on benzodiazepines, barbiturates, and other sedative-hypnotic drugs display withdrawal symptoms that are similar to alcohol withdrawal symptoms except that they may develop as late as 14 days after cessation of drug administration, depending

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on the pharmacokinetic profile of the abused drug. Diazepam, chlorazepate, and chlordiazepoxide are converted to active metabolites with half-lives of up to 200 hours. Phenobarbital’s half-life is as long as 2–6 days. These patients may have symptoms such as anxiety or insomnia for many days before objective manifestations of withdrawal develop. Alprazolam is a short-acting benzodiazepine without active metabolites and can cause withdrawal symptoms within 24 hours of cessation of use. Benzodiazepine withdrawal has most of the same characteristics as severe ethanol withdrawal, except the expected time course for resolution of withdrawal symptoms can last for 10 days. Patients develop the disinhibitory syndrome characterized by progressively worsening agitation, tachycardia, hypertension, fever, hyperthermia, and seizures. No controlled studies have been done addressing the comparative efficacy of various treatment regimens. However, by considering this entity as another form of GABAminergic withdrawal, diazepam and barbiturates become the logical treatment regimen choices. Some authors believe that phenobarbital is a useful first choice for patients with benzodiazepine withdrawal who still have normal vital signs, because patients perceive that the addicting drug has been eliminated. In addition, its long half-life allows an appropriate taper of drug levels without complicating management.161 One approach is to start the patient on a phenobarbital dose that is considered a sedative-hypnotic equivalent (each 10 mg of diazepam is equated with 30 mg phenobarbital), and then each day the patient is administered 10% less of the total dose. For benzodiazepine withdrawal with abnormal vital signs or seizures, diazepam loading in a fashion similar to ethanol withdrawal is an appropriate first choice. Phenobarbital loading can be used in this situation as well.122 Flumazenil is a short-acting benzodiazepine receptor antagonist that is capable of rapidly inducing a withdrawal syndrome in patients who are habituated to benzodiazepines, but not to alcohol (see Antidote in Depth: Flumazenil).35 It is for this reason that flumazenil’s use is discouraged in the overdose setting.75,215,218 Flumazenil may have a role in reversing intoxications in pediatric patients, because the likelihood of chronic use is low. Flumazenil can produce seizures without the onset of consciousness, a particularly dangerous combination. The clinician should expect these seizures to require higher than normal doses of benzodiazepines because of the benzodiazepine receptor antagonism. This need for increased benzodiazepines can last from 1–2 hours, depending on the dose of flumazenil used. In refractory cases, intravenous pentobarbital intubation and mechanical ventilation may become necessary.

GABAB receptors mediate presynaptic inhibition (by preventing Ca2+ influx) and postsynaptic inhibition (by increasing K+ efflux). The postsynaptic receptors appear to have a similar inhibitory effect as the GABAA receptors. The presynaptic receptors provide feedback inhibition of GABA release. Unlike GABAA receptors, these are mediated through G protein messengers. Baclofen is the only clinically important GABAB agonist. The pre- and postsynaptic inhibitory properties of baclofen allow it, paradoxically, to cause seizures in both acute overdose and withdrawal. When the drug is withdrawn, a disinhibition similar to GABAA withdrawal occurs. This effect is probably a result of the reduction of the chronic inhibitory effect of baclofen on postsynaptic GABAB receptors. Although it is more typically sedating in overdose, baclofen also stimulates presynaptic GABAB autoreceptors to decrease release of GABAA. The subsequent disinhibition leads to seizures, hypertension, and coma. Interestingly, many case reports of baclofen withdrawal describe hallucinations and psychosis as prominent symptoms. However, these may be no different than the withdrawal symptoms of GABAA agonists. That many patients experience double vision is difficult to explain.160,182 The development of this withdrawal syndrome typically occurs 24–48 hours after discontinuation of baclofen during an admission to the hospital for an unrelated medical problem. Case reports highlight the development of seizures, hallucinations, psychosis, dyskinesia, and visual disturbances. Intrathecal baclofen pumps have become an effective replacement for oral dosing, but withdrawal can occur following the use of this modality as well. Remember to consider withdrawal when patients are recovering from acute-on-chronic baclofen overdoses. Reinstatement of the prior baclofen-dosing schedule appears to resolve these symptoms within 24–48 hours. Benzodiazepines and GABAA agonists, not phenytoin, are the appropriate treatment for seizures induced by baclofen withdrawal.143

INHALANT WITHDRAWAL

γ-HYDROXYBUTYRATE

Another poorly recognized but widespread source of drug abuse is inhalants. Solvents such as gasoline, ether, and toluene have wellestablished abuse potential, especially in adolescents. These chemicals are capable of producing deep anesthesia. Recent work has determined that anesthetics of this sort are active at the GABAA receptor and produce CNS inhibition. Elaboration of the mechanism specific for solvent of abuse awaits further study, although it is logical to assume they act in a similar fashion.13 Impoverished areas of the world suffer from higher rates of inhalant abuse and a case series from India highlights the sad facts

γ-Hydroxybutyrate (GHB) is a compound found in mammalian brain, that has been investigated as an anesthetic and for treatment of narcolepsy, alcohol dependence, and opioid dependence. Along with its precursors, butanediol and γ-butyrolactone, they are abused for their euphoric, sedative, and purported anabolic effects. The mechanism of action of GHB is not fully known, but appears to have its effect, at least in part, on the GABA receptors. A withdrawal syndrome that resolves in 3–12 days has been reported that appears consistent with this mechanism—insomnia, anxiety, and tremor.67 Occasionally, symptoms can be severe and require high

of this epidemic. These investigators describe 9 children with a mean age of 13.6 years, of low socioeconomic status, whose fathers abused alcohol. All subjects report a daily history of abuse of gasoline and a syndrome of irritability, psychomotor retardation, anhedonia, dry mouth, sleep disturbances, craving, and increase lacrimation with withdrawal of inhalant use. Further research is necessary to determine whether this is a true withdrawal syndrome or some other effect of inhalant abuse.179

GABAB WITHDRAWAL Baclofen

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doses of benzodiazepines.42 Experience suggests that body builders commonly use GHB or its analogs several times daily, and hence are more likely to experience withdrawal than those who use them in a binge style for their euphoric effects.

Case 2. A 45-year-old male was brought to the ED by police officers. The patient was agitated, vomiting, diaphoretic, and complained that he was withdrawing from his methadone. He was incarcerated 24 hours earlier and had not received his methadone for 72 hours. His vital signs were blood pressure, 165/90 mm Hg; respiratory rate, 22 breath/min; pulse, 110 beats/min without orthostatic changes; and rectal temperature, 99.9°F (37.2°C). The man was well developed, well nourished, and appeared older than his stated age. He had mydriasis, profuse diaphoresis, hyperactive bowel sounds, piloerection, and diarrhea. He was given 10 mg of diazepam intravenously. Thirty minutes later he was noted to be sleeping, but was agitated when awakened. The remainder of his symptoms persisted. Methadone 10 mg was administered IM, and his vomiting, diarrhea, piloerection, and hyperactive bowel sound resolved.

PATHOPHYSIOLOGY OF OPIOID WITHDRAWAL Opioids inhibit neurons and alleviate pain when they bind to an opioid receptor, activate Gs proteins, and stimulate K+ efflux currents. The opioid receptors are also linked to the Gi/o proteins. These act through adenyl cyclase and activate inward Na+ current, thus enhancing the intrinsic excitability of a neuron (see Figure 72–2).41 Chronic exposure to opiates (only drugs directly derived from opium) and opioids (all drugs with opioid-receptor efficacy) results in a decreased efficacy of this receptor to open potassium

channels by altering postreceptor, intracellular pathways. When chronic opioid use is present, the expression of adenyl cyclase increases through activation of the transcription factor cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). This results in an up-regulation of cAMP mediated responses such as the inward Na+ channels responsible for intrinsic excitability. The net effect is that only higher levels of opioids result in analgesia and opioid effect. In the dependent patient, when opioid levels drop and this inward Na+ flux is unchecked, the patient experiences withdrawal symptoms. These withdrawal symptoms are largely because of uninhibited activity at the locus ceruleus.38,119,128,133 Furthermore, opioid receptors and central
2 receptors both exert a similar effect on the potassium channel in the locus ceruleus. Clonidine binds to the central
2 receptor and stimulates potassium efflux as opioids do, and will create a partial sedative effect. This explains why clonidine has some efficacy in treating for opioid withdrawal. In addition, naloxone’s antagonistic effect at the opioid receptor seems to reverse the effect clonidine has on this shared potassium efflux channel (Fig. 72–2).72

CLINICAL CHARACTERISTICS Symptoms progress from drug craving, yawning, rhinorrhea, and piloerection to nausea, vomiting, diarrhea, diaphoresis, myalgias, arthralgias, anxiety, fear, and mild tachycardia. Chronicity relates to pharmacology of the opioid of abuse. Methadone withdrawal starts about 24 hours after the last dose and persists for 3–7 days. Heroin withdrawal begins approximately 6 hours after the last dose and is usually fully manifest at 24 hours. Withdrawal is physically and emotionally painful, but not life-threatening as long as adequate hydration and nutritional support are maintained and morbidity from emesis and dehydration can be minimized.

Figure 72–2. Immediate and long-term effects of opioids. The acute effects of both opioids and α2-adrenergic agonists are to increase inhibition through enhanced potassium efflux and inhibited sodium influx. Chronic effects alter gene expression to enhance sodium influx and restore hemeostasis. CREB (cAMP response element-binding protein).

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TABLE 72–1.

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Clinical Differentiation of Drug Withdrawal

Vital Signs Blood pressure Pulse Respiratory rate Temperature

Opioids

Sedative-Hypnotics/Ethanol

Hypertension, normal or orthostatic hypotension when volume depleted Tachycardia Tachypnea Normal

Normal, hypertension, then orthostatic hypotension when volume depleted Tachycardia Tachypnea Hyperthermia

Normal Anxiety Irritability

Abnormal Restlessness Irritability Psychosis, visual hallucinations more common than auditory Disorientation

Yawning Lacrimation Rhinorrhea Mydriasis Tremor Piloerection Restlessness Emesis, nausea Diarrhea with increased bowel sounds Seizures in neonates (only) Muscle pain and spasm

Tremulousness Muscle fasciculations Diaphoresis Seizures

Mental Status

Physical Signs and Symptoms

Table 72–1 compares opioid withdrawal with sedative-hypnotic or ethanol withdrawal.

drawal rarely may require administration of an opioid. This is generally only needed after inadvertent administration of a longacting opioid antagonist such as naltrexone.

TREATMENT Treatment with methadone (10 mg IM or 20 mg po) is enough to blunt withdrawal symptoms without providing euphoria, although it may not eliminate drug craving. Maintenance programs often use higher daily doses to achieve this latter effect. Very high doses (greater than 100 mg of methadone per day) are used to flood opioid receptors so that intercurrent heroin abuse will not result in euphoria, thereby deterring drug-seeking behavior.33,190,191 Clonidine is an effective adjuvant in opioid withdrawal.5,63,72 Doses start at 5–6 µg/kg/d and can get as high as 25 µg/kg/d. Clonidine is most useful in conjunction with methadone maintenance and a structured detoxification program. Clonidine can be considered as a therapeutic alternative in situations where hospital policy does not permit methadone administration. Clonidine, however, does not blunt craving for opioids. Opioid withdrawal can be induced by the use of opioid receptor antagonists or mixed agonist-antagonists in opioid habituated patients. Often, this is the result of administering large doses of naloxone to opioid addicted patients who present with an opioid overdose. In patients suspected of chronic opioid use, use a low initial starting dose (0.05–0.2 mg of naloxone) and assist respiration as needed until a therapeutic effect is observed—usually within a few minutes. Readministration of the dose is based on clinical grounds. If withdrawal is induced, expect symptoms to resolve within 1 hour as the naloxone is eliminated and there is a reemergence of the primary opioid’s effects. More severe with-

RAPID HEROIN DETOXIFICATION AND WITHDRAWAL Naltrexone blocks the euphoric effects of opioid use and discourages recidivism by blunting drug craving.73,96,114,115 Although the mechanism is not entirely clear, the speculation is that mere receptor occupancy by an antagonist is sufficient to blunt cravings. In theory, inducing opioid withdrawal under general anesthesia with high-dose opioid antagonists permits the transition from drug dependency to naltrexone maintenance without drug withdrawal symptoms.111,112,113,157 However, studies demonstrate that withdrawal symptoms may be more intense and persist for up to 1 week after rapid detoxification.174,184 Nonetheless, many patients are encouraged by the promise of a rapid transition to naltrexone maintenance from opioid dependence (Rapid Opioid Detoxification – ROD; Rapid Opioid Detoxification under Anesthesia – RODA; or Ultrarapid Opioid Detoxification – UROD). Many centers report success with this process, and tout it as a safe, comfortable, same day, outpatient treatment for heroin addiction.6,25,74 All studies suggest that the detoxification procedure is physiologically successful when opioid abstinence is measured by the response to antagonist challenge. However, recidivism ranges from 10% to 50% and outpatient psychosocial support is generally lacking.116,171,189 In addition, these patients are sent home with potent medications, such as clonidine, baclofen, octreotide, ondansetron,

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benzodiazepines, and trazodone, to counter the continued withdrawal symptoms. Instead of transitioning to oral naltrexone, an alternative approach is to compound the naltrexone into a pellet and implant it in the subcutaneous tissues.74 This is not an FDA-approved route for the oral drug and there is no parenteral form available. However, emergency physicians and toxicologists may encounter patients who are in naltrexone-induced opioid withdrawal. The literature contains a number of reports of ROD and UROD complications—death, prolonged respiratory depression, and an abstract of a case series of patients who experienced persistent withdrawal symptoms.52,66,146,194 In addition, the use of naloxone may be associated with pulmonary edema, perhaps a result of the excessive release of catecholamines during unrecognized hypercarbia from hypoventilation.10,37 To date, there is only 1 case report of complication of UROD with naltrexone pellet implant; in that case, the patient developed severe rhabdomyolysis.188

CLONIDINE WITHDRAWAL (
2-ADRENERGIC RECEPTORS)
2-Adrenergic receptors are located in the central and peripheral nervous system. Clonidine is a central and peripheral
2 agonist. Stimulation of peripheral postsynaptic
2-adrenergic receptors results in vasoconstriction, bradycardia, and hypertension, and prevents acetylcholine release. This results in some anticholinergic symptoms, especially dry mouth. The peripheral effects manifest only in the initial period after a toxic dose. Stimulation of central presynaptic
2-adrenergic receptors inhibits sympathomimetic output and results in bradycardia, and hypotension.57 Within 24 hours after the discontinuation of clonidine, norepinephrine levels rise as a result of enhanced efferent sympathetic activity.165 Patients who use the clonidine patch may experience withdrawal later than 24 hours, if at all, because a reservoir of the drug in the skin generally allows levels to persist for days. Clonidine elimination half-life is 14 hours, and most patients who manifest withdrawal still have a low level of clonidine in the initial phase. Simultaneous use of -adrenergic antagonists exacerbates withdrawal, as
-adrenergic receptor stimulation is unopposed by -adrenergic antagonism. The first symptoms occur 24 hours after discontinuation of clonidine and include headache, flushing, sweating, hallucinations, and anxiety.26 Hypertensive encephalopathy and death have been reported in rare cases. Within 48 hours the patient’s blood pressure rises to near or above pretreatment levels. There appears to be an association with high-dose therapy (greater than 1.2 mg/d) or concomitant -adrenergic antagonism therapy and an increased likelihood and severity of withdrawal.28,156 Treatment requires reinstatement of the drug by the oral route. Patients unable to swallow may be treated with sublingual clonidine. -Adrenergic antagonists are absolutely contraindicated.

CAFFEINE (ADENOSINE1 RECEPTORS) The release of neurotransmitters is accompanied by passive release of adenosine as a by-product of adenosine triphosphate (ATP) breakdown. This adenosine acts on the presynaptic adenosine1 autoreceptors to decrease further release of neurotransmitters, and on the postsynaptic adenosine1 receptors to terminate

neuronal transmission. Adenosine2 receptors are found on the cerebral vasculature and peripheral vasculature and promote vasodilation44 (Chap. 10). Caffeine antagonizes the inhibitory effect of adenosine (Chap. 39). As a result, acute exposure results in increases in heart rate, ventilation, gastrointestinal motility, gastric acid secretion, and motor activity. Chronic exposure results in tolerance to the effects of large acute administration of the drug. This effect appears to be associated with caffeine’s occupancy of adenosine1 receptors. Chronic caffeine exposure regulates adenosine1 receptors by a variety of theoretical mechanisms, such as increases in receptor number, increases in receptor affinity, or enhancing receptor coupling to the G protein. An animal study demonstrates that the adenosine receptor has a 3-fold increase in affinity for adenosine at the height of withdrawal symptoms. This model suggests that chronic caffeine administration results in increase in receptor affinity for adenosine, thus restoring a state of physiologic balance (normal motor inhibitory tone). When caffeine is withdrawn, the enhanced receptor affinity results in a strong adenosine effect and clinical symptoms of withdrawal: headache (cerebral vasodilation), fatigue, and hypersomnia (motor inhibition).183,190 Symptoms of anxiety, depression, headaches, sleepiness, and decreased alertness and activity peak at 24–48 hours and decrease over 1 week. Most patients correctly identify the source of their symptoms and medicate with the appropriate dose and preferred form of caffeine. Caffeine dependence and withdrawal have been demonstrated in patients who take as little as 129 mg/d of caffeine—the equivalent of an average 5 oz cup of coffee. Clinicians should consider this entity in the patient who is being evaluated for headache symptoms. Although 10% of caffeine users experience withdrawal symptoms, recent work suggests that 1% of men and 5% of women experience symptoms significant enough to interfere with daily acitivities.49

NICOTINE WITHDRAWAL Nicotinic receptors are a type of acetylcholine receptors located in the autonomic ganglia, adrenal medulla, CNS, spinal cord, neuromuscular junction, and carotid and aortic bodies. Nicotinic receptors are fast-response cation channels that are not coupled to G proteins. This distinguishes them from muscarinic receptors, which are coupled to G proteins. They have both excitatory and inhibitory effects. Much remains unknown about these receptors and how they affect addiction and withdrawal (Chap. 73).138,199 Smoking cessation is the primary cause for nicotine withdrawal, although discontinuation of any tobacco product can lead to this syndrome. Cigarette craving is an important problem for hospitalized patients who are not permitted to smoke. Nicotine withdrawal manifests largely as cigarette craving and subjective dysphoric symptoms. There are some symptoms of irritability, restlessness, and a decrease in heart rate and blood pressure. Cardiac symptoms resolve over 3–4 weeks, but cigarette craving may persist for months to years. The nicotine transdermal system (patch) and nicotine polacrilex (gum) can be used to provide nicotine without the carcinogens in tobacco, and are now available over-the-counter. The patches utilize a stepwise reduction in subcutaneous delivery to gradually decrease the nicotine dose and appear to have greater compliance than the gum. Acute relief from withdrawal symptoms is most easily achieved with use of the gum, as rapid chewing re-

CHAPTER 72

leases an immediate dose of nicotine. However, the dose is approximately half of that which the average smoker receives in 1 cigarette, and the onset of action is 30 minutes instead of 10 minutes or less. These pharmacologic changes in delivery minimize the reinforcement and self-reward effects that are so prominent with the rapid nicotine delivery of cigarette smoking. Bupropion has demonstrated efficacy for smoking cessation when administered at 300 mg/d and has a limited impact on anxiety and restlessness, but it does improve mood and concentration. Side effects include seizures at both therapeutic and toxic doses.180

SELECTIVE SEROTONIN REUPTAKE INHIBITOR WITHDRAWAL Evidence has been building to support an SSRI withdrawal uptake inhibitor syndrome (Chap. 58). This syndrome complies with our definition of withdrawal syndromes in that symptoms begin when drug levels drop and reinstatement of the drug abates the syndrome. Most case reports point to venlafaxine as the most common drug involved in this syndrome. Headache, nausea, fatigue, dizziness, and dysphoria are commonly described symptoms. The condition appears to be uncomfortable but not life-threatening, and rapidly resolves with reinstatement of drug of the class and resolves when drug is discontinued after a more gradual taper.4,43,98,118,142,225

NEONATAL WITHDRAWAL SYNDROMES Alcohol and GABAA Agonists Maternal addiction to alcohol can result in a neonatal withdrawal syndrome that begins within 3 days after birth. It is characterized by varying degrees of tremor, nystagmus, clonus, opisthotonos, hypertonia, seizures, sleeplessness, crying, asymmetric or hyperactive reflexes, abnormal Moro reflex, excessive mouthing or rooting, diarrhea, vomiting, inability to feed, startle, sweating, and inability to thermoregulate. This syndrome is not directly correlated with the fetal alcohol syndrome. The syndromes are related to the use of alcohol at different times during pregnancy. Children of mothers addicted to benzodiazepines and barbiturates display the same symptoms.39 Neonatal alcohol withdrawal should be treated the same as adult alcohol withdrawal. The drug with the most clinical use for this condition in pediatrics is phenobarbital. The loading dose is 16 mg/kg over 24 hours to produce a 24-hour serum level of 20–30 mg/mL. This can be maintained with a dose of 2–8 mg/kg per 24 hours. Once withdrawal symptoms are controlled for 72 hours, the phenobarbital dose should be tapered at 10% per day. Elixirs of phenobarbital contain 14–25% ethyl alcohol; parenteral forms contain 67.8% propylene glycol, 10% ethyl alcohol, and 1.5% benzyl alcohol. Both of these preparations have potential risk to the neonate and should be considered possible explanations for metabolic abnormalities (Chaps. 56 and 105).45,160

Opioids The neonatal opioid withdrawal syndrome shares characteristics of the adult opioid withdrawal syndrome: gastrointestinal distress

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(vomiting and diarrhea), irritability, yawning, sneezing, hypertonicity, hyperacusis, diaphoresis, lacrimation, and tremulousness. It typically occurs within 2 weeks of birth. In neonates, mottling, fever, myoclonic jerks, and seizures occur in addition to the usual adult opioid withdrawal symptoms. This latter symptom is only characteristic of opioid withdrawal in neonates and occurs in roughly 8% of children born to mothers on methadone maintenance and only 1% of those born to mothers who use heroin.81,120 Paregoric appears to be more effective than diazepam in controlling and preventing these seizures while preserving the suck reflex. Paregoric is a combination of anhydrous morphine (0.4 mg/mL), camphor, alcohol 46%, and benzoic acid (4 mg/mL). Some clinicians prefer a 1:25 dilution of opium tincture because it contains only 0.7% alcohol and no camphor or benzoic acid. Dosage for either drug is 0.2 mL every 3 hours, increased by 0.05 mL at each dose until withdrawal symptoms are controlled, up to a maximum of 0.7 mL per dose. After the patient is stable, therapy is continued for 3–5 days and decreased gradually over a 2–4week period. Withdrawal from maternal methadone can also be treated with tincture of opium, but special attention should be given to dose and interval, using small doses at short intervals to achieve rapid control of symptoms. Parenteral morphine should be reserved for short-term therapy of only severe withdrawal symptoms because it contains sodium bisulfite and phenol, which may cause anaphylactic reactions and hyperbilirubinemia, respectively, when administered chronically. Methadone has been used for neonatal withdrawal, but its use is discouraged because the long half-life (26 hours) makes dosing adjustments difficult.9,91

Caffeine An infant with irritability, jitteriness, and vomiting may be suffering from caffeine withdrawal. One study detected caffeine in the serum of 6 of 8 infants with these symptoms. All mothers gave a history of heavy caffeine use and none were dependent on other drugs or alcohol. The children’s symptoms persisted for several days and then resolved spontaneously.127,128

ACKNOWLEDGMENTS Kathleen A. Delaney, MD, and Neal E. Flomenbaum, MD, contributed to this chapter in a previous edition.

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179. Seoane A, Carrasco G, Cabre L, et al: Efficacy and safety of two new methods of rapid intravenous detoxification in heroin addicts previously treated without success. Br J Psychiatry 1997;171: 340–345. 180. Shar R, Vankar GK, Upadhaya HP: Phenomenology of gasoline intoxication and withdrawal symptoms among adolescents in India: A case series. Am J Addict 1999;8:254–257. 181. Shiffman S, Johnston JA, Khayrallah M, et al: The effect of bupropion on nicotine craving and withdrawal. Psychopharmacology 2000;148:33–40 182. Siegfried RN, Jacobson L, Chobal C: Development of an acute withdrawal syndrome following the cessation of intrathecal baclofen therapy in a patient with spasticity. Anesthesiology 1992;77: 1048–1050. 183. Silverman K, Evans SM, Strain EC, et al: Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 1992;327:1109–1114. 184. Spangel R, Kirschke C, Tretter F, Holsboer F: Forced opiate withdrawal under anesthesia augments and prolongs the occurrence of withdrawal signs in rats. Drug Alcohol Depend 1998;52:251–256. 185. Spies CD, Nordmann A, Brummer G, et al: Intensive care unit stay is prolonged in chronic alcoholic men following tumor resection of the upper digestive tract. Acta Anaesthesiol Scand 1996;40:649–656. 186. Sporer KA, Lesser SH: Cocaine washed-out syndrome [letter]. Ann Emerg Med 1992;21:112. 187. Squires RF, ed: GABA and Benzodiazepine Receptors, Vol 1. Boca Raton, FL, CRC Press, 1991, pp. 2–10. 188. Stephenson J. Experts debate merits of 1-day opiate detoxification under anesthesia. JAMA 1997;277:363–364. 189. Stolerman IP, Shoaib M: The neurobiology of tobacco addiction. Trends Pharmacol Sci 1991;12:467–473. 190. Strain EC, Mumford GK, Silverman K, et al: Caffeine dependence syndrome. JAMA 1994;272:1043–1048. 191. Strain EC, Stitzer ML, Liebson IA, Bigelow GE: Dose-response effects of methadone in the treatment of opioid dependence. Ann Intern Med 1993;119:23–27. 192. Strain EC, Stitzer ML, Liebson IA, Bigelow GE: Methadone dose and treatment outcome. Drug Alcohol Depend 1993;33:105–117. 193. Sullivan EV, Marsh L, Mathalon DH, et al: Relationship between alcohol withdrawal seizures and temporal lobe white matter volume deficits. Alcohol Clin Exp Res 1996;20:348–354. 194. Taft RH: Pulmonary edema following naloxone administration in a patient without heart disease. Anesthesiology 1983;59:576–577. 195. Tamborska E, Marangos PJ: Brain benzodiazepine binding sites in ethanol dependent and withdrawal states. Life Sci 1986;38:465–472. 196. Tavel ME: A new look at an old syndrome: Delirium tremens. Arch Intern Med 1962;109:129–134. 197. Tavel ME, Davidson W, Batterton TD: A critical analysis of mortality associated with delirium tremens: Review of 39 fatalities in a 9year period. Am J Med Sci 1961;242:58–69. 198. Thomas DW, Freedman DX: Treatment of alcohol withdrawal syndrome: Comparison of promazine and paraldehyde. JAMA 1964; 188:316–318. 199. Thompson WL: Management of alcohol withdrawal syndromes. Arch Intern Med 1978;138:278–283. 200. Thompson WL, Johnson AD, Maddrey WL, et al: Diazepam and paraldehyde for treatment of severe delirium tremens: A controlled trial. Ann Intern Med 1975;82:175–180. 201. Torrens M, Castillo C, San L, del Moral E, Gonzalez, ML, de la Torre R. Plasma methadone concentrations as an indicator of opioid withdrawal symptoms and heroin use in a methadone maintenance program. Drug Alcohol Depend 1998;52:193–200. 202. Trabulsy ME: Cocaine washed out syndrome in a patient with acute myocardial infarction. Am J Emerg Med 1995;13:538–539. 203. Treiman DM: The role of benzodiazepines in the management of status epilepticus. Neurology 1990;40(Suppl 2):32–42. 204. Tunniclif G, Raess BU: GABA Mechanism in Epilepsy. New York, Wiley, 1992, pp. 54–55.

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216. Weinbroum A, Rudick V, Sorkine P, et al: Use of flumazenil in the treatment of drug overdose: A double-blind and open clinical study in 110 patients. Crit Care Med 1996;24:199–206. 217. Williams HE: Alcoholic hypoglycemia and ketoacidosis. Med Clin North Am 1984;68:33–45. 218. Wilson A, Vulcano B: A double blind, placebo-controlled trial of magnesium sulfate in the ethanol withdrawal syndrome. Alcohol Clin Exp Res 1984;8:542–545. 219. Winkler E, Almog S, Kriger D, et al: Use of flumazenil in the diagnosis and treatment of patients with coma of unknown etiology. Crit Care Med 1993;21:538–542. 220. Wojnar M, Wasileski D, Matusmoto H, Cedro A. Differences in the course of alcohol withdrawal in women and men: A Polish sample. Alcohol Clin Exp Res 1997;21:1351–1355. 221. Woo E, Greenblatt DJ: Massive benzodiazepine requirements during acute alcohol withdrawal. Am J Psychiatry 1979;36:821–823. 222. Worner TM: Relative kindling effect of readmissions in alcoholics. Alcohol Alcohol 1996;31:375–380. 223. Wretlind M, Pilbrant A, Sundwall A, Vessman J: Disposition of three benzodiazepines after single oral administration in man. Acta Pharmacol Toxicol (Copenh) 1977;40:28–39. 224. Young GP, Rores C, Murohy C, Dailey RH: Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med 1987; 16:847–850. 225. Zajecka J, Tracy KA, Mitchell S: Discontinuation symptoms after treatment with serotonin reuptake inhibitors: A literature review. J Clin Psychiatry 1997;58:291–297. 226. Zanis DA, Woody GE: One-year mortality rates following methadone treatment discharge. Drug Alcohol Depend 1998;52: 257–260.

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73

NICOTINE AND TOBACCO PREPARATIONS Morton E. Salomon

Nicotine MW Toxic blood level Toxic dose

At 8:15 AM an 11-month-old boy was found eating cigarette butts out of an ashtray. The parents cleaned his lips and mouth with cold water. Twenty minutes later the child vomited three times. The parents contacted their regional poison center, which advised them to bring the child immediately to an emergency department (ED). En route, via ambulance, the child vomited again. On presentation to the ED at 9:00 AM, the child was noted to be tremulous and diaphoretic with excessive salivation. He had a glassy-eyed look and did not interact with his parents. His vital signs were: blood pressure, 128/78 mm Hg; pulse, 150 beats/min; respiratory rate, 28 breaths/min; and temperature, 99.7°F (37.6°C). Pulse oximetry measured 96% saturation on room air. Pupils were 3 mm and reactive to light. The skin was pale without rashes or bruises. The anterior fontanel was open (1 cm) and flat. The mouth was clear of particulate matter. Examination of the chest, heart, and abdomen was unremarkable. Pulses were strong. The neurologic examination was nonfocal. At 9:10 AM, the child had a generalized seizure lasting less than 15 seconds. There was no incontinence, eye rolling, or focal features. The ED staff placed a 28-French orogastric tube into the stomach and lavaged with 100 mL aliquots of 0.9% sodium chloride. Lavaging produced a scant amount of brown particulate material along with other stomach contents. After the stomach contents were cleared, 10 g of activated charcoal were delivered through the orogastric tube, which was then replaced by a nasogastric tube. Over the next 30 minutes, the child became increasingly lethargic. Neurologic examination demonstrated progressively more hypotonia, and his deep tendon reflexes became undetectable. His respiratory rate decreased to 18 breaths/min and he was breathing diaphragmatically with little intercostal muscle movement. The pulse had decreased to 84 beats/min and the blood pressure had decreased to 76/50 mm Hg. His skin was mottled and cool. The pulse oximeter registered 88–89%. An arterial blood gas analysis done prior to placing the child on oxygen showed pH, 7.44; PCO2, 46 mm Hg; and PO2 57 mm Hg. At 9:45 AM the child was intubated and placed on a ventilator. Copious clear secretions were noted from the mouth and endotracheal tube and the child was given 0.2 mg of atropine IV. The complete blood count (CBC), electrolytes, glucose, calcium, magnesium, and renal function tests done at the time of admission were within normal limits. Four hours after presentation, the child was more alert and breathing more effectively and began fighting the ventilator. He was sedated with a continuous midazolam infusion, but was gradually

= = = =

162 daltons 50 ng/mL 1–2 mg (children) 4–8 mg (adults)

weaned from the respirator and extubated 11 hours after the ingestion. He was discharged home 48 hours after ingestion in stable condition. Followup examination 15 days later revealed no apparent sequelae.

Fifty million Americans—25% of the adult population— smoke cigarettes despite antismoking public education campaigns, widespread knowledge of its health consequences, and decreasing social acceptance.6,75 In the United States, 350,000 deaths annually are attributable to cigarette smoking, making it the single most important cause of preventable premature mortality.54 It is now widely accepted that tobacco use is addictive and that nicotine is the component primarily responsible for dependency.69 Nicotine is a tertiary amine. It is a colorless, bitter-tasting, highly water-soluble, volatile liquid that is weakly alkaline (pKa = 8.0–8.5).6 The principal source of nicotine today is the tobacco plant, Nicotiana tabacum, from which nicotine was first isolated in 1826.13 Nicotine also can be isolated from multiple plant species in the Solanaceae family. Nicotiana tabacum is not the only tobacco plant in this family. The first tobacco to be brought back from the New World to Europe was Nicotiana rustica, which contains a much higher concentration of nicotine (approximately 18%) and which is still used in “Turkish tobacco.”37 Nicotine is also found in small concentrations in plants outside the Nicotiana genus, and even in plants outside the Solanaceae family. In addition, there are a number of alkaloids with chemical structures and physiologic activity similar to that of nicotine in tobacco plants and botanical species related to tobacco.37 Nornicotine, anabasine, and anabatine are structurally similar alkaloids also found in tobacco. Anabasine is the principal alkaloid found in Nicotiana glauca.62 Lobeline, derived from Lobelia inflata, or “Indian tobacco,” is frequently used as a nicotine substitute.31 Cystisine, found in mescal beans, is used for its mind-altering properties. Coniine, the lethal alkaloid in “poison hemlock,” is also chemically related to nicotine.

HISTORY AND EPIDEMIOLOGY The principal sources of nicotine exposure and poisoning are tobacco products: cigarettes, cigars, pipe tobacco, chewing tobacco, and snuff. Nicotine is also the essential component of smoking-

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cessation products such as nicotine gum, nicotine patches, and nicotine nasal and oral spray. Nicotine had a brief application as an animal tranquilizer and was used extensively as an agricultural insecticide in the 1920s and 1930s; formulations of this product are still used by “organic” gardeners.

Sources and Uses of Nicotine Cigarettes. Cigarettes are the most widely used tobacco products in Western culture and the most likely culprit in nicotine poisoning. When a cigarette is burned, the smoker inhales both gaseous and particulate matter. Nicotine is found in the particulate phase of cigarette smoke, along with tar. The total nicotine content of a “regular” American cigarette varies between 13 and 20 mg. “Low nicotine” cigarettes contain half this amount, and many European cigarettes contain up to 30 mg of nicotine.8,20,67 When a cigarette is smoked, more than half the nicotine escapes in the sidestream smoke and a large fraction remains in the butt and filter.2 As a result, a typical cigarette delivers 0.5–2.0 mg of nicotine (average, 1.0 mg) to the smoker.31 This amount depends on the total nicotine content of the cigarette as well as the individual’s smoking technique. The nicotine content written on a cigarette package is determined by burning cigarettes on mechanical smoking machines in a standardized manner.43 A smoker, on the other hand, extracts variable amounts of nicotine from a cigarette to maintain a steady blood nicotine level. Smokers vary the degree of nicotine extraction by altering the rate of puffing, the puff volume, the depth and duration of inhalation, and the size of the residual butt.6,43 African Americans extract, on average, 30% more nicotine per cigarette smoked than whites.55 When smokers switch from “regular” to “low-yield” cigarettes, they often maintain a similar nicotine intake by increasing the number of cigarettes they smoke and by puffing in a more vigorous manner43 (see Table 73–1). Not all cigarettes are made from pure tobacco. It is common, especially in Asia, to create cigarettes out of a mixture of tobacco and other products. “Kreteks” are cigarettes composed of 60% tobacco and 40% ground clove. In 1984, 66 billion of these cigarettes were sold worldwide. In the United States, they are especially popular with adolescents because of their pleasant odor and euphorigenic effect. Unfortunately, kreteks are more addicting than tobacco alone.37 Moreover, eugenol, the major active ingredient in cloves, is believed to be the probable cause of the severe lower respiratory complications—acute lung injury and hemorrhage—that occurs in some users.37

TABLE 73–1.

Sources of Nicotine

Source

Content (mg)

Delivered (mg)a

1 whole cigarette 1 low-yield cigarette 1 cigarette butt 1 cigar 1 g of snuff (wet) 1 g of chewing tobacco 1 piece of nicotine gum 1 nicotine patch 1 nicotine nasal spray

13–30 3–8 5–7 15–40 12–16 6–8 2 or 4 8.3–114 0.5

0.5–2.0 0.1–1.0 — 0.2–1.0 2.0–3.5 2.0–4.0 1.0–2.0 5.0–22/24 h 0.2–0.4

a

Delivered through intended use of standard dose.

Smokeless Tobacco. Smokeless tobacco, especially snuff, has regained popularity in the United States. Because smoking is not involved, the public generally believes that smokeless tobacco is more socially acceptable and less of a health risk.23,37 In fact, in comparison to nonsmokers, there is as much as 48 times the risk of oropharyngeal cancers among long-time users of smokeless tobacco, in addition to other oral and nonoral health hazards.12,13,37 Smokeless tobacco comes in two varieties: chewing tobacco and snuff. Snuff is a finely cut tobacco powder packaged dry or moist. In Europe, especially England, small pinches of dry snuff are inhaled through the nostrils. In the United States, dry and wet snuff are usually “dipped.” This involves placing a bite-size amount of tobacco (a “quid”) between the mucous membranes and the gums. Chewing tobacco is generally packaged as “twists”— leaf tobacco twisted into ropelike portions—or “plugs”—shredded tobacco pressed into cakes. These forms are chewed or simply placed in the gingival recess. Generally, the nicotine from smokeless tobacco dissolves in the saliva and is absorbed through the mucous membranes of the mouth. However, approximately onethird of smokeless tobacco users swallow their saliva, absorbing additional nicotine in the intestinal tract.12,13,66 Snuff contains approximately 14 mg of nicotine per gram of tobacco. A typical quid contains 1.5–2.5 g of tobacco, which the user “dips” for 20–30 minutes. Ten percent of the available nicotine crosses the oral mucosa, producing a total nicotine dose of 2.0–3.5 mg/dip. Tobacco chewers use approximately 7 g of tobacco at a time. The nicotine content of a typical “chaw” is 7.8 mg/g of tobacco. Only 8% of this nicotine is absorbed through the oral mucosa, because the pH of chewing tobacco is only 6.5. Ultimately, the tobacco chewer gets approximately the same dose of nicotine or slightly more than the tobacco snuffer.11 The smokeless tobacco user who takes 8–10 dips or chaws per day gets a nicotine dose equivalent to 30–40 cigarettes per day, and cotinine concentrations found in their urine are similar to those found in the urine of smokers.5,11

Less-Common Sources. Although poisoning from smokeless tobacco usually occurs by unintentional ingestion in children, 1 case report of nicotine poisoning occurred when a child licked the contents of a spittoon.21 Another unusual source of nicotine poisoning is tobacco enemas. On occasion, tobacco has been soaked in water and the juice of this extract added to enemas for the treatment of pinworm. This practice has produced at least 1 reported case of severe nicotine poisoning.20 Green-leaf tobacco sickness (GTS) occurs when a tobacco harvester handles dew-laden tobacco leaves. The nicotine dissolves in the water and is absorbed through the worker’s skin, if cutaneous precautions are not taken.6,37 Transcutaneous nicotine poisoning is also reported in smugglers who hide tobacco leaves under their clothing.37 Nicotine salts such as nicotine sulfate were popular pesticides in the 1920s and 1930s. These compounds generally contain 40% nicotine; when they come in contact with moist skin, significant doses of nicotine are absorbed. Several cases of severe nicotine poisoning from insecticide skin exposure or ingestion, including deaths, have occurred.9,37,52 Although industrial-scale manufacture of nicotine insecticides was discontinued by 1950, these products may still be available through catalogues and Web sites catering to the organic gardener.

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Gum. Nicotine is prepared in the form of gum to assist abstinent smokers with withdrawal symptoms. Nicotine resin gum (Nicorette) is packaged in two strengths, 2 mg and 4 mg per stick. It is designed to be chewed slowly and intermittently. When used correctly, blood concentrations of nicotine are less than those achieved through cigarette smoking, even when 4-mg gum is chewed. Because of alkaline buffers, approximately 53–72% of the nicotine in the gum is absorbed through the buccal mucosa. Additional amounts can be absorbed through swallowed saliva.6 However, when the gum is chewed rapidly and vigorously, nicotine concentrations in the blood can rise rapidly, producing adverse effects, especially in children.67 Severe nicotine poisoning in a 20-month-old child occurred from the use of nicotine gum.65 Moreover, adverse effects are reported in adults who have used the gum while continuing to smoke.48,67 If the gum is swallowed, it is less likely to be toxic because the nicotine is released and absorbed slowly during GI transit, producing low blood concentrations.6 Patches. There are currently four nicotine-releasing adhesive patches available to aid in the treatment of smoking cessation. These patches, designed for 16–24 hours of use, vary in size and nicotine release rates, and contain 8.3–114 mg of nicotine per patch. Only a portion of the total nicotine load of the patch is actually absorbed during the cutaneous application. Nasal Spray and Inhaler. In 1996, a nicotine nasal spray (Nicotrol) was released in the United States as another treatment modality for withdrawal symptoms during smoking cessation. The metered-dose inhaler contains 100 mg of nicotine in a concentration of 10 mg/mL and is designed to deliver 200 equivalent puffs. Each puff contains 0.5 mg of nicotine of which slightly more than half will pass into the circulation through the nasal mucosa.47 Absorption is diminished slightly by rhinitis and delayed by the use of
-adrenergic decongestants.38 The recommended dose is 2 sprays (1 mg)—1 in each nostril—every 30–60 minutes. The user titrates the dosing frequency to withdrawal symptoms, using a maximum of 40 doses (80 puffs) per day and creating a steadystate serum nicotine level of 6–18 ng/mL. A nicotine metered-dose oral inhaler for smoking cessation was recently released. The device is designed to mimic smoking by providing airway stimulation as well as nicotine replacement. Absorption of nicotine occurs primarily through the buccal and pharyngeal mucosa, but slow deep inhalation can redirect some nicotine into the pulmonary tree and achieve absorption there. An average steady-state serum nicotine level of 7 ng/mL was achieved in a 2-day trial of 15 subjects.39

PHARMACOLOGY AND PHARMACOKINETICS Table 73–2 summarizes the pharmacologic characteristics of nicotine.

Absorption The typical cigarette smoker will adjust his or her use of cigarettes and pattern of smoking to maintain an average nicotine concentration of 30 ng/mL.6 Nicotine is readily absorbed from the buccal

NICOTINE AND TOBACCO PREPARATIONS

TABLE 73–2.

Pharmacologic Characteristics of Nicotine

Absorption Volume of distribution Protein binding Metabolism

Half-life Elimination

1077

Lungs, oral mucosa, skin, intestinal tract, gastric acidity inhibits absorption Approximately 1 L/kg 5–20% 80–90% metabolized in the liver, remainder in lung and kidney; principle metabolites are cotinine, nicotine-1′-N-oxide 1–4 h, shorter in smokers (average, 2 h); halflife of cotinine is 19 h 2–35% excreted unchanged in urine

mucosa, respiratory tract, intestinal tract, and skin. The usual site of absorption is the lungs. Inhaled nicotine from cigarette smoke reaches the brain in approximately 8 seconds, with central nervous system (CNS) levels of nicotine rising rapidly and then declining rapidly as the drug is redistributed to other tissues.6,31 The cigarette smoker achieves a blood nicotine concentration of 5–30 ng/mL after a single cigarette.6 Nicotine from cigar and pipe tobacco as well as chewing tobacco, snuff, and nicotine resin chewing gum is generally absorbed through the buccal mucosa. Pipe and cigar tobacco are air-cured to achieve an alkaline pH of 8.50. Smokeless tobaccos and nicotine gum are buffered. The alkaline pH of all of these products enhances buccal absorption.6 Smokeless tobacco users generally achieve nicotine concentrations comparable to those of cigarette smokers. Pipe and cigar smokers usually average lower nicotine concentrations, unless they inhale the smoke from these products.6 Ingested tobacco is poorly absorbed across the gastric mucosa because the acidic pH of the stomach keeps the nicotine ionized.28,34 Nicotine absorption increases again in the alkaline milieu of the intestines. Nicotine generally achieves a volume of distribution of 1 L/kg. It readily crosses the placenta and is also transmitted in small concentrations in breast milk.6

Metabolism/Elimination Habitual tobacco users generally metabolize 80–90% of their nicotine intake, excreting 10–20% in urine unchanged. Metabolism takes place primarily in the P450 system of the liver, but also, to a lesser extent, in the kidney and lung.9,31 The two major oxidative metabolites of nicotine are cotinine and nicotine–1-N-oxide. Both of these compounds are pharmacologically inactive and are excreted primarily by the kidney.6,31 The half-life of nicotine is 1–4 hours but generally averages 2 hours in chronic users.6,31 Because nicotine metabolism in the liver is an inducible transformation, smokers metabolize the drug more rapidly than nonsmokers. The elimination half-life of cotinine is approximately 19 hours, making cotinine levels in the urine a better marker of recent tobacco use and total tobacco exposure.6,31 Clearance of cotinine is slower in African Americans.55 Renal excretion of unchanged nicotine can vary from 2–35% of the total dose,6 depending on urine flow and urine pH. Experimentally, acidification of the urine traps nicotine ions and enhances direct elimination.6,20 Nonsmokers eliminate a larger proportion of nicotine unchanged in the urine because of their slower hepatic metabolism.34

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Drug Interactions A number of studies demonstrate that smokers have altered metabolism of many commonly used medications. Smokers metabolize the compounds listed in Table 73–3 more quickly than do nonsmokers.31,34 Nicotine itself is metabolized more rapidly in smokers. The therapeutic effectiveness of opioids, benzodiazepines, nifedipine, and -adrenergic antagonists is diminished in smokers.31 Smokers with peptic ulcer disease are also more likely to fail treatment with H2 antagonists and antacids.6 The presumed mechanism for this change in drug metabolism is induction of microsomal enzyme systems. However, because there are 3000 components to tobacco smoke, it is difficult to know exactly which components affect metabolism. In all likelihood, nicotine is not responsible for the induction. For example, IV nicotine does not affect theophylline metabolism in humans.6 It is more likely that polynuclear aromatic hydrocarbons (PAH), released by the combustion of tobacco, are responsible for the induction of P448 microsomal enzymes in the liver.34 Drugs whose metabolism is affected by smoking are in part metabolized by this system. In contrast, drugs using the P450 system exclusively are not affected by chronic smoking.34 This conclusion would be further supported by demonstrating the absence of drug interactions in users of smokeless tobacco, nicotine gum, and transdermal nicotine patches (TNP) users. Nicotine and ethanol are frequently used concomitantly. Animal studies demonstrate that pretreatment with ethanol exaggerates cardiovascular responses to IV nicotine. Heart rate and blood pressure increase in an additive way. Smokers are more apt to suffer from dysrhythmias and sudden death during alcohol use. It is likely that this is the result of increased oxygen demand triggered by additive cardiovascular stimulation.7 Because ethanol does not influence the rate of nicotine metabolism, the etiology of this additive response is unclear.

tremor.31,62 At very high doses, nicotine induces seizures. Studies in mice suggest that nicotine-induced seizures can be controlled by the neuroinhibitory agent 3-
-o1–20-one. It is therefore postulated that nicotine produces seizures at high doses by a CNS disinhibition mechanism at CNS nicotine receptor synapses.40 Gastrointestinal effects are probably mediated by nicotine stimulation of vagal centers in the medulla oblongata. Even at low doses, nicotine exposure produces nausea and vomiting in the inexperienced, nontolerant tobacco user. Nicotine also increases gastroesophageal reflux, probably by either lowering sphincter pressure or increasing acid secretion.59 Diarrhea can be stimulated by larger doses of nicotine, which is probably mediated by both central and parasympathetic excitation.20,31 Nicotine exerts a number of endocrinologic effects either by acting directly on nicotine receptors in the endocrine gland or by stimulating neurohumoral pathways in the CNS. It enhances release of catecholamines. It also stimulates the production of vasopressin (antidiuretic hormone (ADH)), growth hormone, adrenocorticotropin (ACTH), cortisol, prolactin, serotonin, and endorphins. Nicotine also affects pancreatic exocrine functions. Rats pretreated with nicotine doses comparable to the exposure of moderate smokers exhibit increased amylase, trypsin, and chymotrypsin activity.15 With repeated exposure, tolerance develops to many of these effects.6 Nicotine suppresses the appetite for food, especially sweet foods, while increasing basal energy expenditures. These effects explain why nicotine promotes weight loss. Smokers weigh, on average, 6–10 lbs less than nonsmokers. With repeated exposure, tolerance develops to many of these effects.6,31 Habitual use of nicotine also decreases estrogen levels in female smokers, probably by promoting hydroxylation of estradiol. As a result, women who smoke are at increased risk for osteoporosis.

CLINICAL MANIFESTATIONS PATHOPHYSIOLOGY Nicotine binds stereospecifically to select acetylcholine receptors, generally referred to as nicotine receptors6,31 (Chap. 10). There are nicotine receptors throughout the body, particularly in the autonomic ganglia, adrenal medulla, central nervous system, spinal cord, neuromuscular junctions, and chemoreceptors of the carotid and aortic bodies.6,31 In the CNS, the highest density of nicotine receptors can be found in the limbic system, midbrain, and brainstem.6 The physiologic effects on the CNS are similarly multiple, complex, and dose-dependent. At doses commonly encountered with tobacco use there is stimulation of the reticular activating system and an alerting pattern on electroencephalogram (EEG).31,65 There is a facilitation of memory and attention, with a decrease in aggression and irritability.31 Although nicotine might reduce skeletal muscular tone and decrease deep-tendon reflexes, its central and neuromuscular stimulatory effects can also produce

TABLE 73–3.

Drugs with Enhanced Metabolism in Smokers

β Adrenergic antagonists (select agents) Benzodiazepines Caffeine Cyclic antidepressants (select agents) H2 histamine antagonists

Nicotine Opioids Phenacetin Theophylline

More than 60% of reported nicotine exposures produce no toxicity and only 1% produced moderate to major toxicity. This low proportion of serious poisoning is not surprising, because 98% of exposures are unintentional and more than 90% occur in children younger than 6 years of age8 (Chap. 116). Nonetheless, serious exposures do occur, even in young children, and seem to be dose related. In one report, approximately 45% of 51 childhood exposures to nicotine resulted in some degree of symptomatology. Only 8 (16%) of these 51 children required evaluation by a physician and only 4 children (8%) developed significant symptomatology (lethargy, unresponsiveness, limb jerking).67 Similarly, another study reported that only 1 of 20 children who ingested nicotine became moderately ill and required 24 hours of hospitalization.8 Most unintentional exposures in small children result from the ingestion of tobacco products. The tobacco itself usually induces spontaneous vomiting, which limits absorption of the toxin. A child who ingests 1 or more cigarettes or 3 or more cigarette butts has a 90% chance of becoming symptomatic. Conversely, ingestion of smaller amounts will produce symptomatology only half the time.75 In a retrospective review of 10 cigarette ingestions by children, the 4 children who became severely poisoned each ingested at least 2 whole cigarettes.42 One-half piece or more of 2mg nicotine chewing gum usually produces symptomatology in a child.67

CHAPTER 73

Table 73–4 outlines the symptoms associated with acute nicotine exposure. Clinical signs of low concentrations of nicotine, such as those occurring routinely in smokers, include tremor and increased heart rate, respiratory rate, blood pressure, and alertness. In marked contrast to these relatively mild effects associated with cigarette smoking, when nicotine is taken in “toxic” quantities, as in an insecticide exposure for example, the effects are more severe. The symptoms may follow a biphasic pattern in which there is initial stimulation followed quickly by inhibition.62 Early symptoms of toxicity often include nausea, vomiting, diaphoresis, and increased salivation. Cardiovascular signs include tachycardia, hypertension, and pallor (secondary to vasoconstriction). Early neurologic manifestations include headache, dizziness, ataxia, and, in moderately severe cases, confusion as well as visual and auditory distortions.8,62 In the most severe exposures, these generally mild symptoms can be quickly overshadowed by signs of more extreme stimulation, such as seizures, muscle fasciculations, and atrial fibrillation.8,62,65 Although seizures do occur, there are no reports of nicotine-induced status epilepticus in nonexperimental conditions. These symptoms are often succeeded by signs of multisystem depression, such as bradycardia and hypotension, and a curarelike neuromuscular blockade that leads to muscle paralysis, particularly respiratory paralysis.52,62,65 Death is generally attributable to respiratory depression or paralysis (particularly of the intercostal muscles) complicated by increased bronchial secretions or to cardiovascular collapse.9,52,62 Timely and adequate respiratory and cardiovascular support generally leads to full recovery without sequelae.9,52 Vomiting is the most common symptom of nicotine poisoning, occurring in more than 50% of symptomatic patients. However, it is not a reliable sign of toxicity.67 Patients can present with lethargy and respiratory depression without prior vomiting or any other signs of CNS stimulation.9 Moreover, nicotine chewing gum ingestions in children produce vomiting less frequently (20% incidence) than do those with cigarette ingestions.67 Following the ingestion of tobacco products, children usually manifest symptoms within 30–90 minutes. When children chew nicotine gum, symptoms are usually apparent within 15–30 minutes, a result of more rapid absorption through the buccal mucosa.65,67 When death occurs, it usually occurs within 1 hour of exposure. With mild poisonings, symptoms generally last only 1–2 hours after exposure. With severe intoxication, however, full recovery might take 48–72 hours.65 As little as 1 mg of nicotine can produce symptoms in a small child. Four to 8 mg of nicotine might produce symptoms in an adult, especially a nonhabituated victim.20 Forty to 60 mg of nicoTABLE 73–4.

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tine is generally accepted as the lethal dose in adults.20,21,42 See Table 73–1 for the nicotine content of tobacco products and substitutes. In a prospective study of nicotine ingestions in children, the 3 most severely poisoned infants ingested a minimum of 1.4 mg/kg. The 25 asymptomatic children ingested a mean of 0.5 mg/kg, and all asymptomatic children ingested less than 1 mg/kg.67 These numbers indicate a very narrow range between nontoxic and significantly toxic doses. Green-leaf tobacco sickness generally produces a mild to moderate illness consisting of nausea, vomiting, headaches, dizziness, pallor, and diaphoresis.6,37 However, in two recent outbreaks of green-leaf tobacco sickness in Kentucky, nearly 25% of the affected tobacco workers required hospitalization. A significant portion of these poisoned workers were under 18 years.3,46 One study exposed dogs transdermally and orally to three different commercially available nicotine patch systems. The topical administration provided 1–2 mg/kg over 24 hours, producing plasma concentrations as high as 43 ng/mL. Two of 12 topical applications elicited mild symptomatology (salivation and vomiting). Oral exposure up to 13 mg/kg produced maximal plasma concentrations of 73 ng/mL, with only mild symptoms (vomiting) in two of 12 oral challenges.45 Recently published reports from a 2-year postmarketing surveillance study by 34 poison centers describe toxicity from misuse or from unintentional exposure to TNPs. Transdermal application of 2–20 TNPs in 9 adults resulted in very serious toxicity. Eight patients were admitted to intensive care; 4 had refractory seizures; and 4 required assisted ventilation. However, 7 of the 9 patients ingested cointoxicants in suicide attempts, and the maximum nicotine level recorded was only 27 ng/mL.78 Thirty-six exposures in children were less severe. Half the children had topical exposures, while half had bitten, chewed, or swallowed the patches. Nearly 40% developed symptoms, but only 27% required medical evaluation and only 5% were hospitalized for 24 hours or more.77 It seems, therefore, that unintentional exposure to nicotine patches has not yet produced serious toxicity to date.

DIAGNOSTIC TESTING Toxicologic assay for nicotine or its metabolites is of limited value in the management of a patient with an acute poisoning. The presence of nicotine or cotinine in the urine might reflect coincidental active or passive smoke exposure and therefore does not confirm nicotine as the cause of poisoning.65 Serum nicotine levels must be determined shortly after exposure and are difficult to interpret. A serum nicotine level greater than 50 ng/mL generally predicts seri-

Signs and Symptoms of Acute Nicotine Poisoning Gastrointestinal

Respiratory

Cardiovascular

Neurologic

Early (15–60 min)

Abdominal pain Nausea Salivation Vomiting

Bronchorrhea Hyperpnea

Hypertension Tachycardia Pallor

Agitation/anxiety Ataxia/dizziness Blurred vision Confusion Distorted hearing

Headache Hyperactivity Muscle fasciculations Seizures Tremors

Delayed (0.5–4 h)

Diarrhea

Apnea Hypoventilation

Bradycardia Dysrhythmias Hypotension Shock

Coma Hyporeflexia Hypotonia

Lethargy Weakness Muscle paralysis

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ous toxicity, but lower levels can also be significant in the nontolerant patient.62

MANAGEMENT Unintentional ingestions of nicotine in small children almost invariably involve small amounts, with spontaneous vomiting providing adequate decontamination. Thus, many patients do not need medical evaluation. Individuals who ingest 1 or more whole cigarettes or 3 or more cigarette butts, who acquire their exposures from a more toxic source (a nicotine insecticide or a tobacco enema), who develop symptoms other than vomiting, or who are potentially suicidal, should be referred to an ED without delay. Patients with mild symptoms and no complicating circumstances can generally be observed for 4 hours in the ED and then released if symptoms have resolved.62

Initial Management The patient with a significant recent oral exposure, who has not vomited prior to presentation, should be decontaminated by orogastric lavage. Emesis induced by syrup of ipecac should be avoided because nicotine poisoning may cause unexpected seizures or respiratory depression.9,67 Activated charcoal effectively binds nicotine and should be used to reduce absorption in gastrointestinal (GI) exposures. Pharmacokinetic studies indicate that nicotine appears in the GI tract, even when administered IV.67 Because this suggests that nicotine undergoes enteroenteric or enterohepatic circulation, multiple-dose activated charcoal should be administered in patients with serious exposures. In cases of skin exposure to wet tobacco leaves, concentrated nicotine liquid, or nicotine pesticide powder, the patient’s clothing should be promptly removed, bagged, and not returned to the patient and the skin thoroughly washed with soap and water. The medical staff must wear impervious gloves and gowns during these procedures to avoid secondary exposure.

Symptom-Directed Treatment Because of the variety of stimulatory and depressant effects in the neuromuscular, sympathetic, parasympathetic, and central nervous systems, treatment of nicotine toxicity is a complex therapeutic problem. Treatment is based on a symptom analysis with primary emphasis on respiratory support. Seizures are usually treated with a benzodiazepine. Loading the patient with longer-acting anticonvulsants is generally unnecessary.9,42,62 Cardiovascular compromise is treated with atropine for symptomatic bradycardia and fluids for hypotension.62 If hypotension does not respond to fluids, a vasopressor such as dopamine or norepinephrine is recommended.65 By reversing bradycardia with atropine, there is some risk of creating unopposed catecholamine effects. For this reason, some authors also suggest using concomitant phentolamine, an
adrenergic antagonist, in the treatment of nicotine overdose.20,62 Such combined therapy is unnecessary, however, as adrenergic stimulation is rarely life-threatening in nicotine poisoning, and adrenergic antagonism can exacerbate hypotension in the delayed phase. Respiratory compromise, caused by respiratory depression is generally treated with oxygen, intubation and positive pressure ventilation as indicated.

Enhancing Elimination Although nicotine is a weak base (pKa = 8.0–8.5) and excretion can theoretically be enhanced by acidification of the urine, this approach is not advisable.9,62 The potential risks of acidification in a patient with seizures and possible rhabdomyolysis outweigh the theoretical benefits.62 Furthermore, because the symptoms in nicotine poisoning are generally short-lived, acidification is unnecessary. Fluid diuresis may also enhance elimination and is safer but also is unnecessary due to the limited urinary elimination.9

Antidotes There is no specific antidote for nicotine poisoning. Pempidine and mecamylamine demonstrate both competitive and noncompetitive antagonism to the central effects of nicotine,44 and hexamethonium, a ganglionic blocking agent, prevents nicotine-induced seizures in animals.62 None of these agents has been used, either experimentally or clinically, to treat overdoses in humans. Although their application is theoretically of interest, new approaches with these agents are not likely to be developed because severe nicotine poisoning is rare and nonspecific supportive measures are almost always adequate when initiated in a timely manner.

NICOTINE WITHDRAWAL AND TREATMENT Tobacco use meets all of the World Health Organization (WHO) definitions of addiction. There is an overpowering compulsion to continue taking the drug. There is a tendency to develop tolerance to its effects and therefore keep increasing the dosage. Psychologic and physical dependency develops, and the absence of tobacco produces discomfort in the smoker. Finally, tobacco has detrimental consequences for both the individual user and society at large.49 Tobacco addiction occurs with forms of tobacco besides cigarettes, especially with smokeless tobacco. Of course, many smokeless tobacco users switch to this product to wean themselves from cigarettes.49,56 Individuals dependent on tobacco, like any other substance-dependent individuals, go through multiple cycles of quitting and relapsing. While spontaneous quitting without any special treatment program is the most common route to abstinence, the achievement rate by this method is only 1% of users per year.6,35 Women cigarette smokers have a lower success rate than men.53 Smokers are much more likely than nonsmokers to have other substance dependencies.35 Conversely, 80–95% of alcohol and drug abusers also smoke cigarettes. It has been suggested that nicotine use promotes the release of endogenous endorphins. Therefore, withdrawal from nicotine might have a strong biochemical resemblance to withdrawal from opioids.16 In fact one study was able to precipitate withdrawal symptoms in nicotine-dependent rats with subcutaneous naloxone and then reverse the abstinence symptoms with morphine sulfate.41 On the other hand, nicotine’s neurochemical effects on the brain, and on other neurotransmitters such as dopamine, closely resemble that of other psychostimulants. (For an in-depth discussion of the physiology of withdrawal see Chap. 72.)

CHAPTER 73

With so many substances involved in cigarette smoking, it is quite likely that tobacco dependency is a complex addiction, involving both psychological components, such as oral gratification, and physical dependency. It is now widely accepted that the primary addictive component of tobacco is nicotine,50,56,75 but this is the subject of some controversy and is supported primarily by indirect evidence.

CLINICAL MANIFESTATIONS OF NICOTINE WITHDRAWAL Manifestations of nicotine withdrawal can occur within 2–8 hours of the last cigarette. In fact, most moderate to heavy smokers experience some withdrawal symptoms as they wake up each morning. Withdrawal reaches maximum intensity at 24–48 hours, and then diminishes over a 2-week period of abstinence. After 1 month, symptoms are gone, except for the cravings for cigarettes and an increase in appetite.6,63 Approximately 80% of smokers experience withdrawal symptoms when quitting, and withdrawal is nearly universal among smokers using 20 or more cigarettes per day.6 Nicotine withdrawal is not confined to cigarette smokers alone. The same syndrome is reported in smokeless tobacco users and chronic users of nicotine chewing gum.6,49 Most of the symptoms associated with tobacco withdrawal are subjective, leading to an overall feeling of dysphoria. These manifestations, widely described in the literature, are summarized in Table 73–5.14,27,31,36,49 The most dramatic and intense symptom of tobacco abstinence is a craving for cigarettes, which can continue for months to years.6 Cravings for cigarettes are less intense and diminish more quickly in people who are totally abstinent, as compared to those who are only partially abstinent.63 One study evaluated 7 smokers in a battery of computerized performance tasks over a 24-hour period of abstinence. With increasing abstinence, the smoker’s responses showed increased latencies and decreased accuracy.68 Moreover, EEG studies evaluating smokers in withdrawal show a decrease in high-frequency activity and an increase in low-frequency activity, consistent with diminished arousal.31

TABLE 73–5.

Clinical Manifestations of Nicotine Withdrawal

Subjective

Objective

Anger/aggression/hostility Anxiety Blurred vision Confusion Constipation Craving for cigarettes Drowsiness Gastrointestinal upset Headache Hunger Impaired concentration Irritability/impatience Moodiness Restlessness Sleep disturbance

Decreased arousal pattern on EEG Decreased blood pressure Decreased heart rate Diminished psychomotor performance Impaired short-term memory Reduced plasma catecholamines Weight gain

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The most common objective physical manifestation of nicotine abstinence is a decrease in heart rate by a mean of 9 beats/min within the first day of abstinence; it is a unique feature of nicotine withdrawal syndrome.27 This decrease remains constant when measured over the next 5 weeks of abstinence, suggesting that heart rate reduction in tobacco abstinence reflects the absence of stimulation from nicotine, rather than withdrawal symptomatology.76 Plasma levels of epinephrine and norepinephrine also decrease in abstinent smokers. This is probably another manifestation of the absence of nicotine effect and undoubtedly contributes to the reduction in mean heart rate.17

MANAGEMENT OF ACUTE NICOTINE WITHDRAWAL In clinical practice, nicotine withdrawal syndrome is encountered when tobacco users attempt to quit in the interest of their longterm health or when acute illness forces abstinence. The discomfort is a primary obstacle to smoking cessation and contributes significantly, but not solely, to the low success rate of attempts to quit smoking. Therefore, any treatment approach that lessens nicotine withdrawal symptoms, without reinitiating the use of tobacco products, is more likely to aid the effort to quit, which in turn will have many long-term health benefits. An in-depth discussion of smoking cessation management falls outside the purview of a textbook on toxicologic “emergencies.” However, a brief summary is included because of the current medical and public health significance of this subject.

Nicotine Replacement Therapy One approach to the treatment of nicotine abstinence syndrome is to provide nicotine without tobacco. This therapy offers nicotine in a safer, more clinically controllable form that minimizes nicotine withdrawal symptoms. After the patient breaks the smoking habit, the nicotine replacement agent is gradually tapered.60 Nicotine gum is the oldest of the nicotine substitution therapies. It ameliorates many symptoms of nicotine withdrawal, especially feelings of irritability, aggression, and dysphoria. However, it seems less effective in eliminating cigarette craving and increased hunger.10 The effectiveness of nicotine chewing gum in promoting longterm smoking abstinence has been extensively studied.32,71,72 A meta-analysis of all these studies, with special emphasis on double-blind, randomized, placebo-controlled trials with 1 or more years of followup study, indicates that nicotine chewing gum in conjunction with a formal program of behavioral therapy can produce 1-year abstinence rates of 29–49%.1,6,74 On the other hand, when nicotine gum is used in general medical practice, without structured behavioral interventions, improvement in smoking abstinence is short-lived and smoking cessation rates at 6–12 months are similar to those of placebo-treated patients.4,6,32 Unfortunately, many smokers who use nicotine gum to quit develop dependency on the gum itself. As an adjuvant to smoking cessation nicotine gum should be used for a maximum of 3 months. However, several studies have reported continued use of the gum at 1-year followup (6–38% of users.).6,25,26 Self-administration of the gum may reinforce some of the behavioral patterns that sustain smoking. It can be argued that the behavioral compo-

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nents of the addictive process must be decisively interrupted for successful treatment of the addiction.56 TNSs have supplanted chewing gum as the preferred nicotine replacement therapy. Because nicotine patches are easier to use (they require once-a-day application) compliance is better. The dose of nicotine delivered to the patient is more predictable, nicotine steady-state levels in the blood are higher, and the differentsize patches make tapering easier to control. Finally, because no specific behavioral action is required of the patient, other than putting the patch on in the morning, a TNS does not require selfadministration of nicotine by the user and therefore does not mimic oral smoking behavior.56,60 There are four patch systems currently available, each of which comes in several different doses of nicotine. Three of the patch systems are designed for 24-hour use, and the newest is made for 16-hour use to approximate more closely nicotine intake patterns of the smoker.51 The patches generally deliver steady-state nicotine plasma concentrations of 10–15 ng/mL, which are maintained throughout the application of the patch.24 Several double-blind, placebo controlled studies have demonstrated that, at 6–12-month followup, TNS users achieve abstinence 2–4 times more frequently than placebo users.14,19,22,74,75 And many studies have now demonstrated that this long-term efficacy is present even with little or no formal behavioral intervention accompanying the program.1,14,74 The most consistent adverse effect of the TNS is skin irritation at the site of the patch. In one trial, approximately 5% of patients withdrew from the study because they could not tolerate the cutaneous irritation.1 Both NNS and NOI reduce withdrawal symptoms and promote abstinence more effectively than placebo.39,70,73 Both treatment modalities are based on the belief that airway stimulation will mimic smoking more closely and therefore be more effective in reducing cigarette cravings. Furthermore, the application of nicotine to mucous membranes provides a rapid transient rise in serum nicotine and thus reduces cigarette cravings more promptly than slower forms of nicotine delivery.29 Although these characteristics are probably real, the replication of smoking’s airway sensations might actually make long-term abstinence more difficult to achieve. To date there have been no head-to-head comparisons of any of the NRTs. Both TNS and NNS seem to be more effective than nicotine gum in reducing cigarette craving and increased appetite.29,60 A meta-analysis of 53 NRT trials, with data from more than 17,000 patients, concluded that all modalities were better than placebo in promoting abstinence at 6 or more months. The nicotine oral inhaler had the best abstinence odds ratio, but this is based on data from only 1 study, while nicotine gum had the lowest odds ratio.64 Clearly, nicotine replacement therapies are moderately effective in promoting smoking cessation, especially in the short run. To be successful, the patient must eventually face the inevitable— withdrawal from nicotine itself. Theoretically, if other treatment modalities effectively promote tobacco abstinence without the use of nicotine replacement they would have a substantial advantage.

cessation grows out of the observations that nicotine has antidepressive effects; that anxiety and depression are frequent comorbid conditions in nicotine-addicted patients; that dysphoria is a common symptom of nicotine withdrawal; and that women have a more difficult time with nicotine abstinence.30 In a randomized double-blinded placebo-controlled comparison study of sustained-release bupropion, smoking abstinence at 52 weeks was 12% in the placebo group and 23% in the 300-mg per day bupropion group.30 A subsequent trial, compared bupropion SR and nicotine patch, and both together, for smoking cessation efficacy in 893 subjects. The 1-year cessation rate was 16% in the patch group—roughly equivalent to placebo—but was 30% in the bupropion group and 35% in the bupropion-plus-patch group. The bupropion-plus-patch group also had the smallest weight gain.33 The sustained release bupropion dose currently recommended is 150 mg twice a day. Patients should be started on treatment at least 1 week prior to their smoking quit date and continued on treatment for 8 weeks. There is an increased seizure risk with bupropion, but generally not at the doses recommended for smoking cessation unless patients are otherwise seizure prone.33

SUMMARY Nicotine, a tertiary amine from Nicotiana tobacum and other tobacco plants, is found commercially in a number smoking products and smoking-cessation treatment pharmaceuticals. It is commonly absorbed through the buccal mucosa or respiratory epithelium of the lungs, but can also be absorbed from the skin or intestine. Up to 90% of a nicotine “dose” is metabolized by an inducible P450 hepatic biotransformation, producing 2 inactive metabolites that are slowly excreted by the kidneys. It exerts its physiologic effects on selective acetylcholine receptors, primarily in neural tissue. While the vast majority of nicotine exposures are unintentional and occur in children producing mild or no toxicity, severe poisoning and even death can result, and there is a narrow range between non-toxic and significantly toxic doses. Clinical manifestations of consequential poisoning are complex but can be characterized as biphasic, with initial excitation followed quickly by inhibition. Management is symptom directed with special emphasis on seizure control and respiratory support. In terms of smoking cessation management, it should be noted that, although several agents will reduce the severity of nicotine withdrawal, long-term smoking cessation is more difficult to achieve. In many approaches to smoking treatment, the overall mean 6–12-month success rate seems to be approximately 25%.56 This is, of course, much better than the spontaneous abstinence rate of 1%, but as many as 70% of patients who achieve initial abstinence will be smoking again after 1 year.16 Whatever approach one takes in treating tobacco abstinence, it seems the patient must start with a strong desire to quit, avoid unusually stressful situations, and have a social support network that encourages the effort to stop smoking. The most successful programs are multimodality treatments that combine counseling or other behavioral therapies with one or more pharmacologic interventions.

Antidepressant Therapy Antidepressant medications such as bupropion (Wellbutrin SR and Zyban) offer an encouraging alternative to nicotine replacement in smoking cessation. The idea of using antidepressants for smoking

REFERENCES 1. Abelin T, Muller P, Buehler A, et al: Controlled trial of transdermal nicotine patch in tobacco withdrawal. Lancet 1989;1:7–10.

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2. Armitage AK, Dollery CT, George CF, et al: Absorption and metabolism of nicotine from cigarettes. Br Med J 1975;4:313–316. 3. Ballard T, Ehler J, Freund E, et al: Green tobacco sickness: Occupational poisoning in tobacco workers. Arch Environ Health 1995;50: 384–389. 4. Benowitz NL: Nicotine replacement therapy during pregnancy. JAMA 1991;266:3174–3177. 5. Benowitz NL: Nicotine and smokeless tobacco. CA Cancer J Clin 1988;38:244–247. 6. Benowitz NL: Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med 1988;319:1318–1330. 7. Benowitz NL, Jones RT, Jacob P: Additive cardiovascular effects of nicotine and ethanol. Clin Pharmacol Ther 1986;40:420–424. 8. Bonadio WA, Anderson Y: Tobacco ingestions in children. Clin Pediatr 1989;28:592–593. 9. Borys DJ, Seltzer SC, Ling LJ: CNS depression in an infant after the ingestion of tobacco: A case report. Vet Hum Toxicol 1988;30:20–22. 10. Cherek DR, Bennett RH, Grabowski J: Human aggressive responding during acute tobacco abstinence: Effects of nicotine and placebo gum. Psychopharmacology 1991;104:317–322. 11. Connolly GN, Orleans CT, Kogan M: Use of smokeless tobacco in major-league baseball. N Engl J Med 1988;318:1281–1284. 12. Consensus Conference: Health applications of smokeless tobacco use. JAMA 1986;255:1045–1048. 13. Council on Scientific Affairs: Health effects of smokeless tobacco. JAMA 1986;255:1038–1044. 14. Daughton DM, Heatley SA, Prendergast JJ, et al: Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy. Arch Intern Med 1991; 151:749–752. 15. Dubick MA, Palmer R, Lau PP, et al: Altered exocrine pancreatic function in rats treated with nicotine. Toxicol Appl Pharmacol 1988; 96:132–139. 16. Edwards NB, Simmons RC, Rosenthal TL, et al: Doxepin in the treatment of nicotine withdrawal. Psychosomatics 1988;29:203–206. 17. Elgerot A: Psychological and physiological changes during tobaccoabstinence in habitual smokers. J Clin Psychol 1978;34:759–764. 18. Ernster VL, Grady DG, Greene JC, et al: Smokeless tobacco use and health effects among baseball players. JAMA 1990;264:218–224. 19. Fiore MC, Smith SS, Jorenby DE, Baker TB: Effectiveness of nicotine patch for smoking cessation. A meta-analysis. JAMA 1994;271: 1940–1947. 20. Garcia-Estrada H, Fischman C: An unusual case of nicotine poisoning. Clin Toxicol 1977;10:391–393. 21. Goepferd SJ: Smokeless tobacco: A potential hazard to infants and children. J Am Dent Assoc 1986;113:49–50. 22. Gourlay S: The pros and cons of transdermal nicotine therapy. Med J Aust 1994;160:152–159. 23. Gross JY, D’Alessandri R, Powell VL, Rodeheaver A: Smokeless tobacco: Health hazard on the rise. South Med J 1988;81:1089–1091. 24. Gupta SK, Okerholm RA, Coen P, et al: Single and multiple dose pharmacokinetics of Nicoderm. J Clin Pharmacol 1993;33:169–174. 25. Hajek P, Jackson P, Belcher M: Long-term use of nicotine chewing gum: Occurrence, determinants and effect on weight gain. JAMA 1988;260:1593–1596. 26. Hughes JR, Gust SW, Keenan R, et al: Long-term use of nicotine versus placebo gum. Arch Intern Med 1991;151:1993–1998. 27. Hughes JR, Higgins ST, Bickel WK: Nicotine withdrawal versus other drug withdrawal syndromes: Similarities and dissimilarities. Addiction 1994;89:1461–1470. 28. Hurt RD, Dale LC, Croghan GA, et al: Nicotine nasal spray for smoking cessation: Pattern of use, side effects, relief of withdrawal symptoms, and cotinine levels. Mayo Clin Proc 1998;73:118–125. 29. Hurt RD, Offord KP, Croghan IT, et al: Temporal effects of nicotine nasal spray and gum on nicotine withdrawal symptoms. Psychopharmacology 1998;140:98–104. 30. Hurt RD, Sachs D, Glover, ED, et al: A comparison of sustainedrelease bupropion and placebo for smoking cessation. N Engl J Med 1997;337:1195–1202.

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31. Jaffe JH: Drug addiction and drug abuse. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 8th ed. New York, Pergamon Press, 1990, pp. 545–549. 32. Jensen EJ, Schmidt E, Pedersen B, Dahl R: Effect of nicotine, silver acetate and ordinary gum in combination with group counseling on smoking cessation. Thorax 1990;45:831–834. 33. Jorenby DE, Leischow SJ, Nides MA, et al: A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685–691. 34. Jusko WJ: Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev 1979;9:221–236. 35. Kazlowski LT, Wilkinson DA, Skinner W, et al: Comparing tobacco cigarette dependence with other drug dependencies. JAMA 1989; 261:898–901. 36. Kumar R, Cooke EC, Lader MH, Russell MAH: Is nicotine important in tobacco smoking? Clin Pharmacol Ther 1976;21:520–529. 37. Kunkel DB: The toxic emergency: Tobacco and friends. Emerg Med 1985;17:142–158. 38. Lunell E, Molander L, Andersson M: Relative bioavailability of nicotine from a nasal spray in infectious rhinitis and after use of a topical decongestant. Eur J Clin Pharmacol 1995;48:71–75. 39. Lunell E, Molander L, Leischow SJ, Fagerstrom KO: The effect of nicotine vapour inhalation on the relief of tobacco withdrawal symptoms. Eur J Clin Pharmacol 1995;48:235–240. 40. Luntz-Leybman V, Freund RK, Collins AC: 5-alpha-Pregnane-3 alpha-ol-20-one blocks nicotine-induced seizures and enhanced paired-pulse inhibition. Eur J Pharmacol 1990;185:239–242. 41. Malin DH, Lake JR, Carter VA, et al: Naloxone precipitates nicotine abstinence syndrome in the rat. Psychopharmacology 1993;112: 339–342. 42. Malizia E, Andreucci E, Alfani F, et al: Acute intoxication with nicotine alkaloids and cannabinoids in children from ingestion of cigarettes. Hum Toxicol 1983;2:315–316. 43. Marion DJ, Fortmann SP: Nicotine yield and measures of cigarette smoke exposure in a large population. Am J Public Health 1987;77: 546–549. 44. Martin TJ, Suchocki J, May EL, Martin BR: Pharmacological evaluation of the antagonism of nicotine’s central effects by mecamylamine and pempidine. J Pharmacol Exp Ther 1990;251:45–51. 45. Matsushima D, Prevo ME, Gorsline J: Absorption and adverse effects following topical and oral administration of three transdermal nicotine products to dogs. J Pharm Sci 1995;84:365–369. 46. McKnight RH, Levine EJ, Rodgers GC: Detection of green tobacco sickness by a regional poison center. Vet Hum Toxicol 1994;36: 505–510. 47. McNeil Consumer Products Co: Manufacturer’s Product Information. March 1996. 48. Mensch AR, Holden M: Nicotine overdose after a single piece of nicotine gum. Chest 1984;86:801–802. 49. Morse RM, Norvich RC, Graf JA: Tobacco chewing: An unusual case of drug dependence. Mayo Clin Proc 1977;52:358–360. 50. Mulligan SC, Masterson JG, Devane JG, Kelly JG: Clinical and pharmacokinetic properties of a transdermal nicotine patch. Clin Pharmacol Ther 1990;47:331–337. 51. Nicotine patches. Med Lett 1992;34:37–38. 52. Obsert BB, McIntyre RA: Acute nicotine poisoning. Pediatrics 1953; 11:338–340. 53. O’Hara P, Portser SA, Anderson BP: The influence of menstrual cycle changes on the tobacco withdrawal syndrome in women. Addict Behav 1989;14:595–600. 54. Ornish KA, Zisook S, McAdams LA: Effects of transdermal clonidine treatment on withdrawal systems associated with smoking cessation. Arch Intern Med 1988;148:2027–2031. 55. Perez-Stable EJ, Herrera B, Jacob P, et al: Nicotine metabolism and intake in black and white smokers. JAMA 1998;280:152–156. 56. Peters JA: Nicotine-replacement therapy in cessation of smoking. Mayo Clin Proc 1990;65:1619–1623.

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57. Picciotto MR: Common aspects of the action of nicotine and other drugs of abuse. Drug Alcohol Depend 1998;51:165–172. 58. Pickworth WB, Fant RV, Butschky MF, Henningfield JE: Effects of transdermal nicotine delivery on measures of acute nicotine withdrawal. J Pharmacol Exp Ther 1996;279:450–456. 59. Rahal PS, Wright RA: Transdermal nicotine and gastroesophageal reflux. Am J Gastroenterol 1995;90:919–921. 60. Rose JE, Levin ED, Behm FM, et al: Transdermal nicotine facilitates smoking cessation. Clin Pharmacol Ther 1990;47:323–330. 61. Sach DP: Effectiveness of the 4-mg dose of nicotine polacrilex for the initial treatment of high-dependent smokers. Arch Intern Med 1995; 155:1973–1980. 62. Saxena K: Suicide plan by nicotine poisoning: A review of nicotine toxicity. Vet Hum Toxicol 1985;27:495–497. 63. Shiffman SM, Jarvik ME: Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology 1976;50:35–39. 64. Silagy C, Mant D, Fowler G, Lodge M: The effectiveness of nicotine replacement therapies in smoking cessation. Online J Curr Clin Trials 1994; Doc# 113. 65. Singer J, Janz T: Apnea and seizures caused by nicotine ingestion. Pediatr Emerg Care 1990;6:135–137. 66. Smokeless Tobacco. Facts and Comparisons. Lawrence Review of Natural Products, June 1990. 67. Smolinske SC, Spoerke DG, Spiller SK, et al: Cigarette and nicotine chewing gum toxicity in children. Hum Toxicol 1988;7:27–31. 68. Sunder FR, Davis FC, Henninfield JE: The tobacco withdrawal syndrome: Performance decrements assessed on a computerized test battery. Drug Alcohol Depend 1989;23:259–266.

69. Surgeon General’s Report: The health consequences of smoking. Nicotine addition: A report of the Surgeon General. Washington, DC, US Dept. of Health and Human Services, 1988. 70. Sutherland G, Stapleton JA, Russell MAH, et al: Randomized controlled trial of nasal nicotine spray in smoking cessation. Lancet 1992; 340:324–329. 71. Tonnesen P, Fryd V, Hansen M, et al: Effect of nicotine chewing gum in combination with group counseling on the cessation of smoking. N Engl J Med 1988;318:15–18. 72. Tonnesen P, Fryd V, Hansen M, et al: Two and four milligram nicotine chewing gum and group counseling in smoking cessation. Addict Behav 1988;13:17–27. 73. Tonnesen P, Norregaard J, Mikkelsen K, et al: A double-blind trial of a nicotine inhaler for smoking cessation. JAMA 1993;269: 1268–1271. 74. Tonnesen P, Norregaard J, Simonsen K, Sawe U: A double-blind trial of a 16-hour transdermal nicotine patch in smoking cessation. N Engl J Med 1991;325:311–315. 75. Transdermal Nicotine Study Group: Transdermal nicotine for smoking cessation. JAMA 1991;266:3133–3138. 76. West R, Schneider N: Drop in heart rate following smoking cessation may be permanent. Psychopharmacology 1988;94:566–568. 77. Woolf A, Burkhart K, Caraccio T, Litovitz T: Childhood poisoning involving transdermal nicotine patches. Pediatrics (electronic pages) 1997;99:724(e4). 78. Woolf A, Burkhart K, Caraccio T, Litovitz T: Self-poisoning among adults using multiple transdermal nicotine patches. J Toxicol Clin Toxicol 1996;34:691–698.

E. FOOD POISONING

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FOOD POISONING Michael G. Tunik / Lewis R. Goldfrank

Cases 1 and 2. A 30-year-old woman and her 32-year-old husband, on a scuba diving vacation in Puerto Rico, had a local dinner of rice, beans, a large red snapper, home-canned fruit preserves, and wine. That night, approximately 5 hours after dinner, abdominal discomfort and nausea, followed by vomiting and diarrhea, awakened them both. Although they were unsure of the order of events, a throbbing headache, rapid breathing, numbness of the arms, legs, and mouth ensued. Each patient described a feeling of bone and tooth pain with “deep aches in the joints.” The woman stated that when she reached for a warm washcloth to rub on her “freezing skin,” it seemed to her that the warm washcloth felt cold. This distressing symptom of temperature misinterpretation lasted for 2 days. The vomiting abated during the early morning hours, but the nausea and diarrhea continued for several days. Mild, crampy, abdominal pain persisted for approximately 4 days. The following morning, the couple spoke to some of the local inhabitants. Many of them described similar symptoms that would appear after they ate a large fish, such as sea bass, red snapper, grouper, or barracuda. As so many people had the same symptoms, the couple did not seek medical help. On their return to the mainland 10 days later, there were no clinical or physical complaints, thus, they did not seek medical care.

The most common causes of foodborne disease are bacteria— Salmonella spp., Shigella spp., Clostridium perfringens, Staphylococcus aureus, Campylobacter spp., Bacillus cereus, Escherichia coli, group A Streptococcus, Clostridium botulinum, Vibrio cholera; viruses—hepatitis A, E, F, and G, Norwalk virus; parasites—Entamoeba histolytica, Giardia lamblia, Trichinella spiralis; fishborne toxins—scombrotoxin, ciguatoxin, paralytic shellfish; chemicals—heavy metals, monosodium glutamate; and plants—mushrooms108 (Table 74–1).

ity from Tetraodontiformes (puffer fish), Gymnothoraces (moray eels), newts (Taricha and other species) have been recognized. Deep-sea fish, eels, mussels, clams, and crabs are all implicated in diarrheal syndromes. In cases of ciguatera poisoning, the major symptoms are usually neurotoxic and the gastrointestinal (GI) symptoms are minor. Scombroid poisoning, which is exceptionally common, is not associated with neurologic manifestations, but facial flushing, headache, and dysphagia are its major signs and symptoms. Knowing where the fish was caught is often helpful, but refrigerated transport of foods and rapid worldwide travel can complicate the assessment. Scombroid fish poisoning has occurred in the midwestern United States from frozen mahi mahi shipped there.105 Travelers to Caribbean and Pacific islands, as well as individuals traveling within the United States, have suffered from ciguatera poisoning.83 In geographically disparate regions of Canada,116 individuals suffered from domoic acid intoxication caused by the ingestion of cultivated mussels from Prince Edward Island. In the differential diagnosis of foodborne poisons presenting with neurologic symptoms, activities other than eating must always be considered. In particular, sport divers often perform their activities in high-risk areas (Florida, California, and Hawaii), and often during the high-risk periods (May through August), and in the process may sustain an unrecognized bite, sting (from a stingray tail), or laceration (from a deltoid or pectoral fin spine of a lion fish or stonefish) that can cause consequential marine toxicity (Chap. 103).

Ciguatera Poisoning Ciguatera poisoning is one of the most commonly reported vertebrate fishborne poisonings, accounting for almost half of the reported cases in the United States.108 It is endemic to warm-water, bottom-dwelling shore reef fish living around the globe between 35 degrees north and 35 degrees south latitude, including tropical areas such as the Indian Ocean, the South Pacific, and the Caribbean. Hawaii and Florida report 90% of all cases in the United States, most commonly during the spring and summer months, May through August.57 There are more than 500 fish species involved, with the barracuda, sea bass, parrot fish, red snapper, grouper, amber jack, kingfish, and sturgeon the most common sources. The common factor is the comparably large size of the fish involved. Large fish (4–6 lb. or more) become vectors of ciguatera poisoning in accordance with complex feeding patterns inherent in aquatic life. Ciguatoxin can be found in blue-green algae, proto-

FOODBORNE POISONING WITH NEUROLOGIC SYMPTOMS The differential diagnosis of foodborne poisoning presenting with neurologic symptoms is vast (Tables 74–2 and 74–3). Many of these cases are ichthyosarcotoxic (involving toxins from the muscles, viscera, skin, gonads, and mucous surfaces of the fish); rarely, toxicity follows consumption of the fish blood or skeleton. Shellfish poisoning must also be considered. Most episodes of poisoning are not species specific, although particular forms of toxic-

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TABLE 74–1. Epidemiology108 of Foodborne Poisoning Reported to the CDC (1993–1997) Etiology

Cases

Outbreaks

Deaths

Salmonella Escherichia coli a Clostridium perfringens Other parasitic Other viral Shigella Staphylococcus aureus Norwalk virus Hepatitis A virus Bacillus cereus Other bacterial Campylobacter Scombrotoxin Ciguatoxin Streptococcus, group A Listeria monocytogenes Clostridium botulinum Giardia lamblia Vibrio parahaemolyticus Other chemical Yersinia enterocolitica Mushroom poisoning Brucella Trichinella spiralis Heavy metals Streptococcus, other Shellfish Vibrio cholerae Monosodium glutamate

32,610 3,260 2,772 2,261 2,104 1,555 1,413 1,233 729 691 609 539 297 205 122 100 56 45 40 31 27 21 19 19 17 6 3 2 2

357 84 57 13 24 43 42 9 23 14 6 25 69 60 1 3 13 4 5 6 2 7 1 2 4 1 1 1 1

13 8 0 0 0 0 1 0 0 0 1 1 0 0 0 2 1 0 0 0 1 0 0 0 0 0 0 0 0

a

The fatality rate of E. coli 0157:H7 increased dramatically in the late 1990s.

zoa, and the free algae dinoflagellates. These plankton members of the phylum Protozoa are single-celled, motile, flagellated, pigmented organisms thriving through photosynthesis. Photosynthetic dinoflagellates such as Gambierdiscus toxicus and bacteria within the dinoflagellate are the origins of ciguatoxin.36,64,91 These dinoflagellates are the main nutritional source for small herbivorous fish; as these small fish are the major food source for larger car-

TABLE 74–2. Differential Diagnosis of Possible Foodborne Poisoning Presenting with Neurologic Symptoms Myasthenia gravis Botulism MSG (monosodium glutamate) Poliomyelitis Encephalitis Tick paralysis Carbon monoxide Organic phosphorous compounds Anticholinergic poisoning Heavy metals Diphtheria Eaton-Lambert syndrome Bacterial food poisoning Plant ingestions (poison hemlock, Buckthorn) Migraine Bends type I, II, III (caisson disease)

nivorous fish, the ciguatoxin becomes increasingly concentrated in the flesh, adipose tissue, and viscera of larger and larger fish.13 Ciguatoxin is heat-stable, lipid-soluble, acid-stable, odorless, and tasteless. When purified, the toxin is a large (MW 1100 Da), complex ester that does not harm the fish but is stored in tissues.90,121 The molecule binds to the sodium channel in diverse tissues and increases the sodium permeability of the channel.12,122,149 Multiple ciguatoxins are identified in the same fish, perhaps explaining the variability of symptoms and differing severity.91 People can be afflicted after eating fresh or properly frozen fish prepared by all common methods: boiling, baking, frying, stewing, or broiling. The appearance, taste, and smell of the ciguatoxic fish are usually unremarkable. The majority of symptomatic episodes begin 2–6 hours after ingestion, 75% within 12 hours, and all but 4% within 24 hours.13 Symptoms include acute onset of diaphoresis; abdominal pain with cramps, nausea, vomiting, a profuse watery diarrhea; and a constellation of dramatic neurologic symptoms.166 Headaches are common. A sensation of loose, painful teeth may occur. Typically, dysesthesias and paresthesias predominate. Watery eyes, tingling, and numbness of the tongue, lips, throat, and perioral also occur. A strange metallic taste is frequently reported. A reversal of temperature discrimination is reported, but the pathophysiology remains to be elucidated.27 Myalgias, most often in the lower extremities, arthralgias, ataxia, and weakness are commonly experienced.13 Dysuria50 and symptoms of dyspareunia and vaginal and pelvic discomfort may occur in women after sexual intercourse with men who are ciguatoxic.82 Ciguatoxin may also be transmitted in breast milk,22 and can cross the placenta.114 Vertigo, seizures, and visual disturbances (eg, blurred vision, manifestations of scotomata, and transient blindness) are also described. Bradycardia and orthostatic hypotension are also described.45 The GI symptoms usually subside within 24–48 hours; however, cardiovascular and neurologic symptoms may persist for several days to weeks, depending on the amount of toxin ingested. Delayed symptoms may include protracted itching and hiccoughs. Although deaths are reported, none has yet been documented in the United States.108 Mortality is a result of respiratory paralysis and seizures apparently managed without adequate life support. Laboratory analysis using an ELISA (enzyme-linked immunosorbent assay) test for ciguatera toxin can be performed; alternatively, HPLC (high-pressure liquid chromatograph) is accurate. The original mouse bioassay was the standard, but was slow, involved the destruction of animals, and did not differentiate the variants in ciguatoxin structure. A rapid test is under development for field use, a dipstick immunobead assay, that will allow testing of fish without laboratory processing of the toxin-containing tissues.12,62,113 A useful approach to diagnosis and management using laboratory testing is to exclude other diagnostic possibilities and determine the need for, or extent of, specific therapeutic interventions. Initial treatment for victims of ciguatoxin poisoning include standard supportive care for a toxic ingestion.84,166 In most patients, elimination of the toxin is accelerated if vomiting (40%) and diarrhea (70%) have occurred. Unless the patient develops symptoms and seeks medical care within 2 hours of the meal, syrup of ipecac is probably without benefit. There may be some benefit from the administration of activated charcoal and a cathartic. A cathartic (sorbitol, magnesium sulfate, or magnesium citrate) should be given only to patients who do not have diarrhea. In

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TABLE 74–3.

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Common Foodborne Neurologic Diseases (Primary Presenting Symptoms) Onset/Duration*

Symptoms

Ciguatera

2–30 h *Months to years

Tetrodotoxin

Minutes to hours *Days

p, r, ↓bp n, v, d

Neurotoxic shellfish poisoning

15 minutes to 18 hours *Days 30 minutes *Days

b, t, n, v, d, p

15 minutes to 38 hours *Years 12–73 h

a n, v, d, p,r

Paralytic shellfish poisoning

Amnestic shellfish poisoning Botulism

FOOD POISONING

t,p n, v, d

r, p, n, v, d

r

Toxin Source/Toxin*/Mechanism•

Diagnosis/Therapy*

Large reef fish: barracuda, snapper, parrot, sea bass, moray (dinoflagellate, source) *Ciguatoxin • Increased sodium channel permeability Puffer fish, fugu, blue-ringed octopus, newts, horseshoe crab *Tetrodotoxin • Blocks sodium channel Mussels, clams, scallops, oysters, P. brevis: “red tide” *Brevitoxin • ↑ Sodium channel permeability Mussels, clams, scallops, oysters, P. catanella, P. tamarensis *Saxitoxin • Decreases sodium channel permeability Mussels, possibly other shellfish; N. pungens; *Domoic acid • Glutamate analog Home canned foods, ? honey, corn syrups, C. botulinum *Botulinum toxin; • Binds to presynapse, blocks acetylcholine release

Clinical, mouse bioassay, immunoassay *Supportive, mannitol

*Respiratory support

Clinical, mouse bioassay of food, HPLC

Clinical, mouse bioassay of food, HPLC *Respiratory support

Clinical, mouse bioassay of food, HPLC *Respiratory support Immunoassay *Antitoxin, respiratory support

n = nausea; v = vomiting; d = diarrhea; p = paresthesias; r = respiratory depression; b = bronchospasm, t = temperature reversal sensation; a = amnesia, ↓bp = hypotension.

patients with significant GI fluid loss through vomiting and/or diarrhea, intravenous fluid and electrolyte repletion is essential. The orthostatic hypotension may respond to intravenous fluids, atropine, and sympathomimetic agents. The use of IV mannitol may produce a marked decrease in neurologic and muscular dysfunctional symptoms associated with ciguatera. Gastrointestinal symptoms are less responsive to mannitol.112,115 Mannitol should be used with caution, as it may cause hypotension. Vascular reexpansion and cardiovascular stability should be initial treatment priorities. A dose of 1 g/kg of mannitol over 30–45 minutes appears efficacious. Additional controlled clinical studies with mannitol are needed to define its mechanism(s) of action and therapeutic indications. Admission to the hospital for cautious supportive care is essential when the diagnosis is uncertain, or when volume depletion, or any consequential manifestations are present. The differential diagnosis includes botulism, organic phosphorus compound poisoning, and other potentially life-threatening processes (Tables 74–2 and 74–3). The etiology of the symptoms must be rapidly identified to provide specific therapy, if available. Diaphoresis is a common clinical finding and an important factor in the differential diagnosis. Late in the course of ciguatera poisoning amitriptyline at 25 mg orally twice daily may alleviate symptoms.23

Ciguateralike Poisoning Moray, conger, and anguillid eels carry a ciguatoxinlike neurotoxin in their viscera, muscles, and gonads that does not affect the eel itself. The toxin has a complex ester structure that may be structurally very similar to ciguatoxin, and which is thermostable.107 These same eels also possess an ichthyohemotoxin that is resistant to drying but can be destroyed by heating to greater than 65°C (149°F). Individuals who eat these eels may

manifest neurotoxic symptomatology similar to that which occurs with ciguatoxin, or they may show signs of cholinergic toxicity, such as hypersalivation, nausea, vomiting, and diarrhea. Shortness of breath, mucosal erythema, and cutaneous eruptions may also occur. These findings may be present along with the neurotoxic symptoms.58 Management is supportive. Mortality is related to the complications of neurotoxicity, such as seizures and respiratory paralysis.

Scombroid Poisoning Scombroid poisoning was originally described with the Scombroidae fish (including the large dark meat marine tuna, albacore, bonito, mackerel, and skipjack). However, the most commonly ingested vectors identified by the Centers for Disease Control and Prevention are nonscombroid fish, such as mahi mahi and amber jack.108 All of the implicated fish species live in temperate or tropical waters, particularly around California or Hawaii. The ingestion of bluefish in New Hampshire was the probable cause of scombroid poisoning in 5 people,37 and mackerel the likely offender in 28 cases in a prison. The incidence of this disease is probably far greater than was originally perceived. This type of poisoning differs from other fishborne causes of illness in that it is entirely preventable if the fish is properly stored after it is removed from the water. Scombroid poisoning results from eating cooked, smoked, canned, or raw fish. These fish all have a high concentration of histidine in their dark meat. Morganella morganii, E. coli, and Klebsiella pneumoniae, commonly found on the surface of the fish, contain a histidine decarboxylase enzyme that acts on a warm (not refrigerated), freshly killed fish to convert histidine to histamine, saurine, and other heat-stable substances. Saurine has been suggested as the causative toxin of scombroid poisoning. Chro-

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matographic analysis demonstrates that histamine is found as histamine phosphate and saurine is merely histamine hydrochloride.41,103 The term saurine originated from saury, a Japanese dried fish delicacy often associated with scombroid intoxication. The extent of spoilage usually correlates with histamine levels. Histamine levels in healthy fish are less than 0.1 mg/100 g of fish; left at room temperature this level rapidly increases, reaching toxic levels of 100 mg/100 g fish within 12 hours. The appearance, taste, and smell of the fish is usually unremarkable.8 Rarely, the skin has an abnormal “honeycombing” character, or a pungent, peppery taste that may be a clue to its toxicity (Chap. 28). Usually, within minutes to hours after eating the fish, the individual experiences numbness, tingling, or a burning sensation of the mouth, dysphagia, headache, and, of particular significance for scombroid poisoning, a peculiar flush characterized by an intense diffuse erythema of the face, neck, and upper torso.73 Rarely, pruritus, urticaria, angioedema, or bronchospasm ensues. Nausea, vomiting, dizziness, palpitations, abdominal pain, diarrhea, and prostration may develop.49,73,78,97 The prognosis is good with appropriate supportive care and parenteral antihistamines such as diphenhydramine and any of the H2-receptor antagonists such as ranitidine.20 The toxic substance should be removed or absorbed from the gut. Inhaled
2-adrenergic agonists and epinephrine may be necessary if bronchospasm is prominent. Patients usually show significant improvement within a few hours. Elevated serum or urine histamine levels confirm the diagnosis. If any uncooked fish remains, the isolation of causative bacteria from the flesh is suggestive but not diagnostic. A capillary electrophoretic assay makes rapid histamine detection possible.101 Levels of histamine greater than 50 mg/100 g of fish are considered hazardous by the FDA. Isoniazid may increase the severity of the reaction to scombroid fish by inhibiting enzymes that break down histamine.66,161 The patient may be reassured that he or she is not allergic to fish if other individuals experience a similar reaction to eating the same fish at the same time, or if any remaining fish can be preserved and tested for elevated levels of histamine. If this information is not available, an anaphylactic reaction to the fish must be

TABLE 74–4.

considered. Table 74–4 lists the differential diagnosis of flushing, bronchospasm, and headache. Because many people often consume alcohol with fish, alcohol must be considered as an independent variable. The differential diagnosis of the scombrotoxic flush apart from, a disulfiram like reaction, includes ingestion of niacin or nicotinic acid, carcinoid syndrome, Zollinger-Ellison syndrome, and pheochromocytoma. The history and clinical evolution usually establish the diagnosis quickly.

Shellfish Poisoning Healthy mollusks living between 30 degrees north and 30 degrees south latitude ingest and filter large quantities of dinoflagellates. These dinoflagellates form the major source of available ocean food during the “non-R” months (May through August). During this time, these dinoflagellates are responsible for the “red tides” that may be seen from California to Alaska, from New England to St. Lawrence, and across the west coast of Europe.95 The number of toxic dinoflagellates may be so overwhelming that birds and fish die, and humans who walk along the beach may suffer respiratory symptoms caused by aerosolized toxin.96 Ingestion of shellfish, including oysters, clams, mussels, and scallops, contaminated by dinoflagellates or algae may cause neurotoxic, paralytic, and amnestic symptoms. The dinoflagellates most frequently implicated are Ptychodiscus brevis (formerly Gymnodinium breve), the diatom causing neurotoxic shellfish poisoning; Protogonyaulax catanella, and P. tamarensis, which cause paralytic shellfish poisoning; and Nitzschia pungens, the diatom implicated in amnestic shellfish poisoning. Proliferation of P. brevis may cause a red tide, but shellfish poisoning may occur even in the absence of this extreme proliferation. Paralytic shellfish poisoning (PSP) is caused by saxitoxin. Saxitoxin blocks the voltage-sensitive sodium channel in a manner identical to tetrodotoxin (see below). The shellfish implicated are usually clams, oysters, mussels, and scallops. An increased number of shellfish consumed is associated with more severe symptoms. Symptoms usually occur within 30 minutes of ingestion. Neurologic symptoms predominate and include paresthesias and

Common Foodborne Disease Symptoms: Flushing, Bronchospasm, Headache (Primary Presenting Symptoms) Onset

Symptoms/Signs

Cause

Therapy

Anaphylaxis (anaphylactoid)

Minutes to hours

Urticaria, angioedema, bronchospasm, hypotension

Allergens—nuts, eggs, milk, fish, shellfish, peanuts, soy

MSG (mono sodium glutamate)

10–20 min

Monosodium glutamate flavor enhancer, in Chinese and other fast food

Metabisulfites

Minutes

Flushing, ↓ BP, palpitations, facial pressure, headaches, bronchospasm Shivering (children) Flushing, low BP, bronchospasm

Oxygen, epinephrine, Beta-2 adrenergic agonist, Corticosteroids, volume expansion, H-1 & H-2 histamine blockers Oxygen,
-2 adrenergic agonists, volume expansion, avoidance

Scombroid

Minutes to hours

Flushing, low BP, urticaria, headache, pruritis, GI symptoms

Tyramine

Minutes to hours

Tartrazine

1–2 h

Headache, hypertension (INH increases risk) Urticaria, angioedema, bronchospasm

INH=isoniazid.

Preservative used in: wines, salad (bars), fruit, juice, shrimp Large fish—poorly refrigerated; tuna, bonito, albacore, mackerel, mahi mahi (histidine) Wines, aged cheeses Yellow coloring Food additive

See Anaphylaxis, Avoidance See Anaphylaxis, Avoidance

Avoidance As for hypertension, migraines See Anaphylaxis, Avoidance

CHAPTER 74

numbness of the mouth and extremities, a sensation of floating, headache, ataxia, vertigo, muscle weakness, paralysis, and cranial nerve dysfunction manifested by dysphagia, dysarthria, dysphonia, and transient blindness. Gastrointestinal symptoms are less common and include nausea, vomiting, abdominal pain, and diarrhea. Fatalities may occur due to respiratory failure, usually within the first 12 hours after symptom onset. Muscle weakness may persist for weeks. Treatment is supportive, but with early intervention for respiratory failure. Orogastric lavage and cathartics have been used to remove unabsorbed toxin from the GI tract.35,65,88,102,129 Antibodies against saxitoxin have reversed cardiorespiratory failure in animals,15 but this therapy has yet to be used in humans. Assays for saxitoxin include a mouse bioassay, ELISA, and HPLC. HPLC has good interlaboratory accuracy,163 but the differences in saxitoxin derivatives makes standardization of an analytic test difficult.12,85 Neurotoxic shellfish poisoning (NSP), is caused by brevetoxin. Brevetoxin, produced by P. brevis, is a lipid-soluble, heat-stable polyether toxin similar to ciguatoxin. It acts by stimulating sodium flux through the sodium channels of both nerve and muscle.9,28 NSP is characterized by gastroenteritis with associated neurologic symptoms. Gastrointestinal symptoms include abdominal pain, nausea, vomiting, diarrhea, and rectal burning. Neurologic features include paresthesias, reversal of hot and cold temperature sensation, myalgias, vertigo, and ataxia. Other symptoms may include headache, malaise, tremor, dysphagia, bradycardia, decreased reflexes, and dilated pupils. Paralysis is not seen. The combination of bradycardia and mydriasis is unusual, but is also commonly seen with phenylpropanolamine toxicity. The incubation period is 3 hours (range, 15 minutes to 18 hours). The GI and neurologic symptoms appear simultaneously. Other manifestations of brevetoxin toxicity include respiratory irritation, cough, and bronchospasm, which occur when P. brevis is aerosolized by wave action during red tides. Duration of symptoms is on average 17 hours (range, 1–72 hours).102 Brevetoxins can be assayed using mouse bioassay or ELISA, and, more recently, by antibody radioimmunoassay (RIA) and reconstituted sodium channels.118,158 Treatment is supportive and severe respiratory depression is very uncommon. Therapy includes removal of the patient from the environment and the administration of bronchodilators. NSP is not fatal. Amnestic shellfish poisoning (ASP) is caused by domoic acid. The etiologic agent is domoic acid, a structural analogue of glutamic and kainic acids produced by the diatom Nitzschia pungens. The only documented outbreak occurred in Canada in 1987 and affected 107 individuals who had consumed mussels harvested from cultivated river estuaries on Prince Edward Island.116 The possibility for other outbreaks exists, because the diatom Pseu donitzschia australis has been isolated in shellfish from other areas.44 Pelican deaths caused by domoic acid-laden anchovies were reported in 1991. Canada instituted monitoring for domoic acid after this outbreak.155 The death of 400 sea lions in California in 1998 was linked to domoic acid from the diatom N. pungens f multiseries.135 ASP is characterized by GI symptoms of nausea, vomiting, abdominal cramps, and diarrhea, and by neurologic symptoms of memory loss and, less frequently, coma, seizures, hemiparesis, ophthalmoplegia, purposeless chewing, and grimacing. Other symptoms include unstable blood pressure and cardiac dysrhythmias. The onset of symptoms after ingestion of mussels is 5 hours

FOOD POISONING

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(range, 15 minutes to 38 hours). The mortality rate is 2%, with death most frequently occurring in older patients, who suffer more severe neurologic symptoms. Ten percent of victims may suffer long-term antegrade memory deficits, as well as motor and sensory neuropathy. Postmortem examination has revealed neuronal damage in the hippocampus and amygdala.154

Tetrodon Poisoning This type of fish poisoning involves only the order Tetraodontiformes. Although this order of fish is not restricted geographically, it is eaten most frequently in Japan, California, Africa, South America, and Australia.58 Approximately 100 fresh- and saltwater species of this order fish exist, including a number of pufferlike fish such as the globe fish, balloon fish, blowfish, and toad fish.104 Tetrodotoxin found in these fish is also isolated from the blue-ringed octopus40 and the gastropod mullusc,169 and has caused fatalities from ingestion of horseshoe crab eggs.68 In Japan, a local variety of puffer fish, fugu, is considered a delicacy, but special licensing is required to prepare this exceedingly toxic fish. In 1989, the Food and Drug Administration legalized the importation of puffer fish, but prior to exportation from Japan, the fish must be laboratory tested and certified by two Japanese organizations to be tetrodotoxin-free. In addition, certain tetrodotoxin-containing newts (Taricha, notophthalmus, triturus, and cynops), in particular the Taricha granulosa, found in Oregon, California, and southern Alaska, can be fatal when ingested. Most newts and salamanders with bright colors and rough skins contain toxins.24 Tetrodotoxin is a heat-stable (except in alkaline milieu), watersoluble, nonprotein, aminoperhydroquanizole found mainly in the fish skin, liver, ovary, intestine, and, possibly, muscle.58,132 The ovary has a high concentration of the toxin, and is most poisonous if eaten during the spawning season. Tetrodotoxin is detected by mouse bioassay. It is unstable when heated to 100°C (212°F) in acid, distinguishing it from saxitoxin. Tetrodotoxin may be detected using fluorescent spectrometry,11 or detected in the urine of intoxicated patients using a combination of immunoaffinity chromatography with fluorometric high-performance liquid chromatography.71 Neurotoxicity is produced by inhibition of sodiumpotassium pump activity and blockade of neuromuscular transmission.106 Symptoms of tetrodon poisoning typically occur within minutes of ingestion. Headache, diaphoresis, dysesthesias, and paresthesias of the lips, tongue, mouth, face, fingers, and toes evolve rapidly. Buccal bullae and salivation may develop. Dysphagia, dysarthria, nausea, vomiting, and abdominal pain may ensue. Generalized malaise, loss of coordination, weakness, fasciculations, and an ascending paralysis (with risk of respiratory paralysis) occur in 4–24 hours. Other cranial nerves may be involved. In more severe toxicity, hypotension is present. In some studies, mortality has approached 50%.141 Therapy is supportive. Removal of the toxin and prevention of absorption are the essential measures. Supportive respiratory care emphasizing airway protection, including intubation, if necessary, is extremely important.

Less Common Poisonings: Echinoderms The sea urchin usually causes toxicity by contact with its spinous processes, but this Caribbean delicacy is also toxic on ingestion. In preparing it as food, the venom-containing gonads should be removed, as they contain an acetylcholinelike substance that causes

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profuse salivation, abdominal pain, nausea, vomiting, and diarrhea. The starfish is also considered by some to be edible, although there are reports of an asteriotoxin with saponinlike activity that produces nausea and vomiting.

Other Types of Shellfish Poisoning Oyster poisoning can be caused by a highly toxic venerupin extracted from dinoflagellates. Oyster poisoning has a high fatality rate and is localized to Japan. Callistin poisoning is caused by choline- or histaminelike substances, which generate an acute allergic reaction, and is localized to Japan. Adalone poisoning is caused by a photosensitizer that is extracted from Japanese seaweed. Red whelk poisoning is precipitated by a tetramine that produces curarelike symptoms and is reported in Japan.

PREVENTION OF MARINE FOODBORNE DISEASE Careful evaluation of the symptoms and meticulous reporting to local and state health departments, as well as to the Centers for Disease Control and Prevention (CDC), will allow for more precise analysis of epidemics of poisoning from contaminated or poisonous food or fish. Many states and countries have developed rigorous health codes with regard to harvesting certain species of fish in certain areas at certain times. A review of foodborne intoxications reported to the CDC over a 5-year period may be representative of the number and severity of food poisoning in the United States (Table 74–1). Some examples of actions taken by state and foreign health agencies in controlling epidemics of fishborne food poisoning are: • In 1972, the 3230-km Massachusetts coastline was noted to be unsafe for shellfish harvesting. A health emergency was declared because of a blooming of red tide. The state confiscated shellfish and prohibited the marketing, export, and serving of shellfish.95 • The Miami, Florida health code prohibits the sale of barracuda and warns against eating fillets from large and potentially toxic fish containing ciguatoxin. • The Japanese closely regulate preparation and selling of the puffer fish (“fugu”), requiring special training and licensing of preparers. • The Canadian government marks the location and time of harvesting of mussels, and mussels are tested for the presence of domoic acid.44,116

OTHER FORMS OF FISHBORNE POISONING Filefish forms the toxin aluterin, which produces vomiting and diarrhea. Herring, sprat, sardines, and tarpon may contain clupeotoxin, which causes GI and neurologic symptoms. Ratfish, elephantfish, or chimeras may cause rapid central nervous system depression. Lampreys and hagfish may cause cyclostome poisoning with GI complications. Snek, mackerel, and castor-oil fish may cause gemblid poisoning, which is characterized by dramatic purgation. Mullet, goatfish, and rudderfish may cause hallucina-

tions. Sawara (mackerel) and ishingh (sea bass), two Japanese fish, and sandfish can cause hypervitaminosis A. Case 3. A 4-year-old child presented to the Emergency Department with a history of diarrhea, vomiting, and intermittent abdominal pain for 1 week. The family became concerned when blood and mucus appeared in the stool after 4 days. At that time blood tests and stool cultures were obtained at another hospital. Antipyretics were prescribed for fever and instructions regarding hydration were given. No antibiotics or other therapy were offered, and the child’s diarrhea and other symptoms began to resolve. The parents again became concerned when they noticed the child appeared pale, more irritable than usual, had a decreased urine output, and was uninterested in eating at a favorite fast food restaurant. The child was brought to the Emergency Department (ED) for evaluation after a brief generalized seizure. The child was otherwise healthy with no significant medical history, other medication use, or ingestions. The child was attending preschool. Physical examination revealed an afebrile child with normal respirations, blood pressure 125/80 mm Hg, and heart rate 150 beats/min. The child appeared pale and irritable. The remainder of the physical examination was significant for a systolic flow murmur on cardiac auscultation, mild abdominal pain without rebound or guarding, and a liver edge palpable to 3 cm below the right costal margin. No meningeal signs were evident, and the neurologic examination was nonfocal. Laboratory studies were significant for a white blood count of 22,000/mm3 and a hematocrit of 25%; platelet count of 80,000/mm3. A peripheral blood smear revealed many schistocytes and helmet cells. Serum sodium was 128 mEq/L; potassium was 5.9 mEq/L; blood urea nitrogen (BUN) was 40 mg/dL; creatinine was 2.2 mg/dL; and alanine aminotransferase (ALT) was 180 U/L. Coagulation studies and cerebrospinal fluid (CSF) analysis were normal.

FOODBORNE POISONING ASSOCIATED WITH GASTROENTERITIS, ANEMIA, THROMBOCYTOPENIA, AND AZOTEMIA This constellation of findings is typical for the hemolytic uremic syndrome (HUS), which is frequently caused by a bacterial gastroenteritis. The most common organism responsible is E. coli O157:H7. Other bacteria producing a Shigalike toxin can also cause the same findings. Other agents and toxins also implicated as causes of HUS include estrogen-containing oral contraceptives, mitomycin-C, cyclosporin-A, and radiation therapy.117 Other nontoxicologic causes of this clinical picture include autoimmune disease, Kawasaki syndrome, eclampsia of pregnancy, and bacterial enteritis/sepsis leading to disseminated intravascular coagulopathy (DIC) and shock. Laboratory findings typically include a microangiopathic hemolytic anemia, thrombocytopenia, and acute intrinsic renal failure. Other laboratory findings include hyperkalemia, metabolic acidosis, hyponatremia, and hypocalcemia. Liver aminotransferases may be elevated, and pancreatic involvement may produce hyperamylasemia, elevated pancreatic lipase, and hyperglycemia. Most children with hemolytic uremic syndrome are younger than 6 years of age; many are younger than 2 years of age. HUS begins with a prodrome of diarrhea 90% of the time. The diarrhea

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lasts for 3–4 days and frequently becomes bloody. Abdominal pain because of colitis is also common. Other frequent findings include vomiting, altered mental status (irritability or lethargy), pallor, and low-grade fever. At the time of presentation, many children have oliguria or anuria. About 10% of children will present with a generalized seizure at the onset of HUS.140 Postdiarrheal HUS is endemic in Argentina.92 Frequent epidemics occur in North America, and many of these reports describe the association of enterohemorrhagic E. coli (EHEC) or E. coli O157:H7 with postdiarrheal HUS.25,94,109,111,124,165 Postdiarrheal HUS is seen most frequently during the summer months, matching the peak incidence of positive stool cultures in cattle (the most common source of the organism).59 Food products from cattle (ground beef, milk, yogurt, cheese) and water contaminated with fecal material are the common sources.33,55,148 Contaminated water used in gardens and unpasteurized apple cider have also caused bloody diarrhea and HUS caused by EHEC.17,30 EHEC, including E. coli O157:H7, produces a toxin similar to the toxin produced by Shigella dysenteriae type I, referred to as Shigalike toxin (SLT) or verotoxin.43,123 The proposed mechanism for SLT damage is intestinal absorption, bloodstream access to renal glomerular endothelium, intracellular adsorption via glycolipid receptors, ribosomal inactivation, and cell death.111 In animal models, organ damage is more severe if endothelial cells have high concentrations of globotriaosylceramide receptors. This may explain the propensity for renal, gastrointestinal, and central nervous system involvement in children. Endothelial cell damage and other pathologic processes, including platelet and leukocyte activation, triggering of the coagulation cascade, as well as the production of cytokines, also occur.70,162 More than one type of SLT exists; SLT-1, SLT-2 as well as variants on SLT-2 structure have been identified.18 Detection of E. coli O157:H7 through stool culture early in the course of disease is useful. The recovery decreases after the first week of illness.117,151 E. coli O157:H7 almost always produces SLT; therefore, if stool cultures are negative, enzyme immunoassay (EIA) and polymerase chain reaction tests should be used to detect SLT in the stool.26 Treatment of HUS should focus on meticulous supportive care, with fluid and electrolyte balance being a priority. Peritoneal dialysis or hemodialysis should be instituted early for azotemia and for hyperkalemia, acidosis, or fluid overload. Red blood cells are transfused to maintain hemoglobin levels above 6 g/dL, and platelets to maintain hemostasis, especially before invasive procedures. Hypertension may be treated with short-acting calcium channel blockers (nifedipine 0.25–0.5 mg/kg/dose orally), and seizures with benzodiazepines. Many therapies have been used for HUS, including heparin, fibrinolytics, IV immunoglobulin, freshfrozen plasma, vitamin E, and antiplatelet agents. None has been obviously beneficial and some have been deleterious.137 Plasmapheresis has been used in nondiarrheal HUS and in recurrent HUS after renal transplants. In a controlled trial, antibiotics did not change the course or outcome of children with postdiarrheal HUS.120 Anti-SLT-2 antibodies have protected mice from SLT-2 toxicity, but intravenous immunoglobulin with SLT-2 activity has not improved outcome in children with HUS. A phase 1 study of the feasibility of using synthetic SLT receptors attached to a chromosorb to prevent HUS is being performed.7,157 The mortality from HUS with good supportive care is approximately 5%; another 5% of victims suffer end-stage renal disease

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or cerebral ischemic events and chronic neurologic impairment. Prolonged anuria (more than 1 week) or oliguria (more than 2 weeks) or severe extrarenal disease may serve as markers for higher mortality and morbidity.117 Strategies to prevent the spread of E. coli O157:H7 and subsequent HUS include public education regarding thorough cooking of beef to achieve a well-done presentation, pasteurization of milk and apple cider, and thorough cleaning of vegetables. Public health measures include education of clinicians to consider E. coli O157:H7 in patients with bloody diarrhea, and routine capability of microbiology laboratories to culture E. coli O157:H7 and provide for EIA or PCR determination of SLT. Public health departments should provide active surveillance systems to identify early outbreaks of E. coli O157:H7 infection.

FOODBORNE POISONING ASSOCIATED WITH DIARRHEA AND AN ELEVATED TEMPERATURE The initial differential diagnosis for acute diarrhea involves several etiologies: infectious (bacterial, viral, parasitic, and fungal), structural (including surgical), metabolic, functional, toxininduced, and food-induced. The differential diagnosis is described in greater detail in Chap. 22. An elevated temperature may be caused by invasive organisms, including Salmonella spp., Shigella spp., Campylobacter spp., invasive E. coli, Vibrio parahaemolyticus, and Yersinia spp., as well as some viruses. Episodes of acute gastroenteritis not associated with fever are usually caused by organisms producing toxins, including S. aureus, B. cereus, C. perfringens, enterotoxigenic E. coli, and viruses.52, 99 Fecal leukocytes are typically found in patients with shigellosis, salmonellosis, Campylobacter enteritis, typhoid fever, invasive E. coli colitis, V. parahaemolyticus, Y. enterocolitica, and ulcerative colitis. In all of these, except typhoid fever, the leukocytes are primarily polymorphonuclear, whereas in typhoid fever, they are mononuclear. No stool leukocytes are noted in cholera, viral diarrhea, noninvasive E. coli diarrhea, or nonspecific diarrhea.61 The timing of onset of diarrhea after exposure or the incubation period can be useful in differeniating its causes. Extremely short incubation periods of less than 6 hours are typical for Staphylococcus, B. cereus (type I), enterotoxigenic E. coli,93,128,153 and preformed enterotoxins, as well as roundworm larvae ingestions. Intermediate incubation periods of 8–24 hours are found with C. perfringens, B. cereus (type II enterotoxin), enteroinvasive E. coli,34,98 and salmonella. Longer incubation periods are seen in other bacterial causes of acute gastroenteritis (Table 74–5). The three most likely etiologies are infectious, drug or chemical toxins, and foodborne. These three etiologies are not mutually exclusive. The differential diagnosis must be made among these groups when the time from exposure to onset of symptoms is brief, all of the nonbacterial infectious etiologies (viral, parasitic, fungal, and algal) except for upper GI invasion by roundworm larvae can be eliminated. The possibility of a bacterial etiology with enterotoxin production should be considered (Table 74–5).42,52

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TABLE 74–5.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Common Foodborne Disease: Gastrointestinal (Primary Presenting Symptom) Symptoms

Etiology

Onset

A

V

Di

Dy

F

Source

Pathogenesis

Therapy

Staphylococcus spp Bacillus cereus Type I Type II Anasikiasis

2–6 h

+

+

+





Prepared foods: meats, pastries, salads

Heat-stable enterotoxin

Volume expansion

1–6 h 12 h 1–12 h

+ + +

+  +

+ + 

  

  

Heat-labile toxins Heat-labile toxins Intestinal larvae

Volume expansion

Clostridium perfringens Salmonella spp

8–24 h

+



+

+



Fried rice Meats, vegetables Raw fish, sushi, Eustrongyloides, minnows, salmon, cod, herring, squid, tuna Poultry, heat-processed meats

8–24 h





+



+

E. coli Enterotoxigenic Invasive Hemorrhagic

24–72 h 







+

Vibrio cholera

24–72 h





+





Shigella spp

24–72 h

+



+

+



Campylobacter jejuni

1–7 d

+

+

+



+

Yersinia spp

1–7 d

+

+

+



+

Poultry, egg Pets (turtles, lizards, chicks) Water, food Enteric contact Bacteria (invasive) Shiga like toxin Water, food Enteric contact Institutional food handler Household, preschool, enteric contact Milk, poultry Unchlorinated water Mimic appendicitis Pork, milk, pets: (arthritis pharyngitis); rash

Heat-labile enterotoxin Bacteria, endotoxin (Bacteremia) Enterotoxin, heat stable

Enterotoxin Heat labile Bacteria, Endotoxin Bacteria Heat-labile enterotoxin Bacteria Enterotoxin

Endoscopy Laparotomy Removal Volume expansion Antibiotics Volume expansion Electrolytes Antibiotics Renal, hematologic support Electrolyte replacement Antibiotics

Antibiotics

Antibiotics

A = abdominal pain; V = vomiting; Di = diarrhea; Dy = dysentery; F = fever.

EPIDEMIOLOGY Epidemiologic analysis is of immediate importance, particularly when GI diseases strike more than one person in a group. The questions raised in Table 74–6 must be answered.131 If available,

TABLE 74–6. Epidemiologic Analysis of Gastrointestinal Disease 1. Is the occurrence of the disease in a large group significant enough to be consistent with foodborne disease (two or more cases)? 2. Is the symptomatology in affected individuals well defined and similar? 3. Is the onset, time, and duration of illness similar among affected group members (incubation)? 4. What are the possible modes of transmission (ie, contact, food, water)? 5. Is there a relationship between the time of exposure of the group and the mode of transmission? 6. Do attack rates differ for age, gender, or occupation? 7. Can it be determined which foods were served and to whom? Can the items which were not eaten by those who did not become ill be identified? 8. What is the food-specific attack rate? 9. How was the food procured? How was it stored? 10. Was cooking technique adequate? 11. Was personal hygiene acceptable? 12. Was there animal contamination?

an infectious disease consultant or infection control officer may be called for assistance. Alternatively, assistance from state and local health departments should be sought. Often only the Centers for Disease Control or state health department have the resources to investigate and confirm a presumptive diagnosis in an outbreak. Sophisticated techniques such as toxin detection, matching the organism in the food by phage type with a food handler, matching an organism by phage type with other persons, the isolation of 10 or more organisms per gram of implicated food,34,42 or polymerase chain reaction (PCR) identification of bacterial or plasmid DNA are potentially useful, although generally not possible using the laboratory and personnel available in most hospitals.51,63,146 Structural, metabolic, and functional causes can often be eliminated. As in these diseases, neither a significant grouping of cases nor a limited clinical history is characteristic. Foodborne parasites such as Trichinella spiralis (trichinosis), Toxoplasma gondii (toxoplasmosis), and G. lamblia (giardiasis) must be considered although acute gastrointestinal symptoms are not usually prominent.

Staphylococcus Species In cases of suspected food poisoning with a short incubation period, the physician should first assess the risk for staphylococcal causes. The usual foods associated with staphylococcal toxin production include milk products and other proteinaceous foods, cream-filled baked goods, potato and chicken salads, sausages,

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ham, tongue, and gravy. Piecrust can act as an insulator, maintaining the temperature of the cream filling and occasionally permitting toxin production even during refrigeration.6 An assessment must routinely be made for the presence of lesions on the hand or nose of any food handlers involved. Unfortunately, “carriers” of enterotoxigenic staphylococci are difficult to recognize because they usually lack lesions and appear healthy.63 A fixed association between a particular food and an illness would be most helpful epidemiologically, but clinically this rarely occurs. Factors such as environment, host resistance, nature of the agent, and dose make the results surprisingly variable. Patients with staphylococcal food poisoning rarely have a significant temperature elevation, although in a review of 2992 documented cases, 16% had a subjective sense of fever.63 Abdominal pain, nausea followed by vomiting, and diarrhea dominate the clinical findings. Diarrhea does not occur in the absence of nausea and vomiting. The mean incubation period is 4.4 hours with a mean duration of illness of 20 hours. Most enterotoxins are produced by Staphyloccus aureas coagulase-positive species. These enterotoxins initiate an inflammatory response in gastrointestinal mucosal cells and lead to cell destruction. These enterotoxins may have a dramatic effect on the emesis center in the brain and diverse other organ systems. Discrimination of unique S. aureus isolates from foodborne outbreaks can be made using restriction fragment length polymorphisms analysis by pulsed-field gel electrophoresis.147

Salmonella Species Salmonella enteritidis infections are a great concern in the United States. Two particular outbreaks define very special problems. In the 1980s, there were recurrent outbreaks associated with grade A eggs or food containing such eggs. In the past, such outbreaks of salmonella enteritis were attributed to infection of the egg with salmonella (from the chicken’s gastrointestinal tract) through cracks in the shell. More recently, outbreaks have involved noncracked, nonsoiled eggs.100 In these cases, presumably the salmonella has infected the eggs before the shell was formed. In either case, people who consume raw or undercooked eggs are most at risk for salmonella enteritis. Raw eggs may be found as ingredients of chocolate mousse, hollandaise sauce, eggnog, egg-creams, caesar salads, and homemade ice cream. Whole, partially cooked eggs may be eaten as sunny-side-up or poached eggs.4,145 The second group of outbreaks was associated with raw milk,119 which has become very popular in certain communities for unclear reasons. Inadequate microwave cooking also may cause small outbreaks.38 Chronic diarrheal syndromes110 of an ill-defined nature result. These outbreaks are of great concern because they frequently involve multiple-drug-resistant salmonella infections.31 Campylobacteriosis, brucellosis, listeriosis, and tuberculosis also result from consuming raw milk. Drinking pasteurized milk may not be protective. An outbreak of salmonellosis resulting in more than 16,000 culture-proven cases was traced to one Illinois dairy. The probable cause of the outbreak was a transfer line connecting raw and pasteurized milk containment tanks.127 Additional concern has developed over the widespread use of antibiotics in animal feed. Meats, poultry, and manure-fertilized vegetables now frequently contain resistant bacterial strains that place virtually the entire population at risk.31,127 Household pets known to harbor salmonella also places families at risk. Chicks, turtles, and iguanas carry salmonella and frequently transmit the

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organism to household contacts, including infants, who are at particular risk for invasive diseases.2

Campylobacter jejuni Campylobacter jejuni, a curved gram-negative rod, is a major cause of bacterial enteritis. The organism is most commonly isolated in children younger than 5 years of age and in adults 20–40 years of age. Campylobacter enteritis outbreaks are more common in the summer months in temperate climates. Although most cases of Campylobacter enteritis are sporadic, outbreaks are associated with contaminated food and water.152 The most frequent sources of Campylobacter in food are raw or undercooked poultry products39 and unpasteurized milk.168 Birds are a common reservoir, and small outbreaks are associated with contamination of milk by birds pecking milk-container tops.142 Contaminated water supplies are also a frequent source of Campylobacter enteritis involving large numbers of individuals.21 C. jejuni is heat-labile; cooking of food, pasteurization of milk, and chlorination of water prevent human transmission. The incubation period for Campylobacter enteritis varies from 1 to 7 days (mean, 3 days). Typical symptoms include diarrhea, abdominal cramps, and fever. Other symptoms may include headache, vomiting, excessive gas, and malaise. The diarrhea may contain gross blood, and frequently leukocytes are present on microscopic examination.39 Illness usually lasts 5–6 days (range, 1–8 days). Rarely, symptoms may last for several weeks. Severe presentations include lower GI hemorrhage, abdominal pain mimicking appendicitis, a typhoidlike syndrome, reactive arthritis, and meningitis. The organism may be detected by using polymerase chain reaction identification techniques.48 Treatment is supportive consisting of volume resuscitation, and may include quinolone antibiotics in more severe cases.

Group A Streptococcus Bacterial infections not usually associated with food or food handling may occasionally be transmitted by food or food handling. Streptococcal pharyngitis can be transmitted by food prepared by an individual with streptococcal pharyngitis. 32

Clostridium botulinum In the last 3 decades, a median of 4 cases of foodborne botulism, 3 cases of wound botulism, and 71 cases of infant botulism have been reported annually to the Centers for Disease Control.139 Home-canned fruits and vegetables, as well as commercial fish products, are among the common foods causing botulism. The incubation period is usually 12–36 hours; typical symptoms include some initial GI symptoms, followed by malaise, fatigue, diplopia, dysphagia, and rapid development of small muscle incoordination.86 In botulism, the toxin is irreversibly bound to the neuromuscular junction, where it impairs the presynaptic release of acetylcholine.79 The diagnosis of botulism must be made immediately, and aggressive respiratory therapy must be initiated if the patient is to survive. Additional therapeutic measures include administering antitoxin (Chap. 75 and Antidote in Depth: Botulinum Antitoxin). The differential diagnosis of botulism includes myasthenia gravis, atypical Guillain-Barré syndrome, tick-induced paralysis, and certain chemical ingestions (see Tables 75–1 and 75–3).

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Yersinia enterocolitica Yersinia enterocolitica is a gram-negative coccobacillus that causes enteritis most frequently in children and young adults. Typical clinical features include fever, abdominal pain, and diarrhea, which usually contains mucus and blood.10,150,164 Other associated symptoms include nausea, vomiting, anorexia, and weight loss. The incubation period may be 1 day to 1 week or more. Less-common features include prolonged enteritis, arthritis, pharyngeal and hepatic involvement, and rash. Yersinia is a common pathogen in many animals, including dogs and pigs. Sources of human infection include milk products, raw pork products, infected household pets, and person-to-person transmission.19,56,87 Infections may be diagnosed based on cultures of food, stool, blood, and, less frequently, skin abscesses, pharyngeal cultures, or cultures from other organ tissues (mesenteric lymph nodes, liver). Yersinia may also be identified with polymerase chain reaction.69 Therapy is usually supportive; however, patients with invasive disease (eg, bacteremia, bacterial arthritis) should be treated with intravenous antibiotics. Ciprofloxacin and third-generation cephalosporins are highly bacteriocidal against Yersinia spp.

Listeria monocytogenes Listeriosis transmitted by food usually occurs in pregnant women, their fetuses, the elderly, and immunocompromised individuals (corticosteroid use, malignancy, diabetes, renal disease, HIV infection).5,16,136,160 Typical food sources include unpasteurized milk, soft cheeses such as feta, and undercooked chicken. Individuals at risk should avoid the usual sources and should be evaluated for listeriosis if typical symptoms of fever, severe headache, muscle ache, and pharyngitis develop. Treatment with intravenous ampicillin or trimethoprim-sulfamethoxazole is indicated for systemic listerial infections.

Drug- and Toxin-Induced Diseases Careful assessment of the possibility of a foodborne pesticide poisoning is essential. Aldicarb contamination has occurred in hydroponically grown vegetables, and watermelons contaminated with pesticides.54 Eating malathion-contaminated chapatti and wheat flour has resulted in 60 intoxications and 1 death29 (Chap. 89). The possibility of unintentional acute heavy metal ingestion must also be considered. This type of poisoning most typically occurs when very acidic fruit punch is served in metal-lined containers. Antimony, zinc, copper, tin, or cadmium in a container may be dissolved by an acid food or juice medium. Insecticides, rodenticides, arsenic, lead, or fluoride preparations can be mistaken for a food ingredient. These poisonings usually have a rapid onset of signs and symptoms after the exposure.

Mushroom-Induced Disease Some species produce major GI effects. Amanita phalloides, the most poisonous mushroom, usually causes GI symptoms as well as hepatotoxic effects with a delay to clinical manifestations. The rapid onset of symptoms may suggest some of the gastroenterotoxic mushrooms (Chap. 76).

Spicy Food Certain religious or cultural customs, such as eating bitter herbs at a Passover seder125 or wasabi143 at a sushi bar, are associated with

syncope. The precipitant in both instances is horseradish. Despite severe oropharyngeal or abdominal pain, no hematemesis, hematochezia, or fever is noted with horseradish. Gastric mucosal contact with pepperoni or jalapeño peppers (capsaicin) may produce a similar syndrome.53

Intestinal Parasitic Infections The popularity of eating raw fish, usually from Japanese restaurants, has led to an increase in reported intestinal parasitic infections. The etiologic agents are typically roundworms (Eustrongylidis anisakis) or fish tapeworms (Diphyllobothrium spp.). Symptoms of anisakiasis, or eustrongylidiasis, that are localized to the stomach typically occur 1–12 hours after eating raw fish, whereas symptoms of lower intestinal involvement may be delayed for days or weeks. Typical gastric symptoms include nausea, vomiting, and severe crampy abdominal pain that may mimic a gastric ulcer; typical lower intestinal symptoms include abdominal cramping and, with perforation of the intestinal wall by the larvae, severe localized abdominal pain, rebound, and guarding, which may mimic an acute abdomen (appendicitis). Without an adequate dietary history (of eating raw fish), the diagnosis may be almost impossible to establish. Therapy would be directed toward the most likely diagnostic entity (gastric ulcer or appendicitis). Diagnosis is usually established on visual inspection of the larvae (on endoscopy, laparotomy, or pathologic examination), which are typically pink or red. Raw fish that may contain eustrongylides include minnows (Fundulus spp.) and other bait fish. Anisakis simplex and Pseudotterranova decipiens are Anisakidae that may be found in several types of frequently consumed raw fish, including mackerel, cod, herring, rockfish, and salmon, as well as yellowfin tuna and squid. Reliable methods of preventing ingestion of live anisakid larvae are freezing (4°F (20°C) for 60 hours) or cooking (140°F (60°C) for 5 minutes).67,76,126,133,167 Diphyllobothriasis (fish tapeworm disease) is caused by eating uncooked fish that harbor the parasite. Hosts include, but are not limited to, herring, salmon, pike, and whitefish. The symptoms are less acute than with intestinal roundworm ingestions, and usually begin 1–2 weeks after ingestion. Signs and symptoms include nausea, vomiting, abdominal cramping, flatulence, abdominal distension, diarrhea, and anemia (megaloblastic). Diagnosis is based on a history of ingesting raw fish and on identification of the tapeworm proglottids in stool.159 Treatment with niclosamide, praziquantel, or paromomycin is usually effective.1

Monosodium Glutamate The so-called “Chinese restaurant syndrome” is induced by ingestion of monosodium glutamate (L-sodium glutamate; MSG). Individuals present with burning, facial pressure, headache, flushing, chest pain, GI symptoms usually limited to nausea and vomiting, and, infrequently, life-threatening bronchospasm3 and angioedema.144 Intensity and duration of the symptoms are dose-related, with significant variation in individual responses to the amount ingested.134,170 Monosodium glutamate causes “shudder attacks” or a seizurelike syndrome in young children. Absorption is more rapid following fasting, and the typical burning symptoms rapidly spread over the back, neck, shoulders, abdomen, and, occasionally, the thighs. Gastrointestinal symptoms are rarely prominent. Symptoms can usually be prevented by prior ingestion of food. When symptoms do occur, they usually last approximately 1 hour. The syndrome is not limited to patrons of Chinese restaurants. It is

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a reaction to MSG, which is used frequently in many restaurants. Monosodium glutamate is also marketed as an effective flavor enhancer.14 Many sausages and canned soups contain heavy doses of MSG. MSG (regarded as “safe” by the Food and Drug Administration) can also be the cause of other acute and bizarre neurologic symptoms. The pathophysiology has not been clarified, although studies implicate glutamate receptors. Another foodborne toxin with gastrointestinal symptoms is also associated with Chinese restaurants and eating of reheated fried rice. Bacillus cereus type I is the causative organism, and bacterial overgrowth and toxin production causes consequential early onset nausea and vomiting. Bacillus cereus type II has a delayed onset of similar gastrointestinal symptoms, including diarrhea.47

Anaphylaxis and Anaphylactoid Presentations Some foods and foodborne toxins may cause allergic or anaphylacticlike manifestations, that are also referred to as “restaurant syndromes”138 (Table 74–4). The similarity of these syndromes complicates a patient’s future approach to safe eating. Isolating the precipitant is essential so that the risk can be effectively assessed. Manufacturers of processed foods should provide an unambiguous listing of ingredients on package labels. Sensitive individuals (or their parents) must be rigorously attentive.130,171 Confirmation may necessitate controlled double-blind oral challenge tests, and those with severe reactions should be protected by the immediate availability of epinephrine and antihistamine. Attempts to avoid allergic reactions to dairy products by avoiding dairy-containing foods may fail. Nondairy foods may still contain flavor enhancers of a dairy origin (partially hydrolyzed sodium caseinate and the like) and can cause morbidity and death in allergic individuals.46 Individuals with known food allergies frequently fail to carry prescribed spring-injected epinephrine syringes, believing that the allergen is easily identifiable and avoidable.72 Food additives to consider include antibiotics, aspartame, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nitrates or nitrites, and parabens esters.89 Regulation of these preservatives is limited, and agents such as sulfites are so ubiquitously used that it may be hard to predict which guacamole, cider, vinegar, fresh or dried fruits, wines or beers do or do not contain these sensitizing agents.

Vegetables and Plants Plants, vegetables, and their diverse presentations are often involved in food poisonings.60,74,75,80,81 Edible plants and plant products may be poorly cooked, prepared or contaminated. Extensive discussion is found in Chap. 78.

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with Shigella dysenteriae type 2. Four were hospitalized, none had reported long-term sequelae. The Shigella strain is a rare one to cause endemic disease, and the identical strain, as identified by pulse-field gel electrophoresis, was found in 8 of the symptomatic workers, and in the pastries served in the break room, as well as and in the laboratory’s stock culture of Shigella dysenteriae. This suggests purposeful poisoning of food eaten by laboratory personnel. The person responsible, and the motive, remain unknown. The second cases series156 describes a large community outbreak of food poisoning caused by Salmonella typhimurium. The outbreak occurred in the Dalles, Oregon area during the fall of 1984. A total of 751 people suffered salmonella gastroenteritis. The outbreak was caused by intentional contamination of restaurant salad bars and coffee creamer by members of a religious commune using a culture of Salmonella typhimurium purchased before the outbreak of food poisoning. A criminal investigation found a salmonella culture on the religious commune grounds that had Salmonella typhimurium identical to the salmonella strain found in food-poisoning victims, as identified by using antibiotic sensitivity, biochemical testing, and DNA restriction endonuclease digestion of plasmid DNA. It took more than a year for this purposeful salmonella outbreak to be linked to terrorist activity. Reasons for the delay in identifying the outbreak as a purposeful food poisoning include: (a) no apparent motive; (b) no claim of responsibility; (c) no pattern of unusual behavior in the restaurants; (d) no disgruntled restaurant employees identified; (e) epidemic exposure curves indicated multiple time points for contamination, suggesting a sustained source of contamination, not a single act; (f) no previous event of similar nature as a reference; (g) other possibilities seemed more likely (eg, repeated unintentional contamination by restaurant workers); and (h) fear that the publicity necessary to aid the investigation might generate copy cat criminal activity. The delay in publication of the event (almost 10 years) was also due to fears of copycat activity. The activity of the Japanese cult Aum Shinrikyo and its use of biologic weapons appear to have provided the motivation to release this publication in the hopes that similar purposeful food poisoning patterns may be identified more quickly in the future. The capacity for infecting large numbers of people with foodborne agents that are easy to obtain and disperse is clearly exemplified by the purposeful salmonella outbreak in Oregon, and the apparently unintentional salmonella outbreak which resulted in more than 16,000 culture-proven cases traced to contamination in 1 Illinois dairy where the probable cause of the outbreak was a transfer line connecting raw and pasteurized milk containment tanks.127

SUMMARY

FOOD POISONING AND BIOTERRORISM The threat of terrorist assaults has received increased attention recently and is discussed elsewhere in this text (Chap. 100). Food as a vehicle for intentional contamination with the intent of causing mass suffering or death has occurred in the United States.77,156 In the first report,77 12 laboratory workers suffered gastrointestinal symptoms, primarily severe diarrhea, from consuming food served in the staff break room which had been purposefully contaminated

The diversity of etiologies for food poisoning involves almost all aspects of toxicology. Our concerns represent the natural toxicity of a product such as a plant or animal, the contamination of these in the field or in the processing in a factory or in the home preparation or storage. These events may be intentional or unintentional, but they may alter our approaches to general nutrition and society. The current debates about the role of government in food preparation and protection range from bacteria such as E. Coli 0157:H7, to prions in Creutzfeldt-Jacob disease (bovine encephalopathy), to genetically altered materials such as corn. Future discussions of food poisonings and interpretations of the impor-

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tance of these problems may dramatically alter our food sources and their preparation.

ACKNOWLEDGMENT Robert H. Kirstein, MD contributed to this chapter in a previous edition.

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46. Gern JE, Yang E, Evrard HM, et al: Allergic reactions to milk-contaminated “nondairy” products. N Engl J Med 1991;324:976–979. 47. Giannella RA, Brasile A: Hospital food-borne outbreak of diarrhea caused by Bacillus cereus: Clinical, epidemiologic, and microbiologic studies. J Infect Dis 1979;139:366–370. 48. Giesendorf BA, Quint WG: Detection and identification of Campylobacter spp. using the polymerase chain reaction. Cell Mol Biol 1995;41:625–638. 49. Gilbert RJ, Hobbs G, Murray CK, et al: Scombrotoxic fish poisoning: Features of the first fifty incidents to be reported in Britain (1976–1979). Br Med J 1980;2:71–72. 50. Gillespie RJ, Lewis JH, Pearn ATC, et al: Ciguatera in Australia: Occurrence, clinical features, pathophysiology, and management. Med J Aust 1986;145:584–590. 51. Goossens H, Giesendorf BA, Vandamme P, et al: Investigation of an outbreak of Campylobacter upsaliensis in day care centers in Brussels: Analysis of relationships among isolates by phenotypic and genotypic typing methods. J Infect Dis 1995;172:1298–1305. 52. Grady GF, Keush GT: Pathogenesis of bacterial diarrheas. N Engl J Med 1971;285:831–841, 891–900. 53. Graham DY, Smith JL, Opekun AR: Spicy food and the stomach: Evaluation by endoscopy. JAMA 1988;260:3473–3475. 54. Green MA, Henmann MA, Wehr HM, et al: An outbreak of watermelon-borne pesticide toxicity. Am J Public Health 1987;77: 1431–1434. 55. Griffin PM, Tauxe RV: The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E. coli, and the associated hemolytic uremic syndrome. Epidemiol Rev 1991;13: 60–98. 56. Gutman LT, Ottesen EA, Quan TJ, et al: An inter-familial outbreak of Yersinia enterocolitica enteritis. N Engl J Med 1973;288: 1372–1377. 57. Habekost RC, Fraser IM, Halstead BW: Observations on toxic marine algae. J Wash Acad Sci 1955;45:101–103. 58. Halstead BW: Poisonous and Venomous Animals of the World. Princeton, NJ, Darwin Press, 1978. 59. Hancock DD, Besser TE, Kinsel ML, et al: The prevalence of Escherichia coli O157.H7 in dairy and beef cattle in Washington State. Epidemiol Infect 1994;113:199–207. 60. Hardin JW, Arena JM: Human Poisoning from Native and Cultivated Plants. Chapel Hill, NC, Duke University Press, 1969, pp. 69–73. 61. Harris JC, Dupont HL, Hornic RB: Fecal leukocytes in diarrheal illness. Ann Intern Med 1972;76:697–703. 62. Hokama Y, Asahina AY, Shang ES, et al: Evaluation of the Hawaiian reef fishes with the solid phase immunobead assay. J Clin Lab Anal 1993;7:26–30. 63. Holmberg SD, Blake PA: Staphylococcal food poisoning in the United States: New facts and old misconceptions. JAMA 1984;251: 487–489. 64. Holmes MJ, Lewis RJ, Poli MA, et al: Strain-dependent production of ciguatera precursors (gambiertoxins) by Gambierdiscus toxicus (Dinophyceae) in culture. Toxicon 1991;29:761–765. 65. Hughs JM, Merson MH: Fish and shellfish poisoning. N Engl J Med 1976;295:1117–1120. 66. Hui JY, Taylor SL: Inhibition of in vivo histamine metabolism in rats by foodborne and pharmacologic inhibitors of diamine oxidase, histamine-N-methyl transferase, and monoamine oxidase. Toxicol Appl Pharmacol 1985;81:241–249. 67. Intestinal perforation caused by larval Eustrongyloides—Maryland. MMWR Morb Mortal Wkly Rep 1982;31:383–389. 68. Kanchanapongkul J, Krittayapoositpot P: An epidemic of tetrodotoxin poisoning following ingestion of the horseshoe crab Carcinoscorpius rotundicauda. Southeast Asian J Trop Med Public Health 1995;26:364–367. 69. Kapperud G, Vardund T, Skjerve E, et al: Detection of pathogenic Yersinia enterocolitica in foods and water by immunomagnetic sepa-

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

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BOTULISM Lewis R. Goldfrank / Neal E. Flomenbaum

A 27-year-old woman was in excellent health until 3 days before admission, when her family gathered for dinner following the funeral of her mother-in-law. Shortly thereafter, the patient began experiencing dysphagia and dysarthria and seemed generally anxious. She saw her family physician, who prescribed diazepam. The day prior to her admission, the patient became dyspneic. She began to communicate by writing when talking became impossible. Writing soon became difficult as well, and the patient complained of having trouble walking and lifting her head. She would not eat and vomited food when she was force-fed. She then began to look straight ahead without moving her eyes. The next day she was taken to the closest hospital, where the physicians in attendance noted the peculiarity of the symptoms, the fact that she was taking diazepam, and the temporal relationship to the funeral of her mother-in-law. The family physician was called from the emergency department and told of the new symptoms that had developed during the previous 2 days. Struck by the resemblance to the mother-in-law’s symptoms prior to her death of a presumed myocardial infarction, he recommended an IM injection of saline as a placebo and discharge of the patient. Shortly after the patient returned home, she became increasingly dyspneic and cyanotic, and then had a cardiopulmonary arrest. The husband initiated CPR until the paramedics arrived and took over. Physical examination on admission revealed an apneic, intubated, comatose young woman with a blood pressure of 90/40 mm Hg, pulse of 80 beats/min, and rectal temperature of 97.0°F (36.1°C). Her left pupil was 4 mm in diameter, the right pupil was 3 mm, and both were sluggishly responsive to light. The heart and lungs were unremarkable. The abdomen was soft, and bowel sounds were diminished. The stools were negative for occult blood. There was no response to painful stimuli or coldwater caloric testing. Her upper extremities were flaccid, with absent reflexes. The patient had increased extensor tone in her legs, 2+ patellar reflexes, ankle clonus, and generalized myoclonic jerks. Cerebrospinal fluid (CSF) examination was normal as was edrophonium (Tensilon) testing. An electromyogram (EMG) demonstrated increased muscle action potentials with rapid repetitive stimulation and posttetanic potentiation. Botulism was diagnosed and the patient was given 2 vials of trivalent botulinal antitoxin and two 375-mg doses of guanidine over 6 hours. (The patient presented in 1974. Guanidine is rarely, if ever, used currently in the management of botulism. See discussion in the sixth edition of this work). However, her condition steadily

deteriorated and she died 3 days after admission. Postmortem examination revealed cerebral edema and herniation. Examination of stomach contents revealed undigested mushrooms, from which Clostridium botulinum type B was isolated. Because of the patient’s presentation, the mother-in-law’s hospitalization was reviewed: Twelve days before the daughter-in-law’s first symptoms, the mother-in-law experienced nausea, vomiting, abdominal cramps, and distension, and she was treated with an antiemetic. Three days later, she complained of a dry throat, dysphagia, and chest pains. Two days after that, she had dyspnea as well. When an electrocardiogram (ECG) revealed inverted T waves in the precordial leads and occasional premature ventricular contractions, she was hospitalized to “rule out myocardial infarction.” The day after the mother-in-law’s admission she was even more dyspneic and stuporous and was also noted to have dilated, sluggishly reactive pupils. She was then intubated and became more alert. However upon extubation the next day, she developed respiratory distress and required reintubation. A tracheostomy was then performed but she became febrile and died 2 days later. Following the daughter-in-law’s hospitalization and death, the body of the mother-in-law was exhumed, and an autopsy revealed bronchopneumonia, an enlarged heart, and mushroom fragments in the small intestines. The mushroom fragments yielded C. botulinum type B. When the diagnosis of botulism was first considered, and before the mushrooms were implicated, all family members who had been at the funeral meal were admitted to the hospital for observation. At that time, a third member of the family reported having difficulty swallowing. This woman was the only other family member who had eaten mushrooms at the funeral meal. She was given 1 vial of trivalent botulinal antitoxin, and her symptoms resolved in 3 days. Her stool specimens later revealed C. botulinum type B. Twenty days after being given the antitoxin, the woman developed severe arthralgias and fever suggestive of serum sickness. Many of the other family members were understandably anxious and some complained of dry throat, headache, or tingling in their extremities, although none had eaten any of the mushrooms, and none had stools positive for C. botulinum type B. Most were discharged from the hospital within 24–48 hours.39 A carefully obtained history revealed that the mother-in-law canned her own peppers, eggplant, artichokes, and mushrooms without pressure-cooking. When these remaining canned foods were obtained from the house and examined, only the mushrooms were found to contain C. botulinum type B.

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EPIDEMIOLOGY Contrary to popular opinion, when botulism is diagnosed, multiple cases per occurrence do not necessarily follow. Between 1976 and 1988, hundreds of outbreaks occurred, involving more than 400 persons in total, but approximately 70% involved only 1 person, approximately 20% involved 2 persons, and only 10% involved more than 2 persons (mean number of 2.7 cases per outbreak).103 It is of interest that when only sporadic patients were affected, they were more severely ill, with 85% requiring intubation as compared to only 42% requiring intubation in multiperson outbreaks. 103 There are approximately 1.25 cases of foodborne botulism per 10 million people annually in the United States.52 Currently, the etiologies of botulism are 72% infant, 24% foodborne, 3% wound, and 1% adult type.79 Although only 4% of foodborne botulism is associated with food purchased in restaurants; these outbreaks usually affect large numbers of individuals and account for more than 40% of the total number of reported cases.52 Commercial food processing accounts for only 2% of reported cases with vegetables (peppers, beans, mushrooms, tomatoes, and beets, with or without meat) thought to be the causative agents in about 70%, meat in 17%, and fish in 13% of cases. Recently, concern was raised regarding minimally processed foods such as soft cheeses that lack sufficient quantities of intrinsic barriers to botulinum toxin production such as salt and acidifying agents.73 These foods become high-risk agents when refrigeration standards are violated. The US Food and Drug Administration is reviewing recommendations for appropriate measures to take in processing such foods.94,95 Common home-canning errors responsible for cases include failure to pressure-cook and allowing food to putrefy at room temperature. In recent years, outbreaks of botulism have been associated with specialty foods consumed by different ethnic groups: chopped garlic in soy oil by Chinese in Vancouver, British Columbia;62,86 fried lotus rhizome solid mustard in Japan;64 uneviscerated salted fish—called kapchunka—eaten by Russian immigrants in New York City,47,91 and the same food-called faseikh—eaten by Egyptians in Egypt.100 Other outbreaks have involved fermented salmon eggs, seal, and whale skin consumed by Inuits and Native Americans in Alaska,99 and heat-shrink-wrapped meat roll (Matambre) consumed in Argentina.98 It is important to be aware of new trends and unusual presentations or locations of botulism and to institute preventive education: although 90% of type E outbreaks have occurred in Alaska because of home-processed fish or meat from marine animals,52 1 incident occurred in New Jersey.28 More recently, 3 cases of botulism involving members of the Native American church followed ingestion of a ceremonial tea made from the buttons of dried, alkaline-ground peyote cactus that had been prepared in a watercovered refrigerated jar. The resultant alkaline and anaerobic milieu presumably fostered the growth of toxin from naturally occurring spores.35 There is an ever increasing concern with regard to botulinum toxin as a biological weapon4a. The medical and public health issues associated with terrorism and botulinum toxin increase the relevance of this chapter in the twenty first century (see Chapter 100). The case fatality ratio is about 12% for type A botulism and about 10% for types B and E.49,61,90 Approximately 67% of pa-

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tients with type A require intubation, as compared to 52% of patients with type B botulism and 39% of those with type E botulism.103 Although the median incubation period for all patients is 1 day, it ranges from 0 to 7 days for type A, 0 to 5 days for type B, and 0 to 2 days for type E.103 Physicians may need to respond more rapidly to a potential epidemic of type E, but they should be prepared for greater complication rates associated with type A.103 When the type of toxin is unknown, the case fatality rate may remain as high as 50%, a figure comparable to general mortality rates in the past.49,61,90 The improvement in case fatality rates for all types of botulism probably represents increasing awareness of the problem associated with earlier diagnosis and use of antitoxin, in conjunction with better and more easily accessible life-support techniques.

CHARACTERISTICS OF CLOSTRIDIUM BOTULINUM Clostridium botulinum is a spore-forming, anaerobic, gram-positive bacillus. Although classified as a single species, it consists of three distinct genetic variants: C. botulinum, which produces toxin types A, B and E; C. barati, which produces toxin type F; and C. butyricum, which also produces toxin type E.36,79 Rare instances of both adult and infant botulism are attributed to C. barati and C. butyricum.58,65 Eight distinct toxins, designated types A through G, with C
and C, have been identified to date. Although these toxins have slightly different mechanisms of action, the ultimate effects on vesicle release of acetylcholine and the resultant clinical syndromes are identical. All spores of this species are dormant and highly resistant to damage. They can withstand boiling at 100°C (212°F) for hours, although 30 minutes of moist heat at 120°C (248°F) usually destroys them. Germination of spores in food is promoted by a pH greater than 4.5, a sodium chloride content less than 3.5%, or a low nitrite level. Most viable organisms produce toxin in an anaerobic milieu with temperatures above 27°C (80.6°F), although some strains produce toxins even when conditions are not optimal. Type E botulinal organisms can produce toxin at temperatures as low as 5°C (41°F). To prevent spore germination, acidifying agents such as phosphoric or citric acid are employed in canning or bottling foods low in acid content, such as green beans, corn, beets, asparagus, chili peppers, mushrooms, spinach, figs, olives, and certain nonacidic tomatoes. As opposed to the spores, the toxin itself is heat-labile and can be destroyed by heating to 80°C (176°F) for 30 minutes or to 100°C (212°F) for 10 minutes. At high altitudes, the boiling point may be as low as 94.7°C (202.5°F), which may require a minimum of 30 minutes of boiling to destroy the toxin. Under high-altitude conditions, pressure cooking at 13–14 lb of pressure is often necessary to achieve appropriate temperatures to destroy the toxin. Clostridium botulinum spores are ubiquitous and are present in soil, seawater, and air. Botulism outbreaks can occur anywhere in the world,46,99 and in recent years, have been reported from such diverse areas as Iran, the former Soviet Union, Japan, France, Belgium, Portugal,49 Scandinavia, and Canada. The general distribution of strains in the United States: type A strain is found west of the Mississippi,12,54 type B is found east of the Mississippi particularly the Allegheny range,8 and type E is found in the Pacific northwest.83 Types A and B are typically found in poorly processed meats and vegetables and type E is commonly found in

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FOOD POISONING

fish products. Type G has not been associated with naturally occurring disease. Food contaminated with C. botulinum types A and B often do not look or smell normal and appear putrefied because of the action of proteolytic enzymes. In contrast, however, type E organisms are saccharolytic, not proteolytic, and therefore food contaminated with type E toxin may look and taste normal.

PATHOPHYSIOLOGY Botulinum toxin is the most poisonous substance known. The LD50 for mice is 3 million molecules injected intraperitoneally. The oral human lethal dose is 1 µg (106 g) per kilogram. Because the toxin is often demonstrated only in the stool and is presumably biodegraded or inactivated in great part in the gastrointestinal tract, it is difficult to determine what percentage of the toxin is actually absorbed.21 The toxin is a protein consisting of a single polypeptide chain, with a MW of 900,000 Da, which

includes a nontoxic protein, and a 150,000 MW neurotoxic component. To become fully active, the 150,000 MW neurotoxin must undergo proteolytic cleavage to generate a heavy chain (MW 100,000) that is linked by a disulfide bond to a light chain (MW 50,000). It is the dichain form of the molecule that is responsible for both the toxicity and therapeutic benefits (see below).36,81,82 The dichain form binds rapidly and irreversibly to the cell membrane and is uptaken by endocytosis. The heavy chain is responsible for cell membrane binding67a. Once inside the cell, the light chain acts as a zinc-dependent endoprotease to cleave polypeptides that are essential for exocytosis.44,74 Different botulinum toxins share the mechanism of cell entry, but there appears to be a unique mechanism of preventing acetylcholine release for each individual botulinum toxin.80 This reduction in presynaptic function impairs cholinergic transmission at all acetylcholine-dependent synapses in the peripheral nervous system (Fig. 75–1), but does not affect the central nervous system or axonal conduction.82 Anticholinesterase (cholinergic) drugs, such as edrophonium (Tensilon), have no effect on the action of the toxin, but may affect

Figure 75–1. Botulinum toxin consists of two peptides linked by disulfide bonds. The heavy chain is responsible for specific binding to acetylcholine-containing neurons (the heavy chain of tetanus toxin is specific for glycine-containing neurons). Following binding to the cell surface, the entire complex undergoes endocytosis and subsequent translocation of the light chain into the nerve cell cytoplasm. The light chain, which is shared by tetanus toxin, contains a zinc-requiring endopeptidase, that cleaves proteins required by the docking/fusion complex critical to neuroexocytosis. Type B botulinum toxin and tetanus toxin target both VAMP/synaptobrevin, a docking protein located on the acetylcholine-containing synaptic vesicles (synaptosome). Type A and E botulism toxins proteolyse SNAP, a component of the presynaptic cell-membrane docking complex (associated with syntaxin). After destruction of these important components of the docking complex, neurotransmitter release cannot proceed, resulting in clinical findings consistent with acetylcholine (botulism) or glycine (tetanus) deficiency. The mechanism of action of tetanus toxin is identical to that of Type B botulinum toxin. VAMP vesicle-associated membrane protein; SNAP synaptosomal associated protein.

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patients clinically if they still can release acetylcholine. The prolonged and variable period of recovery, that occurs after exposure to botulinum toxin, is directly related to the extent of the neuromuscular blockade and the neurogenic atrophy as well as the nerve ending and presynaptic membrane regeneration rates.33,56

first victim of an epidemic or an isolated victim is often misdiagnosed at a stage when the person could still be saved.17,18 The definitive CDC criteria for the diagnosis of botulism are met when a patient presents with a neurologic disorder manifested by a descending paralysis and at least one of the following:

SIGNS AND SYMPTOMS Foodborne Botulism (Adult Type) (In Vitro)

■ ■ ■ ■

Although botulism is the most dreaded of all food poisonings, the initial phase of the disease, which occurs during the first day following ingestion, is often so subtle as to go unnoticed. Unfortunately, botulism is often misdiagnosed on the first visit to a physician.15,104 When gastrointestinal symptoms are striking, and food poisoning is suspected, the differential diagnosis should also include more acute poisonings, such as heavy metals, plants, mushrooms, and the common bacterial, viral, and parasitic agents discussed in Chap. 74. Because the initial presentation of botulism is often subtle, and because physicians are so infrequently confronted with the disease (especially compared to the relatively more common diseases included in the differential diagnosis), there are often serious delays in initiating appropriate management (Table 75–1). This is particularly true of type E botulism, in which initial gastrointestinal signs may be much more prominent than neurologic signs.5 The

The early GI symptoms of botulism include nausea, vomiting, abdominal distension, and pain. There may or may not be a time lag (from 12 hours to several days, but typically not more than 24 hours) before one or more of the following symptoms appears, constipation, dry or sore mouth and throat, blurred vision and impaired accommodation, dysphonia (typically manifested by a nasal quality to the voice), dysarthria, diplopia, descending, bilaterally symmetric motor paralysis beginning with abducens (VI) or oculomotor (III) nerve palsy (frequently resulting in strabismus); dysphagia (at times predominant and severe); mydriasis (often fixed); respiratory insufficiency; and urinary retention (Table 75–2). Although many of these initial signs and symptoms are anticholinergic in nature, the mental status, sensory, and reflex examinations all usually remain normal. When medial rectus palsy, ptosis, and

TABLE 75–1.

electromyographic findings typical of botulism C. botulinum in stool or a wound botulinum toxin in serum, stool, or implicated food samples a compatible clinical illness in a person who is epidemiologically linked to a laboratory-confirmed case.4a,52

Botulism: Clues in the Various Phases of the Differential Diagnosis

Condition

Diagnostic Findings

Aminoglycoside poisoning Anticholinergic poisoning Buckthorn (Karwinskia humboldtiana) Carbon monoxide Cerebrovascular accident (midbrain) Diphtheria (polyneuritis) Eaton-Lambert syndrome

Postanesthetic paralysis, intraoperative exposure Mydriasis, vasodilation, fever, tachycardia, ileus, dry mucosa, altered mental status Rapidly progressive ascending paralytic neuropathy with quadriplegia

Elapidae (coral snake) envenomation Encephalitis Food poisoning (bacterial) Guillain-Barré syndrome (Miller-Fisher variant) Inflammatory myelopathies (acute myelitis, transverse myelitis) Magnesium toxicity Multiple sclerosis

Myasthenia gravis Organic phosphorous compounds Paralytic shellfish poisoning Poliomyelitis Polymyositis Tick (Dermacentor spp)related paralysis

Headache, nausea, altered sensorium, tachypnea, elevated carboxyhemoglobin Asymmetric focal findings, abnormal CT Exudative pharyngitis, cranial polyneuropathy (late) cardiac manifestations, hypotension Neoplasm, ophthalmoplegia (rare), no respiratory paralysis posttetanic facilitation on EMG, calcium channel blocking antibodies Following envenomations: euphoria, lightheadedness, fasciculations, tremor, weakness, salivation, nausea, vomiting followed by bulbar palsy, paralysis including slurred speech, diplopia, ptosis, dysphagia, dyspnea, and respiratory compromise Fever, mental status abnormalities, seizures, elevated CSF protein, and pleocytosis Rapid onset of disease, absence of cranial nerve findings Acute inflammatory demyelinating polyneuropathy, absent deep-tendon reflexes, ataxia, elevated CSF protein without cells, denervation and prolonged nerve conduction velocity on EMG Complete (transverse) or incomplete spinal syndrome: posterior column myelopathy with ascending paresthesias or ascending spinothalamic findings or Brown-Sequard syndrome. Typically follows viral illness, back pain, progressive paraparesis, asymmetric ascending paresthesias in legs. CSF: 5–50 lymphocytes/mm3 Oral or intravenous exposure to magnesium, respiratory compromise, diffuse flushing, weakness, hypermagnesemia Weakness, visual blurring (optic neuritis), sensory disturbances, diplopia, ataxia. Lesions separated in space and time. Mononuclear cell pleocytosis in CSF. Evoked-reponse testing: slow or abnormal conduction in visual, auditory, somatosensory, or motor pathways; abnormal MRI with a paramagnetic dye (gadolinium) Aggravation of fatigue with exercise, positive edrophonium (Tensilon) test, acetylcholine receptor antibodies Salivation, lacrimation, urination, defecation, fasciculations, bronchorrhea Incubation 40

CNS = central nervous system; ICP = intracranial pressure; PNS = peripheral nervous system; GI = gastrointestinal; Heme = hematologic; Misc = miscellaneous.

culmination of a long history of lead exposure. As total dose increases, these symptoms are almost always preceded first by measurable biochemical and physiologic impairment, followed, in turn, by subtle prodromal clinical effects that may only become apparent in hindsight (Fig. 80–6). In general, it is considered that children are more susceptible than adults to toxicity for a given dose (eg, measured blood lead level); however, the data for this regard primarily concern effects on the CNS, reflecting the aforementioned issues of blood-brain barrier immaturity and early childhood neurodevelopment. Symptomatic Children. Acute lead encephalopathy is the most severe presentation of pediatric plumbism. Encephalopathy is characterized by pernicious vomiting and apathy, bizarre behavior, loss of recently acquired developmental skills, ataxia, incoordination, seizures, altered sensorium, or coma. Physical examination may reveal papilledema, oculomotor or facial nerve palsy, diminished deep-tendon reflexes, or other evidence of increased intracranial pressure.51,307 There may be pallor if there is coexisting anemia in patients with more chronic exposure. Encephalopathy usually occurs in children aged 15–30 months, is associated with BLLs >100 µg/dL although it is reported with BLLs as low as 70 µg/dL,224 and tends to occur more commonly in summer months.65 The reason for this seasonal prevalence is poorly understood, although it may reflect the increase in lead dust exposure that typically occurs during warm summer months.313 Milder but ominous symptoms that may portend incipient encephalopathy include sporadic vomiting, hyperirritable or aggressive behavior, periods of lethargy interspersed with lucid intervals, and decreased

Figure 80–6. The biochemical and clinical effects of lead in children and adults. (Modified from Royce SE, Needleman HL: Case Studies in Environmental Medicine. Lead Toxicity. Atlanta, Agency for Toxic Substances and Disease Registry, 1992.)

interest in play activities. Many patients seek medical advice for vomiting and lethargy during the 2–7 days prior to onset of frank encephalopathy.65 Additional symptoms include anorexia, constipation, and intermittent abdominal pain.62,224 Physical examination of such children is usually without specific abnormalities. Subencephalopathic symptomatic plumbism usually occurs in children 1–5 years old and is associated with BLLs >70 µg/dL, but may occur with levels as low as 50 µg/dL. Unfortunately, common complaints in well children of this age (“terrible two’s,” with functional constipation and who don’t eat as much as parents expect) often overlap with the milder range of reported symptoms of lead poisoning. It is not infrequent that parents whose child was diagnosed by routine blood screening recognize milder symptoms only in hindsight, after chelation treatment (“it seemed as if the child was going through a phase”).104 This is especially true currently, when symptomatic plumbism is rarely reported.51,52 Other uncommon clinical presentations are described,62 including isolated seizures without encephalopathy (indistinguishable from idiopathic epilepsy), chronic hyperactive behavior disorder, isolated developmental delay, progressive loss of cortical function simulating degenerative cerebral disease, peripheral neuropathy (reported particularly in children with sickle-cell hemoglobinopathy),95 and a syndrome of colicky abdominal pain, vomiting, constipation, and myalgias of trunk and proximal girdle muscles.

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Death and serious neurologic sequelae occurred frequently when encephalopathy was common.63 Mortality was 65% in the prechelation era, dropping to 10 µg/dL, the currently accepted level of concern.45 As noted previously in the discussion of pathophysiologic effects, the subclinical toxicity of lead in this population centers around subtle effects on growth, hearing, and neurocognitive development. This last effect, in particular, is the subject of intense research interest and scrutiny.81 Numerous studies attempt to elucidate and quantify cognitive and behavioral deficits in children with BLLs below those typically associated with symptomatic plumbism (125), and an approximate 4-fold increase in those with a severe deficit (IQ 150 µg/dL). Other manifestations of symptomatic lead poisoning in adults involve CNS, peripheral nerve, hematologic, renal, gastrointestinal, rheumatologic, and endocrine/reproductive findings.148,240,249 Subencephalopathic CNS findings include changes in mood and cognition. Subtle neurocognitive abnormalities demonstrable by neuropsychiatric testing are being found in adults as well as children with modest elevations in blood lead. Such studies have documented abnormal psychometrics and nerve conduction in workers recently exposed to lead as BLLs rose to above 30 µg/dL.168 Early symptoms, at BLLs of 40–80 µg/dL, include increased tiredness at the end of the day, disinterest in leisure-time pursuits, falling asleep easily, moodiness,

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and irritability. As for children, these early symptoms may be so subtle as to be recognized only in hindsight after the patient is away from the exposure. Subclinical effects on reproductive function and blood pressure may be apparent in this range of exposure, as detailed earlier. As exposure increases (BLL >80 µg/dL, or air levels of 0.3–0.5 mg/m3), new symptoms develop, including headache, memory loss, decreased libido, and insomnia. Gastrointestinal effects may appear, including metallic taste, abdominal pain, decreased appetite, weight loss, and constipation. Musculoskeletal and rheumatologic complaints at this stage include muscle pain, muscle weakness (especially upper extremity, dominant side), joint tenderness, numbness of the legs, occasional paresthesias, tremor, and hyperreflexia. Many patients at this stage have mild anemia. Patients with prolonged exposure at this level are at risk for chronic nephropathy. As exposure increases further (BLLs >100 µg/dL), attacks of colic may appear, anemia is virtually always present, and the patient is at significant risk for peripheral nerve palsy or encephalopathy. Physical examination findings will vary with degree of severity. Mild and moderate symptoms usually occur in patients with normal examination findings.83 In encephalopathic patients, typical changes of stupor, coma, posturing, and papilledema are noted. Milder abnormal neurologic findings include dominant wrist or hand weakness, paresthesia, or tremor. Grayish stippling of the retina circumferential to the optic disk is described by one author,277 but disputed by others.215 A bluish-purple gingival lead line (Burton line), representing lead sulfide precipitation, is described rarely in adult patients with poor oral hygiene. Abdominal guarding and tenderness are occasionally observed. Patients with gout may have typical joint findings of acute arthritis. Severely anemic patients may exhibit pallor. Careful neuropsychologic testing may reveal abnormalities of memory span, rapid motor tapping, visual motor coordination, and grip strength.76 Table 80–6 summarizes the spectrum of symptoms and signs associated with adult lead poisoning.240

Organic Lead Clinical symptoms of tetraethyl lead (TEL) toxicity are usually nonspecific initially, and include insomnia and emotional instability.31,249 Nausea, vomiting, and anorexia may occur. The patient may exhibit tremor and increased deep-tendon reflexes. In more severe cases, these symptoms progress to an encephalopathy with delusions, hallucinations, and hyperactivity, which may resolve or deteriorate to coma and, occasionally, death. Severe cases may also develop hepatic and renal injury. Of note, in contrast to inorganic lead poisoning, patients with significant TEL toxicity do not consistently manifest hematologic abnormalities or elevations of heme synthesis pathway biomarkers. In addition, there is not a close correlation of neurotoxicity severity with measured BLL.132

ASSESSMENT Clinical Diagnosis in Symptomatic Patients The physician must consider the diagnosis of lead poisoning in order to recognize this uncommon condition. For all patients in whom plumbism is considered, based on clinical manifestations, the medical evaluation should first include a comprehensive past medical history, including that of foreign body ingestions or gunshot wounds with retained bullets. Further inquiry should elicit oc-

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY by a constellation of clinical features and ancillary studies: age 1–5 years, a prodromal illness of several days’ to weeks’ duration (suggestive of milder lead-related symptoms), occurrence in summer, history of pica and source of lead exposure, the laboratory features noted above, which are equally helpful in young children, radiologic findings of dense metaphyseal “lead lines” at wrists or knees (Fig. 80–2), and/or evidence of recent pica for lead paint particles on abdominal radiographs (Fig. 80–8). In both adults and children, the decision to institute empiric chelation treatment should not deter additional emergent diagnostic efforts to exclude or to confirm other important entities while blood lead levels are pending. An important consideration in this context may be the suspicion of an acute, potentially treatable CNS infection (eg, bacterial meningitis or herpetic encephalitis). Lumbar puncture may be dangerous in patients with lead encephalopathy because of the risk of cerebral herniation. If immediate lumbar puncture is thought to be highly desirable, a computed tomography scan would allow determination of severe cerebral edema, midline shift, or other evidence of especially high risk for herniation. If performed, the minimal amount of fluid necessary for diagnosis (250 µg/dL), and abnormal urinalysis. In this context, it would probably be appropriate to institute presumptive chelation therapy while awaiting lead levels. In children, a similar indication for presumptive treatment would be suggested

A

Laboratory Considerations Laboratory testing is used to augment the evaluation of both lead exposure and lead toxicity. Traditionally, the direct measurement of lead in blood was costly and posed technical obstacles; thus, a reliance developed on using biomarkers derived from lead-induced abnormalities of the heme synthesis pathway and on using

B

Figure 80–8. A. Abdominal radiograph of a child who had massive paint chip ingestion. B. Followup radiograph after whole-bowel irrigation. (Courtesy of Department of Radiology, St. Christopher’s Hospital for Children, Philadelphia, PA.)

CHAPTER 80

enhanced urine lead excretion after chelating agent administration. These indirect assays have waned in utility as levels of concern for lead exposure have decreased concomitantly with technical advances in direct blood lead measurement.122 Several of the indirect biomarkers are reviewed briefly here; for a more in-depth discussion the interested reader is referred to several comprehensive reviews.122,220 Routine Laboratory Tests. As detailed in the sections on hematologic and renal pathophysiolgic effects, lead may cause several changes in routine complete blood count, urinalysis, or renal function tests. These are usually observed only in moderate to severe degrees of exposure. The patient may manifest normochromic or hypochromic microcytic anemia and red blood cell stippling. The urinalysis may be positive for protein and glucose. Renal function tests may reveal elevated blood urea nitrogen and creatinine in patients with chronic lead nephropathy. Radiographic evaluation may be helpful occasionally. The growing long bones, particularly at wrists and knees, in children about 9 months to 5 years of age may reveal characteristic “lead lines” of increased calcification in the zone of provisional calcification (Fig. 80–2). These dense metaphyseal bands take 4–8 weeks of heavy exposure to develop. They are more likely to be significant if the smaller ulna and fibula are involved as well as the larger radius and tibia.29 Lead lines may also be present in flat bones such as ribs, clavicles, and the iliac crest.312 Abdominal radiographs may reveal radiopacities representing lead paint chips or particles and, rarely, lead-containing folk medicines or foreign bodies (Figs. 80–4 and 80–8).34 These findings are usually present for 24–36 hours postingestion.220 One survey found that 26% of children with lead levels >55 µg/dL had abdominal radiopacities.181 Biomarkers of Lead Exposure and Toxicity. The effect of lead on the heme synthesis pathway (Fig. 80–5) and the ease of sampling blood and urine have led to several tests based on enzyme inhibition or accumulation of substrates. The erythrocyte -aminolevulinic acid dehydratase activity is a sensitive marker of lead exposure and shows 50% inhibition at lead levels of only 15 µg/dL. However, the enzyme must be assayed within 24 hours of blood sampling and is so sensitive it cannot distinguish between moderate and severe exposure.122,201 The measurement of accumulated ALA in urine may serve as a useful tool for tracking lead exposure in occupational settings, but today is considered relatively insensitive because it does not rise appreciably until blood lead is >40 µg/dL. The relatively low-cost test of urine ALA continues its value in areas of the world with extensive lead contamination but limited financial resources.122,257 Erythrocytes accumulate protoporphyrin in the presence of iron deficiency or inhibition of heme synthetase by lead. The red cell has an average life span of 120 days, so that erythrocyte protoporphyrin (EP) levels reach a steady state over 3 months and reflect relatively long-term lead exposure.220 A simple fluorometric technique for assaying red cell EP was developed in the early 1970s,222 and for 2 decades this test became the method of choice for lead surveillance. It could utilize a fingerstick drop of blood, was not influenced by surface lead-dust contamination, and also screened for iron deficiency, another prevalent condition of young children. Of note, the terms EP, free erythrocyte protoporphyrin (FEP), and zinc protoporphyrin (ZPP) have often been used interchangeably in the past. This reflects a confusion based on older extraction

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techniques of measuring red cell protoporhyrins.220 In lead-poisoned or iron-deficient red cells, most of the increased EP is bound to zinc. Most current tests measure total red cell EP and obviate the need for extraction and for distinguishing FEP from ZPP. The EP first increases at lead levels of about 17 µg/dL, and thus is also insensitive to lead levels in the 10–25-µg/dL range.122 As such, it is no longer recommended as a surveillance test for childhood lead poisoning. The EP may still be useful for tracking response to therapy and distinguishing acute from chronic lead exposure and as an adjunct to the emergency diagnosis of symptomatic plumbism. Chelatable Lead. The baseline excretion of lead in urine is not generally considered a sensitive biomarker of lead exposure. However, lead excretion after a single dose of the chelator CaNa2EDTA is correlated with blood lead and several heme pathway markers.61,122 A lead “challenge,” “mobilization,” or “provocative” test was developed to evaluate the size of the mobilizable pool of body lead burden, with the hope of pinpointing which asymptomatic patients with modestly elevated blood lead levels would most benefit from a full course of chelation therapy.244 Standardized doses of CaNa2EDTA were administered and 24-hour244 or 8-hour176 urine collections tested for lead excretion, with various formulas proposed for a “positive” test. Several assumptions about the validity of this test are not obvious.122 It is not clear whether positive responders will continue to excrete more lead than poor responders. Conversely, it is not clear that negative tests would imply lack of any value for subsequent chelation. One large series of lead mobilization tests found that the test was positive in only 28% of children with blood lead levels of 40–49 µg/dL, and 66% of children with lead levels of 50–69 µg/dL.303 Most authorities would currently recommend chelation for all patients in the latter group, and many of those in the former.52 It is also possible that single doses of CaNa2EDTA may translocate lead from less vulnerable sites, such as bone, to more vulnerable sites, such as the brain; this is demonstrated in rats.61,74 Finally, the test is cumbersome, difficult technically in children who are not toilet trained, and requires parenteral drug administration, and thus is not risk free. This test is no longer recommended by the American Academy of Pediatrics,5 and seems to be falling out of favor in occupational medicine practice as well.83,122,249 Blood Lead. For many years the use of blood lead as a biomarker for lead exposure was avoided by researchers and clinicians.122 As noted earlier, blood lead has complex kinetics, reflecting the redistribution of lead from other compartments, primarily bone, to blood. Blood sampling required relatively large volumes (5–7 mL) and was costly and technically difficult. However, recently several factors favor the use of whole blood as the primary biomarker for both research and clinical practice. The evolution of atomic absorption spectrophotometry (AAS) allows reliable, sensitive determinations of blood lead as low as 1 µg/dL. The equipment is widely available and some techniques (eg, graphite furnace AAS) require only 0.25 mL blood; newer modifications also allow application to capillary blood samples.249 All the alternative biomarkers discussed above have some inherent limitations, particularly lack of sensitivity at the lower body lead burdens currently of concern. Lastly, virtually all of the recent research associating low-level lead exposure with adverse clinical outcomes, especially neurocognitive deficits in children or renal

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function in adults, have utilized blood lead as the primary biomarker.122 Whole venous blood for lead testing may be collected, after careful skin preparation, through standard stainless-steel needles into special lead-free (tan top) or trace element–free (dark blue top) evacuated tubes (eg, Vacutainers from Becton Dickinson Co). If these are not readily available, standard heparinized tubes (green top) may be used, but elevated values should probably be verified.249 The blood should be mixed thoroughly as soon as possible to ensure anticoagulation. Pediatric blood-lead testing is often hampered by the requirement for venipuncture and relatively large blood volumes. An alternative is the use of capillary sampling by fingerstick puncture. This technique is safe and quick and can be applied to mass screening. Its principal drawback is the potential for contamination by lead-soiled fingertips, and thus an excessive rate of false-positive testing. At least in a controlled research protocol, capillary test results were highly correlated with matched venous samples, with mean capillary-venous differences of less than 1 µg/dL.252 It is imperative that fingers be swabbed thoroughly with alcohol prior to puncture. Fingerstick blood may be collected in capillary tubes or as a dried blood spot on filter paper.279 Venous confirmation of elevated capillary lead levels is still considered mandatory prior to chelation or other significant interventions. The capillary test is considered too inaccurate, because of frequent false-positives, to be of value in the context of adult occupational exposure.249

Other Lead Assays Lead can also be quantified in urine, teeth, and hair. Urine assays are considered insensitive, and hair is unreliable because of surface contamination.220 Shed primary teeth are used in research studies as biomarkers of cumulative childhood lead exposure,197 but are obviously impractical in clinical patient management. Research Methodologies. X-ray fluorescence (XRF) technology estimates tooth30 and bone138 lead, and thus indirectly is a cumulative measure of body lead exposure in epidemiologic studies. Protocols have not yet achieved the standardization that would be required for a clinically useful test. The tests are relatively costly and require the patient to remain still for up to 30 minutes, involve low-dose radiation exposure, and are not widely available.122 The XRF technique may have promise in research studies of issues concerning past chronic heavy lead exposure and a variety of current health outcomes.302

SCREENING Children As evidence accumulated in the 1970s and 1980s that low-level lead exposure was a significant pediatric public health issue, it simultaneously became apparent that the only way to detect elevated lead burdens early in childhood would be to screen widely.53 In October 1991, the CDC recommended that every child in the United States be screened at age 1 year, and, preferably, at age 2 years as well, by whole-blood lead determination. A blood lead of >10 µg/dL was defined as the intervention level.52 However, over the next few years, numerous studies appeared that found a very low prevalence of elevated lead levels in selected communities.27,202,283 Several of these found that a few simple questions re-

garding housing age and condition were predictive for the few children who did have elevated lead levels.27,133,202 Concern grew that overemphasis and misappropriation of resources on universal screening would further compromise higher-priority efforts for targeted screening of the most at-risk populations.133,253 A 1994 national survey found that only 29% of children living in homes built prior to 1960, and only 30% of children in families earning less than $20,000 per year, had been screened.26 At the same time, remarkable cases of extremely elevated blood lead levels (>100 µg/dL) detected on routine screening continued to be reported, especially in minority, inner-city children.79 In response to these developments, the CDC proposed new recommendations in 1997 and 2000,43,46 which were recently endorsed by the American Academy of Pediatrics,4 and are outlined in Table 80–7. This approach emphasizes targeted screening and followup for most children from low-prevalence communities. A recent study examined cost-effectiveness of this recommended approach, and found that only universal screening would detect all BLLs >10 µg/dL and was cost-effective in high prevalence areas. Targeted screening of venous blood was more cost-effective but less sensitive in low- or medium-prevalence communities. In both contexts, venous blood

TABLE 80–7.

Pediatric Screening and Followup Guidelines

Screening Screen 1. All high-risk children at 1 and 2 y (3–6 y if not previously screened) 2. Selected low-risk children (any affirmative answer to risk questions) (high-risk community = 12% of young children with elevated BPb, 27% of homes built before 1950; all children enrolled in Medicaid) Personal Risk Questionnaire 1. Does your child live in or regularly visit a home built before 1950? 2. Does your child live in or regularly visit a home built before 1978 undergoing remodeling or renovation (or has been within 6 mo)? 3. Specific exposure questions: Personal, family history of lead poisoning Occupational, industrial, hobby exposures Proximity to major roadway Hot tap water for consumption Cultural exposures (folk remedies, cosmetics, ceramic food containers, trips, residence outside US, international adoptees) Migrant farm workers, receipt of poverty assistance History of pica for paint chips, dirt History of iron deficiency Followup BPb (mg/dL) 30 days per year must be screened periodically, as outlined in Table 80–8.295 It is illegal to provide medicinal dietary interventions or prophylactic chelation prior to routine screening. It should be noted that the law’s intent is not simply to remove lead-poisoned workers from the worksite, only to replace them with newer employees whose lead burdens are less extensive, but rather to recognize an opportunity to improve workplace hygiene.249 Where the lead standard is being invoked, such as the lead smelting and battery manufacturing industries, clinical lead poisoning and average blood lead levels have decreased impressively.295 In 1993, the lead standard was extended to the construction industry,294 but it is not yet applied to agricultural workers.

TREATMENT There are several caveats about the treatment of lead poisoning. First, the most important aspect of treatment is removal from exposure to lead. Unfortunately, effective implementation of this therapy is often beyond the control of the clinician, but rather depends on a complex interplay of public health, social, and political

TABLE 80–8. OSHA Adult Lead Standard Screening and Followup Summary BPb (
g/dL)

Recommended Action

>60 on a single test; or average >50 of last 3 samples, or all samples over prior 6 mo (requires confirmation within 2 wk) >40–60 100

BAL 450 mg/m2/da CaNa2EDTA 1500 mg/m2/da BAL 300–450 mg/m2/da CaNa2EDTA 1000–1500 mg/m2/da

Mild symptoms or 70–100 Asymptomatic and < 70

Succimer 700–1050 mg/m2/d Usually not indicated

75 mg/m2 IM every 4 h for 5 d Continuous infusion, or 2–4 divided IV doses, for 5 d (start 4 h after BAL) 50–75 mg/m2 every 4 h for 3–5 d Continuous infusion, or 2–4 divided IV doses, for 5 d (start 4 h after BAL) Base dose, duration on BPb, severity of symptoms (see text) 350 mg/m2 tid for 5 d, then bid for 14 d Remove from exposure

Adults Encephalopathy

Children Encephalopathy Symptomatic, or > 70

Asymptomatic: 45–69

20–44 < 20

BAL 450 mg/m2/da CaNa2EDTA 1500 mg/m2/da BAL 300–450 mg/m2/da CaNa2EDTA 1000–1500 mg/m2/da Succimer 700–1050 mg/m2/d or CaNa2EDTA, 1000 mg/m2/da (or rarely, D-penicillamine) Routine chelation not indicated (see text) Chelation not indicated Attempt exposure reduction

75 mg/m2 IM every 4 h for 5 d Continuous infusion, or 2–4 divided IV doses, for 5 d (start 4 h after BAL) 50–75 mg/m2 every 4 h for 3–5 d Continuous infusion, or 2–4 divided IV doses, for 5 d (start 4 h after BAL) Base dose, duration on BPb, severity of symptoms (see text) 350 mg/m2 tid for 5 d, then bid for 14 d Continuous infusion, or 2–4 divided IV, for 5 d (see text) Await current studies (eg, NIEHS TLC) If succimer used, same regimen as per above group See Table 80–9

a

Doses expressed mg/kg: BAL 450 mg/m2 (24 mg/kg); 300 mg/m2 (18 mg/kg). CaNa2EDTA 1000 mg/m2 (25–50 mg/kg); 1500 mg/m2 (50–75 mg/kg) adult maximum 2–3 g/d). Succimer 350 mg/m2 (10 mg/kg). Subsequent treatment regimens based on postchelation BPb and clinical symptoms (see text). BPb = blood lead (g/dL); EP = erythrocyte photoporphyrin; IM = intramuscular; IV = intravenous; NIEHS TLC = National Institute of Environmental Health Sciences supported multicenter study: Treatment of lead-exposed children. Compiled, with permission, from references 5, 52, 148, 192, 224, and 228.

of BAL is given 4 hours later, followed immediately by intravenous (IV) CaNa2EDTA, in maximum concentration of 0.5% solution, at 1500 mg/m2/d (or 50 mg/kg/d)5 as a continuous infusion over several hours or in divided-dose infusions.5,52,224 The delay in initiating CaNa2EDTA infusion is based on past observations of clinical deterioration in encephalopathic patients treated with this agent alone.5,62 Therapy is typically continued with both agents for 5 days, although in milder cases with prompt resolution of encephalopathy and decrease of BLL to 70 µg/dL, should be chelated with a regimen similar to that recommended for encephalopathy. It is likely that this group of patients will require only 2–3 days of BAL, in addition to 5

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days of CaNa2EDTA. The asymptomatic patients in this group might also be adequately treated with DMSA (succimer) and CaNa2EDTA, or even DMSA alone, but these regimens have not been studied to date in such children. Intensive care monitoring may be prudent for such patients as well, at least during the initiation of chelation therapy.192,224 Chelation therapy is widely recommended for asymptomatic children with BLLs between 45 and 70 µg/dL.5,9,52,192 Children without overt symptoms may be treated with succimer, which has documented efficacy in lowering BLLs and short-term safety since its FDA approval in 1991.24,60,124,160,192 Succimer is initiated at 30 mg/kg/d (or 1050 mg/m2/d) orally in three divided doses; this is continued for 5 days, then decreased to 20 mg/kg/d (or 700 mg/m2/d) in two divided doses for 14 additional days.5,123 The original data establishing this empiric dosing regimen were based on surface area rather than body weight.123 For younger children, the alternative dosing by body weight results in suboptimal dosing.236 Although the ability to chelate children orally with succimer makes it tempting to prescribe this medication routinely for outpatient therapy, and some animal evidence suggests succimer does not enhance enteral lead absorption,145 clinical reports suggest that children must be protected from continued lead exposure during succimer chelation.59,60 Home abatement and reinspection should be accomplished before initiation of ambulatory succimer therapy; if this is not feasible, then hospitalization is still warranted. Alternative regimens (for rare patients with succimer intolerance or allergy, or parental noncompliance) would include inpatient parenteral chelation with CaNa2EDTA at 25 mg/kg/d for 5 days,5 or an outpatient oral course of D-penicillamine. Combination chelation therapy with either BAL and CaNa2EDTA or succimer and CaNa2EDTA for patients with lead levels in this range produced comparable reductions in BLLs with both regimens.25 Neither regimen was compared to monotherapy with succimer alone, but the mean decline in postrebound BLLs for the combined succimer and CaNa2EDTa group was significantly better than is typically achieved with succimer alone (
38.5% vs
20% to
30%).24,25 After initial chelation therapy, decisions to retreat are based on clinical symptoms and followup BLLs. Patients with encephalopathy or any severe symptoms, or initial BLL >100 µg/dL, will often require repeated courses of treatment. It is suggested that at least 2 days elapse before restarting chelation. The precise regimen and dosing of chelating agents are determined by ongoing symptomatology and the repeat BLLs (Table 80–10). A third course of chelation should rarely be necessary sooner than 5–7 days after the second course ends.224 For patients with milder degrees of plumbism (eg, asymptomatic, initial BLL 45 µg/mL

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demonstrated a similar reduction in blood lead levels at the end of treatment and at 14 and 33 days following the termination of treatment.18 Blood lead level reductions were approximately 75%, 40%, and 37% at the end of therapy, and at 14 and 33 days posttreatment, respectively. The succimer plus CaNa2EDTA combination was better tolerated. 18

DMPS DMPS (racemic-2,3-dimercapto-1-propanesulfonic acid, Na salt) is an investigational metal chelator which, like succimer, is a water-soluble analogue of BAL.3,7,21 A dose of 15 mg/kg of DMPS is equimolar to 12 mg/kg of succimer. DMPS has been used in the Soviet Union since the late 1950s and is marketed in both oral and parenteral forms in Germany as Dimaval. DMPS seems promising in mercury and arsenic poisoning.3,7,9,12,21,41 DMPS is associated with an increase in the urinary excretion of copper and the development of Stevens-Johnson syndrome.23 Like succimer, DMPS does not appear to redistribute mercury or lead to the brain. More research needs to be done to determine whether DMPS is more advantageous than succimer given its lower LD50 in rodents (5.22 mmol/kg vs 16.5 mmol/kg for succimer).

DOSING Succimer (Chemet) is available as 100-mg bead-filled capsules. In patients who cannot swallow the capsule whole, the capsule can be separated immediately prior to use and sprinkled into a small amount of juice or on apple sauce, ice cream, or soft food, or put on a spoon and followed by a fruit drink. The dosage is 350 mg/m2 in children 3 times a day for 5 days followed by 350 mg/m2 twice a day for 14 days. In adults, the dosage is 10 mg/kg in the same regimen as above. Using 10 mg/kg in children rather than dosing based upon body surface area, as was done during the premarketing trials, may result in patient underdosing.68

UNANSWERED QUESTIONS In spite of the epidemic of lead poisoning, there is a paucity of rigorous data defining the role of succimer. There are many unanswered questions regarding clinical efficacy, pharmacokinetics, and dosage regimens.56,68 These questions include: How exactly does succimer bind lead in the blood? Is it succimer, its active disulfide cysteine metabolites, or both that bind lead? What happens to the cysteine conjugates? How do the kidneys handle the lead chelate? What exactly is reabsorbed in the enterohepatic circulation, succimer, the cysteine metabolites, or the lead chelated form? Should a longer succimer-dosing regimen be used? And, the most important question of all, does succimer chelation improve clinical outcome?

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3. Aposhian HV, Carter DE, Hoover TD, et al: succimer, DMPS and DMPA as arsenic antidotes. Fundam Applied Tox 1984;4:S58–S70. 4. Aposhian HV: succimer and DMPS—Water-soluble antidotes for heavy metal poisoning. Annu Rev Pharmacol Toxicol 1983;23: 193–215. 5. Aposhian HV, Aposhian MM: Meso-2,3-dimercaptosuccinic acid: Chemical, pharmacological and toxicological properties of an orally effective metal chelating agent. Annu Rev Pharmacol Toxicol 1990; 30:279–306. 6. Aposhian HV, Maiorino RM, Dart RC, et al: Urinary excretion of meso-2,3 dimercaptosuccinic acid in human subjects. Clin Pharmacol Ther 1989;45:520–526. 7. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, et al: Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995;97:23–38. 8. Aposhian HV, Maiorino RM, Rivera M, et al: Human studies with the chelating agents, DMPS and succimer. J Toxicol Clin Toxicol 1992;30: 505–528. 9. Aposhian M, Maiorano R, Xu Z, Aposhian HV: Sodium 2,3-dimercapto-1-propanesulfonate (DMPS) treatment does not redistribute lead or mercury to the brain of rats. Toxicol 1996;109:49–55. 10. Aposhian HV, Mershon MM, Brinkley, Hsu CA: Anti-lewisite activity and stability of meso-dimercaptosuccinic acid and 2,3-dimercapto1-propanesulfonic acid. Life Sci 1982;31:2149–2156. 11. Aposhian HV, Taklock CH, Moon TE: Protection of mice against the lethal effects of sodium arsenite: A quantitative comparison of a number of chelating agents. Toxicol Appl Pharmacol 1981;61:385–392. 12. Aposhian HV, Zheng B, Aposhian M, et al: DMPS-Arsenic challenge test. Toxicol Appl Pharmacol 2000;165:74–83. 13. Asiedu P, Moulton T, Blum CB, et al: Metabolism of meso-2,3-dimercaptosuccinic acid in lead-poisoned children and normal adults. Environ Health Perspect 1995;103:734–739. 14. Bankowska J, Hine C: Retention of lead in the rat. Arch Environ Contam Toxicol 1985;14:621–629. 15. Bhattacharya A, Smelser D, Berger O, et al: The effect of succimer therapy in lead intoxication using postural balance as a measure: A case study in a nine-year-old child. Neurotoxicology 1998;19: 57–64. 16. Bentur Y, Brook JG, Behar R, Taitelman U: Meso-2,3-dimercaptosuccinic acid in the diagnosis and treatment of lead poisoning. J Toxicol Clin Toxicol 1987;25:39–51. 17. Besunder JB, Anderson RL, Super DM: Short-term efficacy of oral dimercaptosuccinic acid in children with low to moderate lead intoxication. Pediatrics 1995;96:683–687. 18. Besunder JB, Super DM, Anderson R: Comparison of dimercaptosuccinic acid and calcium disodium ethylenediaminetetraacetic acid versus dimercaptopropanol and ethylenediaminetetraacetic acid in children with lead poisoning. J Pediatr 1997;130:966–971. 19. Bluhm RE, Bobbitt RG, Welch LW, et al: Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. I: History, neuropsychological findings and chelator effects. Hum Exp Toxicol 1992;11:201–210. 20. Buchet JP, Lauwerys RR: Influence of 2,3 dimercaptopropane-1-sulfonate and dimercaptosuccinic acid on the mobilization of mercury from tissues of rats pretreated with mercuric chloride, phenylmercury acetate or mercury vapors. Toxicology 1989;54:323–333. 21. Campbell JR, Clarkson TW, Omar MD: The therapeutic use of 2,3dimercaptopropane-1-sulfonate in two cases of inorganic mercury poisoning. JAMA 1986;256:3127–3130. 22. Chen S, Golemboski KA, Sanders FS, et al: Persistent effect of in utero meso-2,3-dimercaptosuccinic acid (succimer) on immune function and lead-induced immunotoxicity. Toxicology 1999;132:67–69. 23. Chisolm JJ: BAL, EDTA, succimer and DMPS in the treatment of lead poisoning in children. J Toxicol Clin Toxicol 1992;30:493–504. 24. Chisolm JJ: Safety and efficacy of meso-2,3-dimercaptosuccinic acid (succimer) in children with elevated blood lead concentrations. J Toxicol Clin Toxicol 2000;38:365–375.

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71. O’Connor ME, Rich D: Children with moderately elevated lead levels: Is chelation with succimer helpful? Clin Pediatr (Phila) 1999;38: 325–331. 72. O’Flaherty EJ, Inskip MJ, Yagiminas AP, Franklin CA: Plasma and blood lead concentrations, lead absorption and lead excretion in subhuman primates. Toxicol Appl Pharmacol 1996;138:121–130. 73. Okonishnokova IE, Rosenberg EE: Succimer as a means of chemoprophylaxis against occupational poisonings of workers handling mercury. Gig Tr Prof Zabol 1971;15:29–32. 74. Okose P, Jennis T, Honcharuk L: Untoward effects of oral dimercaptosuccinic acid in the treatment of lead poisoning [abstract]. Vet Hum Toxicol 1991;33:376. 75. Pappas JB, Ahlquist T, Winn P, et al: The effect of oral succimer on ongoing exposure to lead [abstract]. Vet Hum Toxicol 1992;34:361. 76. Pappas JB, Ahlquist JT, Allen EM, Banner W: Oral dimercaptosuccinic acid and ongoing exposure to lead: Effects on heme synthesis and lead distribution in a rat model. Toxicol Appl Pharmacol 1995; 133:121–129. 77. Piomelli S, Rosen JF, Chisolm JJ Jr, Graef JW: Management of childhood lead poisoning. J Pediatr 1984;105:523–532. 78. Planas-Bohne F: The influence of chelating agents on the distribution and biotransformation of methylmercuric chloride in rats. J Pharmacol Exp Ther 1981;217:500–504. 79. Rivera M, Zheng W, Aposhian HV, Fernando Q: Determination and metabolism of dithiol-containing agents VIII. Metal complexes of meso-dimercaptosuccinic acid. Toxicol Appl Pharmacol 1989;100: 96–106. 80. Schafer B, Kreppel H, Reichl FX, et al: Effect of oral treatment with BAL, DMPS or succimer in organs of mice injected with arsenic trioxide. Arch Toxicol 1991;14(Suppl):228–230. 81. Shum S, Whitehead J, Vaughn L: Chelation of organoarsenate with dimercaptosuccinic acid. Vet Hum Toxicol 1995;37:239–242. 82. Sigg T, Burda A, Leikin JB, et al: A report of pediatric succimer overdose. Vet Hum Toxicol 1998;40:90–91. 83. Singh PK, Jones MM, Xu Z, et al: Mobilization of lead by esters of meso-2,3-dimercaptosuccinic acid. J Toxicol Environ Health 1989;27: 423–434. 84. Smith D, Bayer L, Strupp B: Efficacy of succimer chelation for reducing brain Pb levels in a rodent model. Environ Res 1998;78:168–176. 85. Smith DR, Calacsan C, Woodlard D, et al: Succimer and the urinary excretion of essential elements in a primate model of childhood lead exposure. Toxicol Sci 2000;54:473–480. 86. Smith DR, Ilustre RP, Osterloh JD: Methodological considerations for the accurate determination of lead in human plasma and serum. Am J Ind Med 1998;33:430–438. 87. Smith DR, Woolard D, Luck ML, et al: Succimer and the reduction of tissue lead in juvenile monkeys. Toxicol Appl Pharmacol 2000;166:230–240. 88. Stewart PW, Blaine C, Cohen M, et al: Acute and longer term effects of meso-2,3 dimercaptosuccinic acid (succimer) on the behavior of lead-exposed and control mice. Physiol Behav 1996:59:849–855. 89. Tandon SK, Singh S, Jain V: Efficacy of combined chelation in lead intoxication. Chem Res Toxicol 1994;7:585–589. 90. Tandon SK, Singh S, Prasad S, Mathur N: Mobilization of lead by calcium versenate and dimercaptosuccinate in the rat. Clin Exper Pharmacol 1998;25:686–692. 91. Thomas G, Fournier L, Garnier R, Dally S: Nail dystrophy and dimercaptosuccinic acid. J Toxicol Clin Exp 1987;7:285–287. 92. Thomas PS, Ashton C: An oral treatment for lead toxicity. Postgrad Med J 1991;67:63–65. 93. Treatment of Lead Exposed Children Trial Group: The treatment of lead-exposed children (TLC) trial: Design and recruitment for a study of the effect of oral chelation on growth and development in toddlers. Ped Perinatal Epidem 1998;12:313–333. 94. Tuntunji MF, al-Mahasneh QM: Disappearance of heme metabolites following chelation therapy with meso 2,3-dimercaptosuccinic acid (succimer). J Toxicol Clin Toxicol 1994;32:267–276.

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95. Wang SC, Ting KS, Wu CC: Chelating therapy with NaDMS in occupational lead and mercury intoxication. Chin Med J (Engl) 1965; 84:437–439. 96. Xue H, Ni W, Xie Y, Cao T: Comparison of lead excretion of patients after injection of five chelating agents. Chung Kuo Yao Li Hsuch Pao 1982;3:41–44. 97. Yu-I L, Chiao-Chen C, Yea-Lin T, Kuang-Sheng T: Studies on antibilharzial drugs VI: The antidotal effects of sodium dimercaptosuccinate and BAL-glucoside against tartar emetic. Acta Physiol Sinica 1957;21:24–32.

98. Zalups RK: Influence of 2,3-dimercaptopropoane-1-sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (succimer) on the renal disposition of mercury in normal and uninephrectomized rats exposed to inorganic mercury. J Pharmacol Exp Ther 1993;267:791–799. 99. Zhang J: Clinical observations in ethyl mercury chloride poisoning. Am J Ind Med 1984;5:251–258.

CHAPTER 80

LEAD

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ANTIDOTES IN DEPTH

Edetate Calcium Disodium (CaNa2EDTA) Mary Ann Howland

CaNa2EDTA combines with lead extracted from soft tissues and body fluids, it forms a stable, soluble, nonionized compound that is subsequently excreted in the urine. Following CaNa2EDTA administration, urinary lead excretion is increased 20–50-fold.

LEAD Humans

Edetate calcium disodium (ethylenediamine tetraacetic acid, CaNa2EDTA) is a chelating agent used for the management of lead poisoning. It has largely been supplanted by succimer for mild to moderate lead toxicity. Although it retains a role for the management of serious lead poisoning and lead encephalopathy in conjunction with dimercaprol, even this role is being challenged by succimer.

CHEMISTRY Edetate calcium disodium belongs to the family of polyaminocarboxylic acids. It has a molecular weight of 374 daltons. It is capable of chelating many heavy metals, but is used primarily in the management of lead poisoning. The term chelate has its origin in the Greek word chele, which means “claw,” implying an ability to tightly grasp the metal.38 Implicit in chelation is the formation of a ring-structured complex. When CaNa2EDTA chelates lead, the calcium is displaced and the lead takes its place, forming a stablering compound.23

PHARMACOKINETICS Calcium disodium EDTA is an ionic, water-soluble compound. The volume of distribution is small because of its polar nature and approximates that of the extracellular fluid compartment in normal individuals.19,23 The volume of distribution is even smaller in patients with renal dysfunction (0.05–0.23 L/kg).29 CaNa2EDTA appears to penetrate cells, such as erythrocytes, poorly.2,19 Less than 5% of CaNa2EDTA gains access to the spinal fluid.19,23 Oral administration is of limited value because of an oral bioavailability of less than 5%. Renal elimination approximates the glomerular filtration rate,28 which correlates with creatinine clearance,29 and results in the excretion of 50% of CaNa2EDTA in the urine in 1 hour and more than 95% in 24 hours.19,23 Dosage adjustments are necessary if CaNa2EDTA is used in patients with renal dysfunction.28,29 The half-life is about 20–60 minutes.3,19,23 When

CaNa2EDTA is capable of reducing blood lead levels during therapy, enhancing renal excretion of lead, and reversing the effects of lead on hemoglobin synthesis.11 Blood lead levels rebound considerably days to weeks following the cessation of CaNa2EDTA, as is the case after termination of other chelators.1,2,20 Although CaNa2EDTA has been used clinically since the 1970s, no rigorous clinical studies have ever been performed to evaluate whether CaNa2EDTA is capable of reversing the neurobehavioral effects of lead. Chelators including CaNa2EDTA are incapable of dramatically decreasing the body burden of lead, because only several milligrams of lead are eliminated during chelation.8,9,31 A study of children with blood lead levels of 25–50 µg/dL who were given 5 days of CaNa2EDTA revealed very little difference in blood lead, bone lead, or erythrocyte protoporphyrin levels when compared to pretreatment values.25 Another study in children demonstrated no additional benefits of CaNa2EDTA on cognitive performance beyond that which was achieved by limiting further lead exposure and correcting an iron deficiency anemia.30 A followup study in children with initial blood lead levels about 30 µg/dL by the same authors suggested an improvement in perceptual motor performance over a 6-month period beyond that which was achieved by the treatment of the iron deficiency anemia.33 However, CaNa2EDTA failed to reverse lead-induced learning deficits in the rat model.13

Animals Animal studies demonstrate a decrease in tissue lead stores including brain levels when measurements are performed at the end of CaNa2EDTA therapy.21 However a rat study that examined the effect of CaNa2EDTA on brain lead levels following a single dose demonstrated a significant increase in brain lead levels,14 suggesting that CaNa2EDTA may initially mobilize lead and facilitate redistribution to the brain. Further doses are then able to enhance lead elimination, reduce blood lead levels and subsequently reduce brain lead levels. This phenomenon may explain why some case reports demonstrate a deterioration in lead encephalopathy when CaNa2EDTA is used without concomitant dimercaprol therapy.

CaNa2EDTA MOBILIZATION TEST The CaNa2EDTA mobilization test for diagnostic purposes was recently scrutinized7 and considered obsolete by some authorities.11 Criticisms include difficulties with administration, unreliability as

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a predictor of total body lead burden, expense, and the risk of worsening toxicity through redistribution of lead to either the kidney or brain.11,12 Advocates suggest that the CaNa2EDTA lead mobilization test is cost saving if it can be used to identify the one-third of moderately lead-poisoned children (25–45 µg/dL) who are most able to excrete lead at an enhanced rate.24 The advocates of the test suggest that the use of outpatient 6–8-hour protocols minimizes administration difficulties,26 and that the potential risk of redistribution of lead to the brain has only been demonstrated in rats,12 and is purely theoretical in humans.26 There are no data to support a detrimental central nervous system (CNS) effect of the CaNa2EDTA challenge test in moderately poisoned children.

ROLE IN THE TREATMENT OF ATHEROSCLEROSIS The treatment of atherosclerosis with disodium EDTA cannot be recommended. Although proponents cite the theoretical benefit of chelating calcium from atherosclerotic plaques, there is no scientific evidence to support this approach.

ADVERSE EFFECTS AND SAFETY ISSUES The principal toxicity of CaNa2EDTA is related to the metal chelate. In mice, the LD50 values of various CaNa2EDTA metal chelates when administered intraperitoneally (IP) are CaNa2EDTA, 14.3 mmol/kg; lead EDTA, 3.1 mmol/kg; and mercury EDTA, 0.01 mmol/kg. When CaNa2EDTA is given to patients with lead poisoning, the sites of major renal toxicity are the proximal tubule and, to a lesser extent, the distal tubule and glomeruli.23 This toxicity may be caused by the release of lead in the kidneys during excretion.23 Of 210 children who received dimercaprol and CaNa2EDTA, 3% developed acute oliguric renal failure, which resolved over time without hemodialysis, and 21% had biochemical evidence of nephrotoxicity.24 Other studies failed to demonstrate any cases of renal failure in more than 1000 patient courses of therapy when CaNa2EDTA was given in divided daily doses of 1000 mg/m2 IV over 1 hour, every 6 hours.26 Lead toxicity also causes renal damage independent of chelation. It is therefore important to monitor renal function closely during CaNa2EDTA administration and to adjust the dose and schedule appropriately.28,29 Nephrotoxicity may be minimized by limiting the total daily dose of CaNa2EDTA to 1 g in children or 2 g in adults, although doses may need to be higher to treat lead encephalopathy. Widely spaced, small doses, while maintaining good hydration seem to increase efficacy and decrease toxicity.28 Other adverse effects of CaNa2EDTA include malaise, fatigue, thirst, chills, fever, myalgias, dermatitis, headache, anorexia, urinary frequency and urgency, sneezing, nasal congestion, lacrimation, glycosuria, anemia, transient hypotension, increased prothrombin times, and inverted T waves.23 Mild increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (usually reversible) and decreases in alkaline phosphatase are frequently reported. Extravasation may result in the development of painful calcinosis at the injection site.34 Depletion of endogenous metals, particularly zinc, iron, and manganese,

may result from chronic therapy.5,37 A decrease in serum dopamine
-hydroxylase, a copper-dependent enzyme, without any demonstrable decrease in serum copper occurred after a single injection of calcium disodium edetate in three adult lead welders.15 The clinical relevance of this is unknown.15 The administration of disodium EDTA can lead to life-threatening hypocalcemia.2 Because CaNa2EDTA has replaced sodium EDTA as the EDTA preparation of choice, hypocalcemia has disappeared as a clinical concern. An animal study suggests that gastrointestinal lead absorption may be enhanced by the intraperitoneal or oral administration of CaNa2EDTA.20 Obviously, removal of lead from the child’s environment should remain the first strategy in the management of lead toxicity. In the event of unintentional exposure to a new lead source, decontamination of the gastrointestinal tract should complement chelation.27 The safety of CaNa2EDTA has not been established in pregnancy, and a risk-to-benefit analysis must be made if its use is considered. In a model of lead poisoning in pregnant rats, fetal resorption decreased and the number of live fetuses increased when CaNa2EDTA was used, although the placental levels of lead were increased.17 Zinc levels were not affected. Another study, however, found that when CaNa2EDTA was given to pregnant rats not poisoned with lead, increases in submucous clefts, cleft palate, adactyly/syndactyly, curly tail, and abnormal ribs and vertebrae occurred.4 These teratogenic effects occurred with doses of CaNa2EDTA comparable to human doses and without causing noticeable changes in the mother except for weight gain. Use of zinc calcium EDTA and zinc EDTA preparations in pregnant rats caused no teratogenic effects at low dose but resulted in the development of submucous cleft palates in 30% of the offspring receiving the higher dose of zinc calcium EDTA.4 This suggests that the incorporation of zinc into EDTA may be protective in pregnant rats.

DOSING AND ADMINISTRATION The dose of CaNa2EDTA is determined by the patient’s body surface area or weight (up to a maximum dose) and the severity of the poisoning and renal function (Chap. 80 and Table 80–10).11,25,30 For patients with lead encephalopathy, the dose of CaNa2EDTA is 1500 mg/m2/d to be given by continuous IV infusion starting 4 hours after the first dose of dimercaprol and after an adequate urine flow is established.10 Combined dimercaprol-CaNa2EDTA therapy is given for 5 days, followed by a rest period of at least 2–4 days, which permits lead redistribution. There is limited evidence to suggest that folic acid, pyridoxine, and thiamine increase the antidotal properties of CaNa2EDTA.35 Before a blood lead concentration is measured, the CaNa2EDTA infusion should be interrupted for 1 hour to avoid a falsely elevated value. For symptomatic children without lead encephalopathy, the dose of CaNa2EDTA is 1000 mg/m2/d in addition to dimercaprol at 50 mg/m2 every 4 hours. However, because of the FDA approval and the demonstrated ability of succimer to reduce brain lead levels in animals, this agent is increasingly replacing the role of CaNa2EDTA in this lead-poisoned pediatric population.9 Because of the pain associated with IM administration, most clinicians recommend that CaNa2EDTA be administered at concentrations ≤0.5% by continuous IV infusion over 24 hours in 5% dextrose or 0.9% NaCl. Concentrations ≥0.5% may lead to throm-

CHAPTER 80

bophlebitis and should be avoided. CaNa2EDTA is not compatible with other solutions. Careful attention to total fluid requirements in children and patients who have or who are at risk for lead encephalopathy is paramount.23,30 Rapid intravenous infusions may worsen lead encephalopathy associated with cerebral edema and increased intracranial pressure. Starting BAL 4 hours prior to CaNa2 EDTA appears to be more effective than starting CaNa2EDTA prior to and simultaneously with BAL in children with acute lead encephalopathy.6 As noted, CaNa2EDTA alone, without BAL, may promote redistribution of lead from soft tissue to brain.11,12,14 Treating with two chelators also reduces the blood lead level significantly faster than does CaNa2EDTA alone, while maintaining a better molar ratio of chelator to lead.6 If CaNa2EDTA is to be administered IM to avoid the use of an IV and fluid overload, then procaine sufficient to produce a final concentration of 0.5% is added to the CaNa2EDTA at 1 mL of a 1% procaine solution for each mL of chelator.23 The procaine minimizes pain at the injection site.

COMBINATION THERAPY WITH SUCCIMER OR DMPS The possible benefit of combining CaNa2EDTA with succimer or 2,3-dimercapto-1-propane-sulfonic acid (DMPS) is under investigation in animals.16,18,36 The combination of CaNa2EDTA with succimer appears more potent than either individual agent in promoting urine and fecal lead excretion, and decreasing blood and liver lead levels, but this approach may increase nephrotoxicity and zinc depletion.

AVAILABILITY Calcium disodium EDTA is available as Calcium Disodium Versenate in 5-mL ampules containing 200 mg of CaNa2EDTA per milliliter (1 g per ampule).23 Disodium edetate (sodium EDTA) should not be considered an alternative to CaNa2EDTA because of the risk of life-threatening hypocalcemia by using sodium EDTA.

SUMMARY CaNa2EDTA reduces blood lead levels, enhances urinary lead excretion, and reverses lead-induced hematologic effects. Studies evaluating long-term effects in reversing lead-induced neurotoxicity have not been performed. CaNa2EDTA remains the standard of care for patients with lead encephalopathy when used in conjunction with dimercaprol. CaNa2EDTA as a diagnostic aid in determining which patients are appropriate candidates for chelation is no longer recommended.11,14 Recommended doses and dosage schedules should not be exceeded and should be reduced when the creatinine clearance is reduced. Patients should be well hydrated to achieve an adequate urine flow prior to and during CaNa2EDTA therapy.

REFERENCES 1. Angle CR: Childhood lead poisoning and its treatment. Ann Rev Pharmacol Toxicol 1993;32:409–434.

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2. Aposhian HV, Maiorinao RM, Gonzalez-Ramirez D, et al: Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995;97:23–38. 3. Bowazzi P, Lanzoni J, Marcussi F: Pharmacokinetic studies of EDTA in rats. Eur J Drug Metab Pharmacokinet 1981;6:21–26. 4. Brownie CF, Brownie C, Noden D, et al: Teratogenic effect of Ca EDTA in rats and the protective effect of zinc. Toxicol Appl Pharmacol 1986;82:426–443. 5. Cantilena LR, Klaassen CD: The effect of chelating agents on the excretion of endogenous metals. Toxicol Appl Pharmacol 1982;63: 344–350. 6. Chisolm JJ Jr: The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J Pediatr 1968;73:1–38. 7. Chisolm JJ Jr: Mobilization of lead by calcium disodium edetate. Am J Dis Child 1987;141:1256–1257. 8. Chisolm JJ Jr: BAL, EDTA, DMSA and DMPS in the treatment of lead poisoning in children. J Toxicol Clin Toxicol 1992;30:493–504. 9. Chisolm JJ Jr: Safety and efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) in children and elevated blood lead concentrations. J Toxicol Clin Toxicol 2000;38:365–375. 10. Coffin R, Phillips LJ, Staples WL, et al: Treatment of lead encephalopathy in children. J Pediatr 1966;69:198–206. 11. Committee on Drugs: Treatment guidelines for lead exposure in children. Pediatrics 1995;96:155–160. 12. Cory-Slechta D, Weiss B, Cox C: Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation. J Pharmacol Exp Ther 1994;13:253–256. 13. Cory-Slechta DA, Weiss B: Efficacy of the chelating agent CaEDTA in reversing lead-induced changes in behavior. J Toxicol Neuro Toxicol 1989;10:685–698. 14. Cory-Slechta DA, Weiss B, Cox C: Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy. J Pharmacol Exp Ther 1987;243:804–813. 15. Deparis P, Caroldi S: In vivo inhibition of serum dopamine B hydroxylase by CaNa2EDTA injection. Hum Exp Ther 1994;13:253–256. 16. Flora GJS, Seth PK, Prakas A, et al: Therapeutic efficiency of combined meso-2,3-dimercaptosuccinic acid and calcium disodium edetate treatment during acute lead intoxication in rats. Hum Exp Toxicol 1995;14:410–413. 17. Flora SJ, Tandon SK: Influence of calcium disodium edetate on the toxic effects of lead administration in pregnant rats. Indian J Physiol Pharmacol 1987;31:267–272. 18. Flora SJS, Bhattacharga R, Vijayaraghauan R: Combined therapeutic potential of meso-2,3-dimercaptosuccinic acid and calcium disodium edetate on the mobilization and distribution of lead in experimental lead intoxication in rats. Fundam Appl Toxicol 1995; 25:233–240. 19. Foreman H, Trujillo T: The metabolism of 14C labeled ethylenediaminetetra-acetic acid in human beings. J Lab Clin Med 1954;43: 566–571. 20. Graziano JH, Leong JK, Friedheim E: 2,3-Dimercaptosuccinic acid: A new agent for the treatment of lead poisoning. J Pharmacol Exp Ther 1978;206:696–700. 21. Jones MM, Basinger MA, Gale GR, et al: Effect of chelate treatments on kidney, bone and brain lead levels of lead-intoxicated mice. Toxicology 1994;89:91–100. 22. Jugo S, Maljkovic T, Kostial D: Influence of chelating agents on the gastrointestinal absorption of lead. Toxicol Appl Pharmacol 1975;34: 259–263. 23. Klaassen CD: Heavy metals and heavy metal antagonists. In: Gilman AG, Goodman LS, Rall TW, Murad F, eds: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996, pp. 1664–1665. 24. Kumark, N: Reversible nephrotoxic reactions to a combined 2,3 dimercapto-1-propanol and calcium disodium ethylene diaminetetraacetic acid regimen in asymptomatic children with elevated blood lead levels. Pediatrics 1982;70:259–262.

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25. Markowitz M, Bijur P, Ruff M, et al: Effects of calcium disodium versenate (CaNa2-EDTA) chelation in moderate childhood lead poisoning. Pediatrics 1993;92:265–271. 26. Markowitz M, Rosen J, Piomelli S, Weinberger H: Personal communication, 1995. 27. McKinney PE: Acute elevation of blood lead levels within hours of ingestion of large quantities of lead shot. J Toxicol Clin Toxicol 2000; 38:435–440. 28. Morgan JW: Chelation therapy in lead nephropathy. South Med J 1975;68:1001–1006. 29. Osterloh J, Becker CE: Pharmacokinetics of CaNa2-EDTA and chelation of lead in renal failure. Clin Pharmacol Ther 1986;40:686–693. 30. Piomelli S, Rosen JF, Chisolm JJ Jr, Graef JW: Management of childhood lead poisoning. J Pediatr 1984;105:523–532. 31. Rosen JF, Markowitz ME: Trends in the management of childhood lead poisonings. Neurotoxicology 1993;14:211–217. 32. Ruff HA, Bijur PE, Markowitz M, et al: Declining blood levels and cognitive changes in moderately lead-poisoned children. JAMA 1993;269:1641–1646.

33. Ruff H, Markowitz M, Bijur P, Rosen J: Relationships among blood lead levels, iron deficiency, and cognitive development in two-yearold children. Environ Health Perspect 1996;104:180–185. 34. Schumacher HR, Osterman AL, Choi SJ, et al: Calcinosis at the site of leakage from extravasation of calcium disodium edetate intravenous chelator therapy in a child with lead poisoning. Clin Orthop 1987;219: 221–225. 35. Tandon SK, Flora ST, Singh S: Chelation in metal intoxication: Influence of various components of vitamin B complex on the therapeutic efficacy of Ca EDTA in lead intoxication. Pharmacol Toxicol 1987; 60:62–65. 36. Tandon SK, Singh S, Jain VK: Efficiency at combined chelation in lead intoxication. Chem Res Toxicol 1994;7:585–589. 37. Thomas DJ, Chisolm J: Lead, zinc, copper decorporation during Ca EDTA treatment of lead poisoned children. J Pharmacol Exp Ther 1986;229:829–835. 38. Williams DR, Halstead BW: Chelating agents in medicine. J Toxicol Clin Toxicol 1982–1983;19:1081–1115.

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81

MERCURY Young-Jin Sue

Mercury MW = 200.59 daltons Normal levels Blood = 750 nmol/L) Values greater than or equal to the action level necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical condition of the patient.

A 16-year-old male presented to the Emergency Department approximately 40 minutes after having intentionally ingested “several teaspoons” of mercuric oxide (HgO) from his chemistry set. On arrival, he was alert and oriented but diaphoretic and vomiting. He complained of midepigastric pain and a metallic taste in his mouth. Initial vital signs were blood pressure, 130/80 mm Hg; pulse, 110 beats/min; respiratory rate, 18 breaths/min; and rectal temperature, 99.7°F (37.6°C). Physical examination revealed an anxious, somewhat pale young man who was repeatedly vomiting blood-tinged, nonbilious material. He had no respiratory distress or drooling. Other than a grayish discoloration of the buccal mucosa, examination of the oropharynx was unremarkable. The lungs were clear. The cardiac examination was normal except for a sinus tachycardia. The abdominal examination revealed a nondistended, soft abdomen, moderately tender to deep palpation in the epigastric region; no masses or organomegaly were appreciated. Rectal examination revealed no trace of blood. Examination of the skin was unremarkable. The neurologic examination was normal except for mild tremulousness. A cardiac monitor was attached to the patient, and he was given 1 L of 0.9% sodium chloride solution (IV) over the subsequent 15 minutes. Results of a complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, glucose, prothrombin time (PT), partial thromboplastin time (PTT), and liver enzymes were within normal limits. Blood was obtained for whole-blood mercury levels, and the bladder was catheterized to collect urine for 24-hour urine mercury quantification. Initial spot urinalysis revealed 2+ proteinuria. Because mercuric oxide may be caustic, endoscopic examination of the upper gastrointestinal (GI) tract was recommended. However, based on this patient’s clinical presentation, the treating physician decided that he was at low risk for penetrating mucosal injury and did not request endoscopy. Gastric lavage via nasogastric tube with milk followed by 0.9% sodium chloride solution was performed, and after lavage, 1 g/kg of activated charcoal was instilled. The electrocardiogram (ECG) was normal except for sinus tachycardia. Upright chest and abdominal radiographs revealed the presence of a radiopaque substance scattered throughout the GI

tract but no extraluminal air. Figures 81–1A and B are abdominal radiographs of a patient with a similar exposure. Whole-bowel irrigation with polyethylene glycol electrolyte lavage solution was begun. The rectal effluent contained flecks of blood. A subsequent abdominal radiograph after whole-bowel irrigation revealed no radiopaque densities.

HISTORY AND EPIDEMIOLOGY The toxicologic manifestations of mercury have become known as a result of thousands of years of medicinal applications, industrial use, and environmental disasters.49,70 Mercury occurs naturally in small amounts as the elemental silver-colored liquid (quicksilver); as inorganic salts, eg, mercuric sulfide (cinnabar), mercurous chloride (calomel), mercuric chloride (corrosive sublimate), and mercuric oxide; and in organic compounds, (methylmercury). In recent centuries, mercury preparations were widely used to treat both syphilis and constipation. The musician Paganini was among the famous persons whose gingivitis, dental decay, ptyalism, and erethism from mercury therapy are described.56 In the 1800s, the United States witnessed an epidemic of “hatters’ shakes” or “Danbury shakes” and “mercurial salivation” in hat industry workers.79 Danbury, CT, was a US center of felt hat manufacturing in which mercury nitrate was used to mat animal furs to make felt (“carrotting”).70,79 In the early 1900s, acrodynia, or “pink disease,” was described in children who received calomel for ascariasis or teething discomfort.15 One of the most devastating epidemics of mercury poisoning occurred as the result of a decade of contamination of Minamata Bay by a nearby vinyl chloride plant during the 1940s. Methylmercury accumulated in the Japanese bay’s marine life and resulted in the poisoning of the local fishing community. Although officially only 121 victims were counted initially, thousands more are believed to have been affected by what has subsequently been named Minamata disease.59,72 The largest outbreak of methylmercury poisoning to date occurred in Iraq in late 1971. Approximately 95,000 tons of seed grain intended for planting and treated with methylmercury as a fungicide were baked into bread for di-

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B

A

Figure 81–1. A chemist ingested mercuric oxide in a suicide attempt. A. Initial plain abdominal radiograph reveals the radiopaque liquid in the stomach. B. A second radiograph shows progrssion of the toxin through the bowel. The patient was followed radiographically as the substance was eventually expelled into the feces.

rect consumption, resulting in widespread neurologic symptoms, 6530 hospital admissions, and more than 400 deaths.5,18,62 In 1997, a scientist succumbed to delayed, progressive neurologic deterioration following dermal exposure to a minute quantity of dimethylmercury.54 Contemporary controversies involving mercury include the potential for toxicity from mercury-containing dental amalgams and mercury-based preservatives (thimerosal) in childhood immunizations. Tables 81–1 and 81–2 show the potential occupational and nonoccupational risks for mercury exposure.

FORMS OF MERCURY AND KINETICS The three important classes of mercury compounds differ with respect to toxicodynamics and toxicokinetics (Table 81–3). Each of the three classes of mercurials produces distinct clinical patterns of poisoning stemming in part from unique and kinetic features

TABLE 81–1.

(Table 81–4). Within each class, the specific poisoning manifestations are determined by route of exposure (eg, inhalational, oral, dermal, or parenteral), rate of exposure, distribution and biotransformation of mercury within the body, and relative accumulation or elimination of mercury by the target organ systems.

Absorption Elemental Mercury. Elemental mercury (Hg0) gains access to the circulation primarily via inhalation of vapor, although slow absorption following aspiration, subcutaneous deposition, and direct intravenous embolization is reported.42,53,76,82 Although elemental mercury is moderately volatile at room temperature, volatilization increases significantly when it is heated. Vaporization may also be hastened by aerosolization. Both occur when elemental mercury is vacuumed.28,64 When inhaled by human volunteers, 75–80% of a stable and radioactive mercury vapor mixture is retained.33,46 Because elemental mercury is negligibly absorbed from normally

Potential Occupational Exposures to Mercury

Elemental

Salts

Organic

Amalgam Barometers Bronzers Ceramic workers Chlorine workers Dentists Electroplaters Jewelers Mercury refiners Paint makers Paper pulp workers Photographers Thermometers

Disinfectants Dye makers Explosives Fireworks makers Fur processors Laboratory workers Tannery workers Taxidermists Vinyl chloride makers

Bactericide makers Drug makers Embalmers Farmers Fungicides Histology technicians Pesticides Seed handlers Wood preservatives

TABLE 81–2.

Nonoccupational Exposures to Mercury

Medicinal

Food

Other

Antiseptics Calomel teething powders Dental amalgam Diuretics Laxatives Sphygmomanometers Stool fixatives Thermometers Weighted nasogastric tubes

Fish Grains and seed, treated Livestock, fed treated grain

Button batteries Chemistry sets Home amalgam extraction Lightbulbs Self-injection Preservatives “Magico-religious” use

CHAPTER 81

TABLE 81–3.

Classes of Mercury Compounds

Elemental mercury Inorganic mercury salts

Organic mercury compounds

Formula

Example

Hg0 Hg+ HgCI Hg2+ HgCI2 Short-chain, alkyl-mercury compounds Long-chain, aryl-mercury compounds

Quicksilver Mercurous ion Calomel Mercuric ion Mercuric chloride Methylmercury Ethylmercury Methoxyethylmercury Phenylmercury

functioning gut, it is usually considered nontoxic when ingested. Abnormal gastrointestinal (GI) motility prolongs mucosal exposure to elemental mercury and increases subsequent ionization to more readily absorbed forms. Similarly, anatomic GI abnormalities such as fistulae or perforation may be associated with extravasation of mercury into the peritoneal space where elemental mercury is oxidized to more readily absorbed inorganic forms. Inorganic Mercury Salts. The principal route of absorption for inorganic mercury salts is the GI tract. Inorganic mercury salts are absorbed after dissociation of ingested soluble divalent mercuric salts such as mercuric chloride (HgCl2). Approximately 10% of such compounds is absorbed from the gut.46 Absorption of a relatively insoluble monovalent mercurous compound, such as calomel (HgCl), is thought to depend on its oxidation to the divalent form.55 Mercuric oxide, a poorly water-soluble compound commonly found in disc batteries, was well-absorbed from ligated gastrointestinal segments of rats, possibly following conversion to chlorides in gastric acid.24 Inorganic mercury salts are also absorbed across skin and mucous membranes, as evidenced by urinary excretion of mercury following the dermal application of mercurial ointments and powders containing HgCl.78 The degree

TABLE 81–4.

Primary route of exposure Primary tissue distribution Clearance Clinical effects CNS

Pulmonary Gastrointestinal Renal Acrodynia Therapy

Differential Characteristics of Mercury Exposure Elemental

Inorganic (Salt)

Organic (Alkyl)

Inhalation

Oral

Oral

CNS, kidney

Kidney

CNS, kidney, liver

Renal, GI

Renal, GI

Methyl:GI Aryl: renal, GI

Tremor

Tremor, erethism

+++ +

— +++(caustic)

Paresthesias, ataxia, tremor, tunnel vision, dysarthria — +

+ + BAL, DMSA

+++(ATN) ++ BAL, DMSA

+ — DMSA (early)

MERCURY

1241

of dermal absorption varies by concentration of mercury, skin integrity, and the lipid solubility of the vehicle. With substantial dermal exposures to inorganic mercury salts, skin absorption may be difficult to distinguish from concomitant absorption via other routes, such as ingestion. Organic Mercury Compounds. As with inorganic mercury salts, organic mercury compounds are primarily absorbed from the GI tract. Methylmercury, considered the prototype of the short-chain alkyl compounds, is about 90% absorbed from the gut.46 Aryl and long-chain alkyl compounds have been reported to have greater than 50% gastrointestinal absorption.55 Although both dermal and inhalational absorption of organic mercury compounds have been reported, precise quantitation and exclusion of concomitant absorption by ingestion are difficult to determine.20,23,80,81

Distribution and Biotransformation After it is absorbed, mercury distributes widely to all tissues, predominantly the kidneys, liver, spleen, and central nervous system (CNS). The initial distributive pattern into nervous tissue of elemental and organic mercury differs from that of the inorganic salts because of their greater lipid solubility. Elemental Mercury. Although peak levels of elemental mercury are delayed in the CNS as compared to other organs (2–3 days vs 1 day),11 significant accumulation in the CNS may occur following an acute, intense exposure to elemental mercury vapor. Conversion of elemental mercury to the charged mercuric cation within the CNS favors retention and local accumulation of the metal there. As Hg0 does not covalently bind to other compounds, its toxicity depends on its oxidation initially to the mercurous ion (Hg+) and then to the mercuric ion (Hg2+) by the enzyme catalase (Table 81–5).46 Because this oxidation-reduction reaction favors the mercuric cation at steady state, the distribution and late manifestations of metallic mercury toxicity eventually resemble those of inorganic mercury salt poisoning. Conversely, and to a lesser extent, inorganic mercuric ions are reduced to the elemental state, although the site and mechanism of this reaction are not well understood.11,55 Inorganic Mercury Salts. The greatest concentration of mercuric ions is found in the kidneys, particularly within the renal tubules. Very little mercury is found as free mercuric ions. At least in animal studies, administration of mercury induces the renal synthesis of metallothionein, a compound that binds to and detoxifies mercuric ions.10 In blood, mercuric ions are found within the red blood cells and are bound to plasma proteins in approximately equal proportions. Blood concentrations are greatest immediately following inorganic mercury exposure, with rapid waning as distribution to other tissues occurs. Although penetration of the blood-brain barrier is poor because of low lipid solubility, slow elimination and prolonged exposure contribute to consequential CNS accumulation of mercuric ions. Within the CNS, mercuric ions are concentrated in the cerebral and cerebellar cortices. Although inorganic

TABLE 81–5. 0

2Hg [elemental]

Oxidation States of Mercury ←catalase→

(Hg+)2 (unstable) [mercurous]

↔

2Hg2+ [mercuric]

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

mercurials undergo organification in marine life (see the earlier description of the Minamata Bay disaster), the importance of this conversion in humans is unknown.20 Animal studies demonstrate that the placenta functions as an effective barrier to mercuric ions.55

days. Less than 10% of methylmercury is excreted in urine and feces as the mercuric cation.80

Organic Mercury Compounds. Once absorbed, aryl and longchain alkyl mercury compounds differ from the short-chain organic mercury compounds (ie, methylmercury) in an important way. The former possess a labile carbon-mercury bond, which is cleaved shortly following absorption, releasing the inorganic mercuric ion. Thus, the distribution pattern and toxicologic manifestations produced by the aryl and long-chain alkyl compounds beyond the immediate postabsorptive phase are comparable to those of the inorganic mercury salts, but the organification has facilitated absorption and reduced the caustic effects. In contrast, short-chain alkyl mercury compounds possess relatively stable carbon-mercury bonds and are very slowly converted to the mercuric cation.80 Because it is lipophilic, methylmercury readily penetrates the blood-brain barrier and is easily transferred across the placenta. An important consequence of the combination of both of these properties is the devastating neurologic degeneration seen in prenatally exposed infants with Minamata disease. After methylmercury is absorbed in brain tissue, its fate is uncertain. Animal evidence supports the conversion of methylmercury to inorganic mercury in brain tissue.44 Primates fed oral methylmercury daily for periods exceeding 1 year and then killed within a few days of termination of exposure demonstrated an average brain inorganic mercury fraction of only 19%. When the postexposure period was extended to between 150 and 650 days, the inorganic mercury fraction was increased to 88%. Similarly, greater quantities of inorganic mercury relative to total mercury were found in brains of long-term survivors of methylmercury poisoning.21 In one patient who survived 22 years following methylmercury ingestion, autopsy results revealed that the brain mercury was nearly completely in the inorganic form. Methylmercury concentrates in red blood cells (RBCs) to a much greater degree than do mercuric ions, with an RBC to plasma ratio of about 10:1.55 Despite its apparent affinity for nervous tissue and red blood cells, the kidneys and liver are the sites of greatest methylmercury concentration. Because of its extensive sulfhydryl bonds, the deposition of methylmercury in hair at concentrations approximately 250 times that found in whole blood has encouraged attempts to quantify degree of exposure to methylmercury by hair analysis.29,39,71

Mercury’s pervasive disruption of normal cell physiology is believed to arise from its avid covalent binding to sulfur, replacing the hydrogen ion in the body’s ubiquitous sulfhydryl groups. Mercury also reacts with phosphoryl, carboxyl, and amide groups, resulting in widespread dysfunction of enzymes, transport mechanisms, membranes, and structural proteins. Mercury deposits in all tissues. Not surprisingly, the clinical manifestations of mercury toxicity involve multiple organ systems with variable features and intensity. Necrosis of the gastrointestinal mucosa and proximal renal tubules, which occurs shortly after mercury salt poisoning, is thought to result from direct oxidative effect of mercuric ions. An immune mechanism is attributed to the membranous glomerulonephritis and acrodynia associated with the use of mercurial ointments.13,31 Neurologic manifestations of methylmercury poisoning correlated with pathologic findings in the brains of both adults and children believed to have been prenatally exposed.48,72 Grossly, atrophy of the brain was more severe in children when methylmercury was either prenatally or postnatally acquired, when compared with the brains of most adult cases. In the adult brain, neuronal necrosis and glial proliferation were most prominent in the calcarine cortex of the cerebrum and in the cerebellar cortex. In fetal Minamata disease, similar lesions were present but in a more diffuse and severe form. Atrophy of the cerebellar hemispheres, postcentral gyri, and calcarine area of the brain on magnetic resonance images in organic mercury-poisoned patients correlated with clinical findings of ataxia, sensory neuropathy, and visual field constriction, respectively.41

Elimination Elemental Mercury/Inorganic Mercury Salts. Mercuric ions are excreted through the kidney by both glomerular filtration and tubular secretion, and in the GI tract by transfer across gut mesenteric vessels into feces. Small amounts are reduced to elemental mercury vapor and volatilized from skin and lungs. The total-body half-life of elemental mercury and inorganic mercury salts is estimated at approximately 30–60 days.17,46 Organic Mercury Compounds. In contrast to elemental mercury and inorganic mercury salts, the elimination of short-chain alkyl mercury compounds is predominantly fecal. Enterohepatic recirculation contributes to its somewhat longer half-life of about 70

PATHOPHYSIOLOGY

CLINICAL SYNDROMES Elemental Mercury Symptoms of acute elemental mercury inhalation occur within hours of exposure and consist of cough, chills, fever, and shortness of breath. Gastrointestinal complaints include nausea, vomiting, and diarrhea, accompanied by a metallic taste, dysphagia, salivation, weakness, headaches, and visual disturbances. Chest radiography during the acute phase may reveal interstitial pneumonitis and both patchy atelectasis and emphysema. Symptoms may resolve or progress to pulmonary edema, respiratory failure, and death. Survivors of severe pulmonary manifestations may develop interstitial fibrosis and residual restrictive pulmonary disease. The acute respiratory symptoms may occur concomitantly with or lead to the development of subacute inorganic mercury poisoning manifested by tremor, renal dysfunction, and gingivostomatitis. Thrombocytopenia may also occur during the acute phase.28,64 While acute exposure to elemental mercury vapor occurs most commonly in the occupational setting, poisonings caused by mishandling of the metal in the home are reported.36,52,68,73 Numerous attempts at home metallurgy with metallic mercury have resulted in fatalities. In such a home environment, ambient air concentra-

CHAPTER 81

tions of mercury were found to be as high as 900 µg/m3, ultimately necessitating demolition of the home after futile attempts at decontamination.50 The lethal dose of inhaled elemental mercury has not been determined. As with other inhaled toxins, younger individuals may possess greater sensitivity to the pulmonary toxicity of mercury vapor. A 7-month-old infant and the family’s young kitten were the first to succumb to fumes generated during attempts to heat metallic mercury on the kitchen stove.52 Although respiratory toxicity from elemental mercury usually results from inhalation of vapor, massive endobronchial hemorrhage followed by death has occurred following direct aspiration of metallic mercury into the tracheobronchial tree.84 Gradual volatilization of elemental mercury has resulted in chronic toxicity, both in the occupational setting and in the home, from improper handling, such as vacuuming spilled mercury.51,64,73 In a typical case of poisoning following domestic exposure to elemental mercury, two siblings presented with ataxia several weeks after approximately 20 mL of elemental mercury was spilled in their home. Evaluation revealed distal paresthesias, mild weakness, and absent deep-tendon reflexes.73 One child had persistent weakness, visual field defects, and emotional lability despite chelation. The clinical importance of volatilized metallic mercury from dental amalgams for both the dentist and patient has been a point of contention for years. The preponderance of evidence currently refutes the idea that mercury poisoning results from dental amalgams. Several comprehensive reviews of the subject conclude that (a) occupational exposure to mercury from dental amalgam is acceptably low provided that recommended preventive measures (eg, adequate ventilation) are adhered to; (b) the quantity of mercury vaporized from dental amalgam by mechanical forces such as chewing is clinically insignificant; and (c) in very rare cases, hypersensitivity to mercury amalgam may necessitate removal of the amalgam.22,25,26,27,43,67 Unusual cases of chronic toxicity have resulted from intentional subcutaneous or intravenous injection of elemental mercury (Figs. 8–6 and 81–2).35,53 Aside from management specific to mercury toxicity, local wound care and excision of deposits of mercury were additional therapeutic challenges presented by these cases. Radiographs are useful in guiding the removal of the radiopaque deposits.

Inorganic Mercury Salts Acute ingestion of mercuric salts produces a characteristic spectrum from severe irritant to caustic gastroenteritis. Immediately, a grayish discoloration of mucous membranes and metallic taste may accompany local oropharyngeal pain, nausea, vomiting, and diarrhea in addition to abdominal pain, hematemesis, and hematochezia. The lethal dose of mercuric chloride has been estimated at 30–50 mg/kg.11 The hallmarks of severe acute mercuric salt ingestion are hemorrhagic gastroenteritis, massive fluid loss resulting in shock, and acute tubular necrosis. A 27-year-old man presented with hematemesis 24 hours after reportedly ingesting 6 g of mercuric chloride in a suicide attempt. Shortly after admission, he developed hypotension and oliguric renal failure, and then underwent gastrectomy for total gastric necrosis. He remained on hemodialysis until he died of sepsis 3 months later.63 Oropharyngeal injury, nausea, hematemesis, hematochezia, and abdominal pain were prominent symptoms in a series of 54 patients who presented after ingesting up to 4 g of mercuric chlo-

A

MERCURY

1243

B

Figure 81–2. A-P (A) and lateral (B) view of the elbow after an unsuccessful suicidal gesture involving an attempted intravenous injection of mercury in the antecubital fossa. Note extensive mercury deposition, which was partially removed by surgical intervention. (Courtesy of Diane Sauter, MD.)

ride.74 In this group, a fatal outcome was associated with the early development of oliguria (within 3 days). The development of anuria appeared to be related to the dose of mercuric chloride ingested. The histopathologic finding of proximal tubular necrosis following mercuric salt poisoning is thought to result from both direct toxicity to renal tubules by mercuric ions and from renal hypoperfusion caused by shock, suggesting that aggressive fluid therapy may be useful.31 Acute ingestion of mercuric salts is usually intentional, but unintentional ingestion occurs sporadically in children as well as adults.37 A 2-year-old girl developed melena 2 days after swallowing a mercuric oxide–containing disc battery.47 Abdominal radiograph revealed two battery halves surrounded by radiopaque material in the stomach and proximal gut. During surgical removal of the battery fragments, areas of ulceration and bleeding were found in the gastric mucosa. Although ingestion of button batteries containing mercuric oxide is associated with a greater incidence of fragmentation than with other batteries, clinical systemic mercury toxicity by this route has not been reported.45 Mercuric chloride–containing stool preservatives are also a potential source of unintentional inorganic mercury poisoning. Two young children presented with bloody gastroenteritis and proteinuria after ingesting 10–20 mL of a polyvinyl alcohol preservative that contained 4.5% mercuric chloride.65 One child had a relatively benign course and was discharged following 5 days of oral chelation. The other required dialysis for renal failure but subsequently recovered without apparent sequelae. Ethnic medicines are yet another source of unintentional inorganic mercury poisoning.38 Because they are not subject to FDA regulation and available without prescription, these substances are often inadequately labeled and of variable composition (Chap. 77).

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Subacute or chronic mercury poisoning occurs after (a) inhalation, aspiration, or injection of elemental mercury; (b) ingestion or application of inorganic mercury salts; or (c) ingestion of aryl or long-chain alkyl mercury compounds. Slow in vivo oxidation of elemental mercury and dissociation of the carbon-mercury bond of aryl or long-chain alkyl mercury compounds result in the production of the inorganic mercurous and mercuric ions. The predominant manifestations of subacute or chronic mercury toxicity include gastrointestinal symptoms, neurologic abnormalities, and renal dysfunction. Gastrointestinal symptoms consist of a metallic taste and burning sensation in the mouth, loose teeth and gingivostomatitis, hypersalivation, and nausea.78 The neurologic manifestations of chronic inorganic mercurialism are described by tremor and the overlapping syndromes of neurasthenia and erethism. Neurasthenia is a symptom complex that includes fatigue, depression, headaches, hypersensitivity to stimuli, psychosomatic complaints, weakness, and loss of concentrating ability. Erethism, derived from the Greek word red, describes the easy blushing and intense shyness of the sufferer. In addition, the symptoms include anxiety, emotional lability, irritability, insomnia, anorexia, weight loss, and delirium. The mercurial tremor is well described in numerous case reports as a central intention tremor that is abolished during sleep. In the most severe forms of mercury-associated tremor, choreoathetosis and spasmodic ballismus may be present. Other neurologic manifestations of inorganic mercurialism include a mixed sensorimotor neuropathy, ataxia, concentric constriction of visual fields (“tunnel vision”), and anosmia. Chronic poisoning with mercuric ions is associated with renal dysfunction, which ranges from asymptomatic, reversible proteinuria to nephrotic syndrome with edema and hypoproteinemia. Renal histology of patients with mercury-associated nephrotic syndrome is suggestive of an immune glomerulonephritis.13 Postmortem examination of the kidneys from two women who died following chronic abuse of mercurous chloride–containing laxatives revealed severe proximal tubular atrophy and mercury deposition within the cortical interstitium and renal macrophages.77 An idiosyncratic hypersensitivity to mercury ions is thought to be responsible for acrodynia or “pink disease,” which is an erythematous, edematous, and hyperkeratotic induration of the palms, soles, and face, and a pink papular rash seen largely in a subset of children exposed to mercurous powders. The rash is described as morbilliform, urticarial, vesicular, and hemorrhagic. This symptom complex also includes excessive sweating, tachycardia, irritability, anorexia, photophobia, insomnia, tremors, paresthesias, decreased deep-tendon reflexes, and weakness. The acral rash may progress to desquamation and ulceration. The prognosis is favorable after withdrawal from mercury exposure. Acrodynia was vividly described 50 years ago in 41 children, many of whom were treated with mercurous chloride calomel-containing powders or ointments.78 The authors observed that the development of acrodynia following exposure to mercury was more common in younger children, did not seem to correlate with dose, and was not necessarily related to urine concentrations of mercury. Childhood acrodynia has become uncommon since the abandonment of mercurial teething powders and diaper rinses. Occasional case reports are still noted, however. An 8-year-old child developed acrodynia with a scarlatiniform rash, irritability, and myalgias after playing with elemental mercury for several days.3 Particularly striking were the presence of an unremittingly pruritic, vesicular eruption of the hands and feet, profuse diaphoresis which necessitated four or five changes of clothes each day, and

the child’s maintenance of a rigid fetal position. A 23-month-old child developed acrodynia following exposure to mercury from shattered fluorescent light bulbs,75 and a 4-year-old boy developed acrodynia and increased urinary mercury excretion 10 days after the interior of his home was painted with phenylmercuric acetate–containing paint. The paint used was subsequently found to contain approximately 3 times the concentration of mercury recommended by the Environmental Protection Agency (EPA). In 1990, the EPA banned mercury-containing compounds from interior paints.2 However, mercury-containing paints manufactured prior to that ruling or marketed for outdoor use can still be sold. Thimerosal is an example of an aryl or long-chain alkyl mercury compound that results in chronic inorganic mercury toxicity. It is a compound that is widely used as a preservative in the pharmaceutical industry (Chap. 56). Although initial kinetics suggest a stable ethyl-mercury bond, the later elimination phase more closely resembles that of the inorganic mercury compounds. Thimerosal is approximately 50% mercury by weight. Although it is generally considered safe, toxicity and death can occur following both intentional overdose and excessive therapeutic application of Merthiolate (0.1% thimerosal or 600 µg/mL mercury). An 18-month-old child with chronic otitis media and bilateral tympanostomy tubes developed neurologic symptoms after receiving a total of 1.2 L of Merthiolate as an ear irrigant over a period of 4 weeks. A substantial amount was believed to have been swallowed after draining through the tympanostomy tubes.61 Examination of the child revealed irritability, ataxia, tremors, and opisthotonic posturing. Despite chelation with N-acetyl penicillamine (NAP), the child died 3 months after hospitalization. A 44-year-old man developed gastritis, renal failure, delirium, and polyneuropathy following intentional ingestion of 5 g of thimerosal.58 He survived with supportive care and the use of oral chelating agents, dimercaptopropane sulfonate (DMPS) and dimercaptosuccinic acid (DMSA). Recent concern that the cumulative dose of thimerosal in childhood immunizations may exceed federally recommended maximum mercury doses (Environmental Protection Agency, 0.1 µg/kg/d; Agency for Toxic Substances and Disease Registry, 0.3 µg/kg/d; Food and Drug Administration, 0.4 µg/kg/d) led to a call by the American Academy of Pediatrics to reduce or eliminate thimerosal from vaccines. Currently, vaccinations contain 25 µg or less of mercury per 0.5 mL of vaccine.4 Many immunizations contain no thimerosal. Although sensitization following use in vaccinations has been reported in atopic children,57 clinical mercury toxicity is not reported in appropriately immunized children. A rise in blood mercury levels following a single dose of hepatitis B vaccine was demonstrated in preterm infants.69 This rise, while greater than that seen in a control group of term infants, has uncertain clinical significance. Until an alternate preservative is developed for use in childhood vaccines, the use of thimerosal is required for vaccines distributed in multidose vials, an economic necessity in developing countries. At the present time, there is clearly more evidence for risk to child health from the diseases targeted for prevention by the vaccines than from thimerosal. For infants born to hepatitis B surface antigen–negative mothers, the Academy recommends that initiation of the vaccine series should be deferred until the infant is 2–6 months of age.

Organic Mercury Compounds In contrast to the inorganic mercurials, methylmercury produces an almost purely neurologic disease that is usually permanent ex-

CHAPTER 81

cept in the mildest of cases. Although the predominant syndrome associated with methylmercury is that of a delayed neurotoxicity, acutely, gastrointestinal symptoms, tremor, respiratory distress, and dermatitis may occur.20,80 Characteristically, clinical manifestations follow the initial poisoning by a latent period of weeks to months. Consequently, the lethal dose is difficult to determine for methylmercury. The Agency for Toxic Substances and Disease Registry minimal risk level with respect to developmental effects is set at 0.04 µg/kg for acute oral exposure.11 The lipophilic property and slower elimination of methylmercury may contribute to its profound neurologic effects.23 Infants exposed prenatally to methylmercury were the most severely affected individuals in the Minamata Bay environmental catastrophe. Often born to mothers with little or no manifestation of methylmercury intoxication themselves, exposed infants exhibited decreased birth weight and muscle tone, profound developmental delay, seizure disorders, deafness, blindness, and severe spasticity. The development of neurologic symptoms in infants exclusively breast-fed by women exposed to methylmercury after delivery and the detection of mercury in the milk of lactating women are very strong evidence for the risk of mercury poisoning via breast milk.23,40 Several weeks after ingesting the methylmercury-contaminated grain in Iraq, cases of paresthesias involving the lips, nose, and distal extremities began to appear. Symptomatic patients also noted headaches, fatigue, and tremor. More serious cases progressed to ataxia, dysarthria, visual field constriction, and blindness. Other neurologic deficits included hyperreflexia, hearing disturbances, movement disorders, salivation, and dementia. The most severely affected patients lay in a mute rigid posture punctuated only by spontaneous crying, primitive reflexive movements, or feeding efforts.62 While the outlook for methylmercury neurotoxicity is generally considered dismal, observations over the subsequent 2 years in 49 Iraqi children poisoned during the 1971 outbreak revealed complete resolution or at least partial improvement in all but the most severely affected.5 Of 40 symptomatic children, 33 mildly to severely affected children showed partial to complete resolution of symptoms. The 7 children classified as “very severely poisoned” remained physically and mentally incapacitated. While neurologic disease is by far the dominant manifestation of methylmercury poisoning, dermatitis, electrocardiographic abnormalities (ST segment changes), and renal tubular dysfunction are also associated with this poisoning.23,34 Dimethylmercury is another short-chain organic mercury compound. Its extreme toxicity was tragically demonstrated by the delayed fatal neurotoxicity that developed in a chemist who inadvertently spilled dimethylmercury on her gloved hands. Over a period of several days, she developed progressive difficulty with speech, vision, and gait. Despite chelation and exchange transfusion, she died within several months of the exposure.54 Neuropathologic examination of her brain revealed lesions in the cerebellum, temporal lobe, and visual cortex.66

INITIAL MANAGEMENT After initial assessment and stabilization, the early toxicologic management of mercury poisoning includes termination of exposure by removal from vapors; washing exposed skin; gastrointestinal decontamination; supportive measures such as hydration and

MERCURY

1245

humidified oxygen; baseline diagnostic studies such as serum laboratories, radiographs, and electrocardiogram; consideration of cointoxicants; and meticulous monitoring. Inhalation of mercury vapors or aspiration of metallic mercury may result in life-threatening respiratory failure, and in this situation, stabilization of cardiorespiratory function is the initial priority. Postural drainage and endotracheal suction may be effective in removing aspirated metallic mercury. Parenteral deposition of subcutaneous or intramuscular mercury may be amenable to surgical excision if well localized (Fig. 81–2). Ingestion of inorganic mercuric salts may lead to cardiovascular collapse caused by severe gastroenteritis and third-space fluid loss. Gastrointestinal decontamination of ingested inorganic salts of mercury is particularly problematic because of the salts’ caustic nature and risk for perforating injury. Endoscopic examination of the upper gastrointestinal tract is suggested by some prior to attempts at gastric emptying and lavage. However, one series of mercuric chloride poisonings reported recovery without long-term gastrointestinal sequelae in patients who did not succumb to renal failure.74 Therefore, unless there is high suspicion for penetrating gastrointestinal mucosal injury, removal of mercury from absorptive surfaces should take priority over endoscopic evaluation. Lavage with protein-containing solutions such as milk or egg whites has been advocated in the belief that mercury may be bound to the administered sulfhydryl-containing proteins and thereby be more readily removed by subsequent lavage.8 Until this is rigorously studied, it is probably not harmful and may be of benefit. Metals are among the substances that are often stated to be poorly adsorbed to activated charcoal. Nevertheless, the serious nature of late sequelae following mercury absorption, the typically small quantities of mercury ingested, and evidence that inorganic mercuric compounds have substantial adsorption to activated charcoal (800 mg mercuric chloride to 1 g activated charcoal in one in vitro study6) justify administration of the adsorbent. Whole-bowel irrigation with polyethylene glycol solution may be useful in removing residual mercury, and therefore should be used and followed by obtaining serial radiographs. Included in the initial management of mercury poisoning is consideration for environmental decontamination. Elemental mercury spilled onto solid surfaces should be adsorbed to sand and the resulting mixture then be swept into tightly sealed containers. Ideally, a mercury decontamination kit should be used. The kit consists of calcium polysulfide, which contains excess sulfur to convert mercury to water-insoluble mercuric sulfide (cinnabar). Absorbent surfaces, such as carpets, should be removed. Spilled mercury compounds should not be vacuumed because vacuuming could volatilize the substances.16 Guidance for decontamination of major spills and disposal of materials can be provided by local and federal hazardous materials agencies.

LABORATORY The dual findings of unexplained neuropsychiatric and renal abnormalities in an individual should alert the examiner to the possibility of mercurialism, as should an at-risk occupation or access by the patient to a mercurial product (Tables 81–1 and 81–2). Occupational or environmental exposure and a consistent clinical scenario may be suggestive of mercury poisoning, but demonstration of mercury in blood, urine, or tissues is necessary for

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

confirmation of exposure. Of the many methods available to measure mercury, cold atomic absorption spectrometry is rapid, sensitive, and accurate, but cannot distinguish the various forms of mercury. Thin-layer and gas chromatographic techniques can be used to distinguish organic from inorganic mercury.20 Blood should be collected into a trace-element collection tube obtained from the laboratory performing the assay. Urine should be collected for 24 hours into an acid-washed container obtained from the laboratory. Attempts to measure or otherwise handle the specimen should be avoided to prevent contamination. There is considerable overlap among concentrations of mercury found in the normal population, asymptomatic exposed individuals, and patients with clinical evidence of poisoning. There is no definitive correlation between either blood or urine mercury levels and mercury toxicity.11,29 However, mercury is virtually undetectable in the nonpoisoned individual, and levels less than 10 µg/L and 20 µg/L for whole blood and urine, respectively, are generally considered normal. Following long-term exposure to mercury vapor, levels as low as 35 µg/L for blood and 150 µg/L for urine may be associated with nonspecific symptoms of mercury poisoning.30 Urine mercury levels may correlate roughly with exposure severity and neuropsychiatric symptoms associated with inorganic mercury poisoning,11,60 but the relationship to total body burden is probably poor. Urine mercury values have their greatest utility in confirming exposure and monitoring the efficacy of chelation therapy. Whole-blood mercury levels may acutely reflect inorganic mercury load, but become less reliable as redistribution to tissues takes place. Because of the very minimal urinary excretion of organic mercury, urine mercury levels are not useful in evaluating methylmercury poisoning. Because of the relative concentration of methylmercury in red blood cells, total body methylmercury burden may be best reflected by blood levels.20 Blood levels may well correlate with acute toxicity of methylmercury. However, as methylmercury distributes to and accumulates in brain, the severity of clinical manifestations probably more closely reflects the degree of the irreversible neuronal destruction that has taken place rather than the current body burden of mercury. Correlation of increasing blood mercury levels with prevalence of paresthesias was suggested in a population of Iraqis studied early in the course of methylmercury poisoning.19 However, in another group of patients, blood levels did not correlate with severity of methylmercury poisoning.62 This apparent discrepancy may have resulted from the finding that paresthesias are among the earliest reported symptoms of methylmercury poisoning. Because mercury accumulates in hair, hair analysis may be a tool for measuring mercury burden. The reliability of this method is questionable because metal incorporation reflects past exposure, and hair avidly binds mercury from the environment. Nevertheless, some authors support its use.39 One analysis comparing organic mercury concentrations in the distal scalp hairs to other organs of cadavers demonstrated significant correlation, with correlation coefficients ranging from 0.59 to 0.82 for the cerebrum and from 0.65 to 0.76 for the kidney.71 The hair was prepared by washing in a nonionic detergent followed by acid digestion. In addition to mercury assays, neuropsychiatric testing, nerve conduction studies, and urine assays for N-acetyl
-D-glucosaminidase and
2-microglobulin are advocated for early detection of subclinical inorganic and organic mercury toxicity.26,34,60

TREATMENT After initial stabilization and decontamination early institution of chelating agents may minimize or prevent widespread effects of mercury resulting from its affinity for essential cellular sulfhydryl groups. A high degree of protein binding and distribution to the brain are responsible for the lack of efficacy of other measures such as peritoneal dialysis and hemodialysis to increase mercury clearance.63 Hemodialysis may nevertheless be ultimately necessary because of the acute renal failure that often follows mercuric chloride poisoning. Chelating agents themselves have thiol groups that are believed to compete with endogenous sulfhydryl groups for the binding of mercury. They thereby prevent inactivation of sulfhydryl-containing enzymes and other essential proteins (Antidotes in Depth: Dimercaprol and Antidotes in Depth: Succimer for further discussion). A history of significant mercury exposure and the presence of typical symptoms of mercury poisoning are sufficient indications for the institution of chelation therapy. Elevated blood and urine mercury concentrations can help support the decision to begin chelation therapy in unclear cases and may also be used to guide duration of therapy. For clinically significant acute inorganic mercury poisoning, dimercaprol (BAL) may be administered for 10 days in decreasing dosages, eg, 5 mg/kg IM once, 2.5 mg/kg IM every 8–12 hours for 1 day, and then 2.5 mg/kg IM every 12–24 hours thereafter until clinical improvement occurs. This dosing regimen of BAL, derived from the use of BAL in lead poisoning, may be adjusted according to clinical response and the occurrence of adverse reactions. Some animal evidence suggests that BAL may increase mercury mobilization into the brain. However, in that instance, phenylmercury and BAL were administered simultaneously. It is unclear whether the increased brain mercury represented altered distribution as a result of a phenylmercury-BAL complex or a BAL-driven redistribution of inorganic mercury.14 When a patient is able to take oral medications, BAL therapy may be augmented with 2,3-dimercaptosuccinic acid (DMSA) at 10 mg/kg orally 3 times a day for 5 days. Adverse effects such as headache, nausea, vomiting, abdominal pain, and diaphoresis may result from the primary ingestion as well as from the chelation therapy, especially when BAL is used. For patients who are not acutely ill or who have been chronically poisoned, initiation of therapy with oral DMSA is recommended, as the adverse effects and pain of administration of BAL are probably not warranted. D-Penicillamine (DPCN) is an orally administered monothiol with adverse effects that include gastrointestinal distress, rashes, leukopenia, thrombocytopenia, and proteinuria (Chap. 82C). Although uncommon when therapeutic doses are used, these adverse effects may seriously limit the utility of the drug. The use of DPCN has largely been supplanted by DMSA. Because the DPCN-mercury chelation compound is excreted exclusively into urine, other agents should be used in the presence of renal failure. N-Acetyl-d,l-penicillamine (NAP), an investigational analogue of DPCN, has been used with variable success for mercury poisoning.9,32 NAP is thought to be a more effective chelator of mercury than DPCN, perhaps because of its greater stability.7 The penicillamines should be administered only after complete gastrointestinal decontamination, as the absorption of mercury may theoretically be enhanced following chelation by penicillamine.

CHAPTER 81

The neurotoxicity of methylmercury and other organic mercury compounds is relatively resistant to treatment, and the optimum mode of therapy is not clear. In rats treated with BAL or DPCN following injection with methylmercury, both agents were effective at reducing tissue mercury and preventing neurologic toxicity if administered within the first day of a methylmercury injection.83 However, neither agent reversed neurologic toxicity when administered 12 days after injection of methylmercury despite a decrease of tissue mercury in rats treated with DPCN. DMPS or 2,3-dimercapto-1-propanesulphonate, an investigational water-soluble analogue of BAL, led to a striking reduction of blood half-life of mercury, ie, 10 days versus 60 days, when compared with DPCN, NAP, and a thiolated resin (half-lives of 24 days, 23 days, and 19 days, respectively) during the outbreak of methylmercury poisoning in Iraq in 1971.19 Clinical improvement was not observed in any treatment group, but it is reasonable to postulate that reducing the total body burden of methylmercury may prevent or limit progression of disease. When studied in mice poisoned with methylmercury,1 DMSA was superior to NAP, DMPS, and a thiolated resin in decreasing brain mercury and increasing urinary excretion. Brain mercury was decreased to 35% of control, and total body burden fell to 19%. A nonabsorbed polythiol resin may reduce the elimination half-life of methylmercury, presumably by interrupting its enterohepatic reabsorption.19,23 Oral N-acetylcysteine enhanced urinary excretion and decreased tissue concentrations of methylmercury in mice.12 A similar effect was not demonstrated for inorganic mercury. The mice were treated for only 48 hours following intraperitoneal injection with methylmercury. The generalizability of these findings to more long-standing human poisonings is unclear. As the neurologic impairment associated with methylmercury is both profound and essentially irreversible, early recognition of poisoning and prevention of neurotoxicity are essential to a successful outcome. Although further investigation is necessary, DMSA may prove to be the treatment of choice for methylmercury poisoning because of its apparently low toxicity and reported efficacy in animal trials.

SUMMARY Mercury poisoning is a complex toxicologic problem associated with a large variety of clinical presentations. An ever-present awareness of the problem, coupled with the knowledge of its differing clinical forms, may serve to guide recognition and treatment. Although some chelating agents do show promise in the treatment of mercury poisoning, neurologic sequelae, particularly those resulting from organic mercury exposures, remain largely irreversible. Promotion of public education regarding the dangers of mercury may aid in the prevention of mercury poisoning.

REFERENCES 1. Aaseth J, Friedheim EAH: Treatment of methyl mercury poisoning in mice with 2,3-dimercaptosuccinic acid and other complexing thiols. Acta Pharmacol Toxicol 1978;42:248–252. 2. Agocs MM, Etzel RA, Parrish G, et al: Mercury exposure from interior latex paint. N Engl J Med 1990;323:1096–1100. 3. Alexander JF, Rosario R: A case of mercury poisoning: Acrodynia in a child of 8. Can Med Assoc J 1971;104:929–930.

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4. American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Environmental Health: Thimerosal in vaccines— An interim report to clinicians. Pediatrics 1999;104(3 Pt 1): 570–574. 5. Amin-Zaki L, Majeed MA, Clarkson TW, Greenwood MR: Methylmercury poisoning in Iraqi children: Clinical observations over two years. Br Med J 1978;1:613–616. 6. Andersen AH: Experimental studies on the pharmacology of activated charcoal; III. Adsorption from gastrointestinal contents. Acta Pharmacol 1948;4:275–284. 7. Aposhian HV, Aposhian MM: N-acetyl-d,l-penicillamine, a new oral protective agent against the lethal effects of mercuric chloride. J Pharmacol 1959;126:131–135. 8. Arena JM: Treatment of mercury poisoning. Mod Treat 1971;8: 619–625. 9. Aronow R, Fleischmann LE: Mercury poisoning in children. Clin Pediatr 1976;15;936–945. 10. Asano S, Eto K, Kurisaki E, et al: Acute inorganic mercury vapor inhalation poisoning. Pathol Int 2000;50:169–174. 11. ATSDR: Toxicologic profile for mercury. Atlanta, GA, USDHHS, 1992. Draft. 12. Ballatori B, Lieberman MW, Wang W: N-Acetylcysteine as an antidote in methylmercury poisoning. Environ Health Perspect 1998;106 (5):267–271. 13. Becker CG, Becker EL, Maher JF, Schreiner GE: Nephrotic syndrome after contact with mercury. Arch Intern Med 1962;110:178–186. 14. Berlin M, Rylander R: Increased brain uptake of mercury induced by 2,3-dimercaptopropanol (BAL) in mice exposed to phenylmercuric acetate. J Pharmacol Exp Ther 1964;146:236–240. 15. Black J: The puzzle of pink disease. J R Soc Med 1999;92:478–481. 16. Campbell D, Gonzales M, Sullivan JB: Mercury. In: Sullivan JB, Krieger GR, eds: Hazardous Material Toxicology. Baltimore, Williams & Wilkins, 1992, pp. 824–833. 17. Clarkson TE: Mercury. J Am Coll Toxicol 1989;8(7):1291–1296. 18. Clarkson TW, Amin-Zaki L, Al-Tikriti SK: An outbreak of methylmercury poisoning due to consumption of contaminated grain. Fed Proc 1976;35:2395–2399. 19. Clarkson TW, Magos L, Greenwood MR, et al: Tests of efficacy of antidotes for removal of methylmercury in human poisoning during the Iraq outbreak. J Pharmacol Exp Ther 1981;218:74–83. 20. Dales LG: The neurotoxicity of alkyl mercury compounds. Am J Med 1972;53:219–232. 21. Davis LE, Kornfeld M, Mooney HS, et al: Methylmercury poisoning: Long-term clinical, radiological, toxicological, and pathological studies of an affected family. Ann Neurol 1994;35:680–688. 22. Eley BM, Cox SW: Mercury from dental amalgam fillings in patients. Br Dent J 1987;163:221–225. 23. Elhassani SB: The many faces of methylmercury poisoning. J Toxicol Clin Toxicol 1982–1983;19:875–906. 24. Endo T, Nakaya S, Kimura R, Murata T: Gastrointestinal absorption of inorganic mercuric compounds in vivo and in situ. Toxicol Appl Pharmacol 1984;74:223–229. 25. Englund GS, Dahlquist R, Lindelof B, et al: DMSA administration to patients with alleged mercury poisoning from dental amalgams—A placebo-controlled study. J Dent Res 1994;73:620–628. 26. Eti S, Weisman RS, Hoffman RS, Reidenberg MM: Slight renal effect of mercury amalgam fillings. Pharmacol Toxicol 1995;76:47–49. 27. Fung YK, Molvar MP: Toxicity of mercury from dental environment and from amalgam restorations. J Toxicol Clin Toxicol 1992;30: 49–61. 28. Fuortes LJ, Weismann DN, Graeff ML, et al: Immune thrombocytopenia and elemental mercury poisoning. J Toxicol Clin Toxicol 1995;33:449–455. 29. Gosselin RE, Smith RP, Hodge HC: Mercury. In: Gosselin RE, Smith RP, Hodge HC, eds: Clinical Toxicology of Commercial Products, 5th ed. Baltimore, Williams & Wilkins, 1984, pp. 262–275.

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

30. Goyer RA: Toxic effects of metals. In: Amdur MO, Doull J, Klaassen CD, eds: Casarett and Doull’s Toxicology: The Basic Science of Poisons, 4th ed. New York, Pergamon Press, 1991, pp. 623–680. 31. Hewitt WR, Goldstein RS, Hook JB: Toxic responses of the kidney. In: Amdur MO, Doull J, Klaassen CD, eds: Casarett and Doull’s Toxicology: The Basic Science of Poisons, 4th ed. New York, Pergamon Press, 1991, pp. 354–382. 32. Hryhorczuk DO, Meyers L, Chen G: Treatment of mercury intoxication in a dentist with N-acetyl-d,l-penicillamine. Clin Toxicol 1982; 19:401–408. 33. Hursh JB, Clarkson TW, Cherian MG, et al: Clearance of mercury (Hg-197, Hg-203) vapor inhaled by human subjects. Arch Environ Health 1976;31:302–309. 34. Iesato K, Wakashin M, Wakashin Y, Tojo S: Renal tubular dysfunction in Minamata disease: Detection of renal tubular antigen and beta2-microglobulin in the urine. Ann Intern Med 1977;86:731–737. 35. Johnson HRM, Koumides O: Unusual case of mercury poisoning. Br Med J 1967;1:340–341. 36. Jung RC, Aaronson J: Death following inhalation of mercury vapor at home. West J Med 1980;132:539–543. 37. Kahn A, Denis R, Blum D: Accidental ingestion of mercuric sulphate in a 4-year-old child. Clin Pediatr 1977;16:956–958. 38. Kang-Yum E, Oransky SH: Chinese patent medicine as a potential source of mercury poisoning. Vet Hum Toxicol 1992;34:235–238. 39. Katz SA, Katz RB: Use of hair analysis for evaluating mercury intoxication of the human body: A review. J Appl Toxicol 1992;12:79–84. 40. Koos BJ, Longo LD: Mercury toxicity in the pregnant woman, fetus, and newborn infant: A review. Am J Obstet Gynecol 1976;126: 390–409. 41. Korogi Y, Takahashi M, Shinzato J, Okajima T: MR findings in seven patients with organic mercury poisoning (Minamata disease). Am J Neuroradiol 1994;15:1575–1578. 42. Krohn IT, Solof A, Mobini J, Wagner DK: Subcutaneous injection of metallic mercury. JAMA 1980;243:548–549. 43. Langan DC, Fan PL, Hoos AA: The use of mercury in dentistry: Critical review of the recent literature. J Am Dent Assoc 1987;115: 867–879. 44. Lind B, Friberg L, Nylander M: Preliminary studies on methylmercury biotransformation and clearance in the brain of primates: II. Demethylation of mercury in brain. J Trace Elem Exp Med 1988; 1:49–56. 45. Litovitz T, Schmitz BF: Ingestion of cylindrical and button batteries: An analysis of 2382 cases. Pediatrics 1992;89:747–757. 46. Magos L: Mercury. In: Seiler HG, Sigel H, eds: Handbook on Toxicity of Inorganic Compounds. New York, Marcel Dekker, 1988, pp. 419–436. 47. Mant TGK, Lewis JL, Mattoo TK, et al: Mercury poisoning after discbattery ingestion. Hum Toxicol 1987;6:179–181. 48. Matsumoto H, Koya G, Takeuchi T: Fetal Minamata disease: A neuropathological study of two cases of intrauterine intoxication by a methyl mercury compound. J Neuropathol Exp 1964;24:563–574. 49. Maurissen JPJ: History of mercury and mercurialism. N Y State J Med 1981;81:1902–1909. 50. Acute, chronic poisoning, residential exposures to elemental mercury –Michigan, 1989–1990. Morb Mortal Wkly Rep 1991;40: 393–395. 51. Mortensen ME, Powell S, Sferra TJ: Elemental mercury poisoning in a household. Morb Mortal Wkly Rep 1990;39:424–425. 52. Moutinho ME, Tompkins AL, Rowland TW, et al: Acute mercury vapor poisoning. Am J Dis Child 1981;135:42–44. 53. Murray KM, Hedgepeth JC: Intravenous self-administration of elemental mercury: Efficacy of dimercaprol therapy. Drug Intell Clin Pharm 1988;22:972–975. 54. Nierenberg DW, Nordgren RE, Chang MB, et al: Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med 1998;338:1672–1676. 55. Nordberg GF, Skerfving S: Metabolism. In: Friberg L, Vostal J, eds: Mercury in the Environment: An Epidemiological and Toxicological Appraisal. Cleveland, CRC Press, 1972, pp. 29–90.

56. O’Shea JG: Was Paganini poisoned with mercury? J R Soc Med 1988;81:594–597. 57. Patrizi A, Rizzoli L, Vincenzi C, Trevisi P, Tosti A: Sensitization to thimerosal in atopic children. Contact Dermatitis 1999;40:94–97. 58. Pfab R, Muckter H, Roider G, Zilker T: Clinical course of severe poisoning with thimerosal. Clin Toxicol 1996;34(4):453–460. 59. Powell PP: Minamata disease: A story of mercury’s malevolence. South Med J 1991;84:1352–1358. 60. Rosenman KD, Valciukas JA, Glickman L, et al: Sensitive indicators of inorganic mercury toxicity. Arch Environ Health 1986;41:208–215. 61. Royhans J, Walson PD, Wood GA, MacDonald WA: Mercury toxicity following Merthiolate ear irrigations. J Pediatr 1984;104:311–313. 62. Rustam H, Hamdi T: Methyl mercury poisoning in Iraq. Brain 1974; 97:499–510. 63. Sauder PH, Livardjani F, Jaeger A, et al: Acute mercury chloride intoxication: Effects of hemodialysis and plasma exchange on mercury kinetic. J Toxicol Clin Toxicol 1988;26:189–197. 64. Schwartz JG, Snider TE, Montiel MM: Toxicity of a family from vacuumed mercury. Am J Emerg Med 1992;10:258–261. 65. Seidel J: Acute mercury poisoning after polyvinyl alcohol preservative ingestion. Pediatrics 1980;66:132–134. 66. Siegler RW, Nierenberg DW, Hickey WF. Fatal poisoning from liquid dimethylmercury: A neuropathologic study. Hum Pathol 1999;30: 720–723. 67. Snapp KR, Boyer DB, Peterson LC, Svare CW: The contribution of dental amalgam to mercury in blood. J Dent Res 1989;68:780–785. 68. Snodgrass W, Sullivan JB, Rumack BH, Hashimoto C: Mercury poisoning from home gold ore processing. JAMA 1981;246:1929–1931. 69. Stajich GV, Lopez GP, Harry SW, Sexson WR: Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants. J Pediatr 2000;136:679–681. 70. Sunderman FW: Perils of mercury. Ann Clin Lab Sci 1988;18: 89–101. 71. Suzuki T, Hongo T, Yoshinaga J, et al: The hair-organ relationship in mercury concentration in contemporary Japanese. Arch Environ Health 1993;48:221–229. 72. Takeuchi T: Pathology of Minamata disease. Acta Pathol Jpn 1982; 32:73–99. 73. Taueg C, Sanfilippo DJ, Rowens B, et al: Acute and chronic poisoning from residential exposures to elemental mercury—Michigan, 1989–1990. J Toxicol Clin Toxicol 1992;30:63–67. 74. Troen P, Kaufman SA, Katz KH: Mercuric bichloride poisoning. N Engl J Med 1951;244:459–463. 75. Tunnessen WW, McMahon KJ, Baser M: Acrodynia: Exposure to mercury from fluorescent light bulbs. Pediatrics 1987;79:786–789. 76. Wallach L: Aspiration of elemental mercury—Evidence of absorption without toxicity. N Engl J Med 1972;287:178–179. 77. Wands JR, Weiss SH, Yardley JH, Maddrey WC: Chronic inorganic mercury poisoning due to laxative abuse. Am J Med 1974;57:92–101. 78. Warkany J, Hubbard DM: Adverse mercurial reactions in the form of acrodynia and related conditions. Am J Dis Child 1951;81:335–373. 79. Wedeen RP: Were the hatters of New Jersey “mad”? Am J Ind Med 1989;16:225–233. 80. Winship KA: Organic mercury compounds and their toxicity. Adv Drug React Ac Pois Rev 1986;3:141–180. 81. Yeh TF, Pildes RS, Firor HV: Mercury poisoning from mercurochrome treatment of an infected omphalocele. Clin Toxicol 1978; 13:463–467. 82. Yotsuyanagi T, Yokoi K, Sawada Y: Facial injury by mercury from a broken thermometer. J Trauma 1996;40:847–849. 83. Zimmer LJ, Carter DE: The effect of 2,3-dimercaptopropanol and Dpenicillamine on methyl mercury induced neurological signs and weight loss. Life Sci 1978;23:1025–1034. 84. Zimmerman JE: Fatality following metallic mercury aspiration during removal of a long intestinal tube. JAMA 1969;208:2158–2160.

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82

METALS Robert S. Hoffman

The immediately preceding chapters of this text provide in-depth discussions of the toxicities of arsenic, lead, and mercury, as does the chapter on thallium that follows. These metals were selected for placement in individual chapters because of their historical relevance, their well-recognized clinical toxicity, and the volume of toxicologic data available for review. Virtually all other metal salts and some elemental forms (Chap. 12) have the potential for acute or chronic toxicity. For many, the available data involve limited animal experiments and rare human case reports, and discussion would not be useful in a text focusing on toxicologic emergencies. This chapter contains three subsections that highlight cadmium, copper, and bismuth. Much like the metals discussed in previous chapters, these three toxins were selected because of their clinical relevance to acute toxicity in humans. For discussions of other metals, the reader is referred to a series of monographs by Donald Barceloux,1–8 as well as Chap. 81 in the 6th edition of this text. As the following three sections are reviewed, the reader should concentrate on similarities that exist between the toxicologic ef-

fects of these and other metal salts. Multiple organ system involvement, including gastrointestinal, neurologic, and renal effects, characterize typical toxicity. Although these common manifestations underlie the principles of acute metal toxicity, unique effects such as the pulmonary manifestations of cadmium, the hematologic and hepatic effects of copper, and the characteristic neurologic effects of bismuth are distinctive.

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REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.

Barceloux DG: Chromium. J Toxicol Clin Toxicol 1999;37:173–194. Barceloux DG: Cobalt. J Toxicol Clin Toxicol 1999;37:201–206. Barceloux DG: Manganese. J Toxicol Clin Toxicol 1999;37:293–307. Barceloux DG: Molybdenum. J Toxicol Clin Toxicol 1999; 37: 231–237. Barceloux DG: Nickel. J Toxicol Clin Toxicol 1999;37:239–258. Barceloux DG: Selenium. J Toxicol Clin Toxicol 1999;37:145–172. Barceloux DG: Vanadium. J Toxicol Clin Toxicol 1999;37:265–278. Barceloux DG: Zinc. J Toxicol Clin Toxicol 1999;37:279–292.

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82A

BISMUTH Rama B. Rao

Bismuth MW = 208.9 daltons Normal Levels Blood = 2–11 µg/L (9–52 nmol/L) Urine = 2000 ng/mL), neurologic events, such as myoclonic jerks, did not have corresponding EEG changes. The authors proposed that an elevated body burden might have an inhibitory effect on the cerebral cortex.9 Imaging studies, such as computed tomography, demonstrate a diffuse cortical hyperdensity of gray matter in encephalopathic patients with blood concentrations >2000 ng/mL. These findings resolve with recovery. Magnetic resonance imaging was normal in another encephalopathic patient.14

TREATMENT Typically, supportive care, including hemodialysis for renal failure, results in a complete recovery. Some authors suggest GI decontamination with activated charcoal and polyethylene glycol solution.43 While the evidence for this is lacking, it is a reasonable first gesture. Chelation therapy with British Anti-Lewisite (BAL) is beneficial in experimental models,41a reportedly beneficial in humans,29a and often recommended, but clear evidence of efficacy is lacking. BAL undergoes biliary elimination, a major advantage over other chelators in patients, such as these, who are expected to develop renal insufficiency. Some authors recommend the additon of dimercaptopropane sulfonate (DMPS), citing that BAL with hemodialysis did not affect clearance, whereas the addition of DMPS to hemodialysis was effective.43 It is uncertain whether the clinical course of the patient was improved. In human volunteers using colloidal bismuth subcitrate, dimercaptosuccinic acid (DMSA) and DMPS, both at a dose of 30 mg/kg, increased urinary elimination of bismuth by 50-fold.41b However, as resolution of renal toxicity is generally observed with supportive care only, the use of chelating agents or hemodialysis in acute overdose without neurotoxicity is probably not indicated. Typically, withdrawal of the source of bismuth results in reversal of symptoms, even in patients with severe encephalopathy. Recovery may take days to weeks, but is usually complete. In an animal model, D-penicillamine was most efficacious in enhancing elimination of bismuth. In a human volunteer model that used therapeutic doses of tripotassium-dicitrato-bismuthate, however, a single dose of D-penicillamine did not enhance urinary excretion.31 It is uncertain how these agents affect the course of encephalopathic patients. Prevention is the most valuable tool in avoiding neurotoxicity. Patients and their families should be taught to recognize the more subtle changes produced by bismuth-induced neurotoxicity as laboratory testing is limited. While blood concentrations of bismuth are not routinely performed, a bismuth concentration above 100 ng/mL or symptoms at lower levels warrant withdrawal of bismuth therapy.

Bismuth Drug Interactions and Reactions Ranitidine, which is frequently prescribed with bismuth compound for dyspepsia or ulcer disease, does not affect the pharmacokinetics of bismuth absorption.22 In the United States, where bismuth subsalicylate is the most common oral bismuth-containing compound, up to 90% of the salicylate is absorbed and detectable by salicylate screening.34 Salicylate toxicity has been reported and salicylate concentrations should be performed in both acute and chronic exposures. Methemoglobinemia from subnitrate salt of bismuth is also described, but uncommon.20

SUMMARY Presently, the most likely manifestations of bismuth toxicity are either neurologic or renal, depending upon the type of compound and whether therapeutic or acute massive overdose occurred. The factors predisposing some individuals to neurotoxicity from therapeutic use of oral bismuth compounds are poorly understood. Thus, patients using therapeutic bismuth with new movement disorders or alterations in mental status should be assessed for possible bismuth-induced encephalopathy.

REFERENCES 1. Akpolat I, Kahraman H, Akpolat T, et al: Acute renal failure due to overdose of colloidal bismuth. Nephrol Dial Transplant 1996;11: 1890–1898. 2. Barnett RN: Reactions to a bismuth compound. Toxic manifestations following the use of the bismuth salt of heptadienecarboxylic acid in suppositories. JAMA 1947;135:28–30. 3. Benet LZ: Safety and pharmacokinetics: Colloidal bismuth subcitrate. Scand J Gastroenterol 1991;25(Suppl 185):29–35. 4. Bennet JE, Wakefield JC, Lacey LF: Modeling trough plasma bismuth concentrations. J Pharmacokinet Biopharm 1997;25:79–106. 5. Bes A, Caussanel JP, Geraud G, et al: Encephalopathie toxique par les sels de bismuth. Rev Med Toulouse 1976;12:810–813. 6. Bierer DW: Bismuth subsalicylate: History chemistry, and safety. Rev Infect Dis 1990;12:S3–S8. 7. Boyette DP, Ahiskie NC: Bismuth nephrosis with anuria in an infant. J Pediatr 1946;28:493–497. 8. Bridgeman AM, Smith AC: Iatrogenic bismuth poisoning: Case report. Aust Dental J 1994;39:279–281. 9. Buge A, Supino-Viterbo V, Rancurel G, Pontes C: Epileptic phenomena in bismuth toxic encephalopathy. J Neurol Neurosurg Psychiatr 1981;44:62–67. 10. Burns R, Thomas DW, Barron VJ. Reversible encephalopathy possibly associated with bismuth subgallate ingestion. Br Med J 1974; 1:220–223. 11. Czerwinski AW, Ginn HE: Bismuth nephrotoxicity. Am J Med 1964; 37:969–975. 12. Emile J, De Bray JM, Bernat M, et al: Osteoarticular complications in bismuth encephalopathy. Clin Toxicol 1981;18:1285–1290. 13. Goldenberg MM, Honkomp LJ, Davis CS: Antinauseant and antiemetic properties of bismuth subsalicylate in dogs and humans. J Pharmacol Sci 1976;65:1398–1400. 14. Gordon MF, Abrams RI, Rubin DB, et al: Bismuth subsalicylate toxicity as a cause of prolonged encephalopathy with myoclonus. Mov Disord 1995;10:220–222. 15. Gryboski JD, Gotoff SP: Bismuth nephrotoxicity. N Engl J Med 1961; 265:1289–1291.

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16. Hasking GJ, Duggan JM: Encephalopathy from bismuth subsalicylate. Med J Aust 1982;2:167. 17. Hudson M, Mowat NAG: Reversible toxicity in poisoning with colloidal bismuth subcitrate. BMJ 1989;299:159. 18. Hundal O, Bergseth M, Gharehnia B, et al: Absorption of bismuth from two bismuth compounds before and after healing of peptic ulcers. Hepatogastroenterology 1999;46:2882–2886. 19. Huwez F, Pall A, Lyons D, Stewart MJ: Acute renal failure after overdose of colloidal bismuth subcitrate. Lancet 1992;340:1298. 20. Jacobsen JB, Huttel MS: Methemoglobin after excessive intake of a subnitrate containing antacid. Ugeskr Laeger 1982;144:2340–2350. 21. Karelitz S, Freedman AD: Hepatitis and nephrosis due to soluble bismuth. Pediatrics 1951;8:772–776. 22. Koch KM, Kerr BM, Gooding AE, Davis IM. Pharmacokinetics of bismuth and ranitidine following multiple doses of ranitidine bismuth citrate. Br J Clin Pharmacol 1996:42:207–211. 23. Kruger G, Thomas DJ, Weinhardt F, Hoyer S: Disturbed oxidative metabolism in organic brain syndrome caused by bismuth in skin creams. Lancet 1976;1:485–487. 24. Lambert JR: Pharmacology of bismuth-containing compounds. Rev Infect Dis 1991;13:S691–S695. 25. Liessens JL, Monstrey J, Vanden Eeckhout E, Djudzman R, Martin JJ: Bismuth encephalopathy. Act Neurol Belg 1978;78:301–309. 26. Martin-Bouyer G, Foulon G, Guerbois H, Barin C: Epidemiological study of encephalopathies following bismuth administration per os. Characteristics of intoxicated subjects: Comparison with a control group. Clin Toxicol 1981;18:1277–1283. 27. Martin-Bouyer G, Weller M: Neuropsychiatric symptoms following bismuth intoxication. Postgrad Med J 1988;64:308–310. 28. McClendon SJ: Toxic effects with anuria from a single injection of a bismuth preparation. Am J Dis Child 1941;61:339–341. 29. Mendelowitz PC, Hoffman RS, Weber S: Bismuth absorption and myoclonic encephalopathy during bismuth subsalicylate therapy. Ann Intern Med 1990;112:140–141. 29a. Molina JA, Calandre L, Bermego F: Myoclonic encephalopathy due to bismuth salts: Treatment with dimercaprol and analysis of CSF transmitters. Acta Neurol Scand 1989;79:200–203. 30. Monseu G, Struelens M, Roland M: Bismuth encephalopathy. Acta Neurol Belg 1976;76:301–308. 31. Nwokolo CU, Pounder RE: D-Penicillamine does not increase urinary bismuth excretion in patients treated with tripotassium dicitrato bismuthate. Br J Clin Pharmacol 1990;30:648–650. 32. O’Brien D: Anuria due to bismuth thioglycollate. Am J Dis Child 1959;97:384–386. 33. Pamphlett R, Stoltenberg M, Rungby J, Danscher G: Uptake of bismuth in motor neurons of mice after single oral doses of bismuth compounds. Neurotoxicol Teratol 2000;22:559–563. 34. Pickering LK, Feldman S, Ericsson CD, Cleary TG: Absorption of salicylate and bismuth from a bismuth subsalicylate containing compound (Pepto-Bismol). J Pediatr 1981;99:654–656. 35. Pollet S, Albouz S, Le Saux F, et al: Bismuth intoxication: Bismuth level in pig brain lipids and in subcellular fractions. Toxicol Eur Res 1979;2:123–125. 36. Randall RE, Osheroff RJ, Bakerman S, Setter JG: Bismuth nephrotoxicity. Ann Intern Med 1972;77:481–482.

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37. Rodilla V, Miles AT, Jenner W, Hawksworth GM: Exposure of human cultured proximal tubule cells to cadmium, mercury, zinc, and bismuth: Toxicity and metallothionein induction. Chem Biol Interact 1998;115:71–83. 38. Ross JF, Broadwell RD, Poston MR, Lawhorn GT: Highest brain bismuth levels and neuropathology are adjacent to fenestrated blood vessels in mouse brain after intraperitoneal dosing of bismuth subnitrate. Toxicol Appl Pharmacol 1994;124:191–200. 39. Sainsbury SJ: Fatal salicylate toxicity from bismuth subsalicylate. West J Med 1991;155:637–639. 40. Serfontein WJ, Mekel R: Bismuth toxicity in man II. Review of bismuth blood and urine levels in patients after administration of therapeutic bismuth formulations in relation to the problem of bismuth toxicity in man. Res Commun Chemical Pathol Pharmacol 1979;26: 391–411. 41. Serfontein WJ, Mekel R, Bank S, et al: Bismuth toxicity in man I: Bismuth blood and urine levels in patients after administration of a bismuth protein complex (bictropeptide). Res Commun Chem Pathol Pharmacol 1979;26:383–389. 41a. Slikkerveer A, Jong HB, Helmich RB, de Wolff FA: Development of a therapeutic procedure for bismuth intoxication with chelating agents. J Lab Clin Med 1992;119:529–537. 41b. Slikkerveer A, Noach LA, Tytgat GN, et al: Comparison of enhanced elimination of bismuth in humans after treatment with meso-2,3 dimercaptosuccinic acid and D,L-2,3-dimercaptopropane-1-sulfonic acid. Analyst 1998;123:91–92. 42. Stevens PE, Bierer DW: Bismuth subsalicylate: History chemistry, and safety. Rev Infect Dis 1990;12:S3–S8. 43. Stevens PE, Moore DF, House IM, et al: Significant elimination of bismuth by haemodialysis with a new heavy metal chelating agent. Nephrol Dial Transplant 1995;10:696–698. 44. Suarez FL, Furne JK, Springfield J, Levitt MD: Bismuth subsalicylate markedly decreases hydrogen sulfide release in the human colon. Gastroenterology 1998;114:923–929. 45. Szymanska JA, Zelazowski AJ, Kawiorski S: Some aspects of bismuth metabolism. Clin Toxicol 1981;18:1291–1298. 46. Taylor EG, Klenerman P: Acute renal failure after bismuth subcitrate overdose. Lancet 1990;335:670–671. 47. Thompson HE, Steadman LT, Pommeranke WT: The transfer of bismuth into fetal circulation after maternal administration of sobisimol. Am J Syp 1941;25:725–730. 48. Tremaine WJ, Sandborn WJ, Wolff BG, et al: Bismuth carbomer foam enemas for chronic pouchitis: A randomized, double-blind, placebocontrolled trial. Aliment Pharmacol Ther 1997;11: 1041–1046. 49. Urizar R, Vernier RL: Bismuth nephropathy. JAMA 1966;198: 207–209. 50. Walsh JH, Peterson WL: Drug therapy: The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med 1995;333:984–991. 51. Wilson APR: The dangers of BIPP. Lancet 1994;334:1313–1314. 52. Zala L, Hunziker T, Braathen LR: Pigmentation following long-term bismuth therapy for pneumatosis cystoides intestinalis. Dermatology 1993;187:288–289.

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82B

CADMIUM Stephen J. Traub / Robert S. Hoffman

Cadmium MW = 112.4 daltons Normal Levels Blood = 15 µg/g creatinine (0.133 µmol/g creatinine) Values greater than or equal to the action levels necessitate clinical intervention. Values below this level may necessitate intervention based on the clinical condition of the patient.

A 53-year-old male who performed metalwork as a hobby became ill approximately 6 hours after welding in his shop. He developed a violent cough, and sought care from a local physician. The physician, who elicited the history of metalwork, diagnosed the patient with metal fume fever, reassured him that his symptoms would pass, and discharged him home. The next morning the patient’s condition worsened, and he presented to a local emergency department complaining of severe shortness of breath. Vital signs were pulse, 117 beats/min; blood pressure, 105/64 mm Hg; respiratory rate, 22 breaths/min and labored; and temperature, 101.3°F (38.5°C). Lung examination revealed diffuse rales. Pulse oxygenation was 87% on room air. The patient was placed on supplemental oxygen, and his oxygen saturation improved to 94%. Arterial blood gas analysis and cooximetry confirmed the patient’s hypoxia and excluded methemoglobinemia and carboxyhemoglobinemia. A chest radiograph showed diffuse interstitial alveolar filling. Further history revealed that the patient had been welding with a cadmium-containing solder without appropriate respiratory precautions. A working diagnosis of cadmium pneumonitis was established. The patient’s respiratory status slowly declined over the course of the next 24 hours, necessitating endotracheal intubation. He was treated with intravenous steroids (dexamethasone 10 mg IV every 6 hours) and broad-spectrum antibiotics (ceftriaxone, 1 g IV every 12 hours), but continued to deteriorate despite aggressive and appropriate supportive care. He expired on hospital day 4.

Cadmium, atomic number 48, is a transitional metal in group IIB of the periodic table. In its pure atomic form, it is a bluish solid at room temperature. It is readily oxidized to a divalent ion, Cd++. Naturally occurring cadmium commonly exists as cadmium sulfide (CdS), a trace contaminate of zinc-containing ores.38 Cadmium sulfide, cadmium oxide, and other cadmium-containing compounds are refined to produce elemental cadmium, which is then used for industrial purposes. When combined with other metals, cadmium forms alloys of relatively low melting points, which accounts for its extensive historical use as a component of solders and brazing rods. Today, the majority of cadmium is used in the production of nickel-cadmium batteries. Other cur-

rent and historical uses of cadmium include its role as a reagent in electroplating, as a pigment, as part of the phosphorescent system in black and white televisions, and as a neutron absorber in nuclear reactors. Cadmium salts have also been used as veterinary antihelminthics.13 Much like lead, there is no known biologic role for cadmium.

HISTORY AND EPIDEMIOLOGY As cadmium processing increased in the last century, so, too, did cadmium toxicity. Cadmium exposure with resultant toxicity usually occurs in one of three settings: environmental, occupational, or hobby work.

Environmental Exposure Environmental exposure to cadmium generally occurs through the consumption of foods grown in cadmium-contaminated areas. Because cadmium is fairly common as an impurity in ores (particularly those containing zinc), areas that mine or refine ores are at highest risk for contamination. Although many countries (such as Sweden46 and Belgium12) have reported on environmental cadmium exposure, the most remarkable historical example of environmental cadmium pollution occurred in Japan. In the 1950s, a mine near the Jinzu river basin in the Toyama prefecture was discharging large amounts of cadmium into the environment, contaminating the rice that was a staple of the local food supply. An epidemic of painful osteomalacia followed, affecting hundreds of people, mostly postmenopausal multiparous women.62 The afflicted were prone to develop pathologic fractures, and were reported to call out “itai-itai” (literally, “ouchouch”) as they walked, because of the severity of their pain.29 These symptoms were ultimately linked to the cadmium. Environmental exposure also occurs in smokers, who have higher blood cadmium levels than do nonsmokers.84 Although this elevation is probably a result of soil contamination in the areas where the tobacco is grown, tobacco smoking is not established as an independent risk factor for cadmium toxicity.

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Occupational Exposure Welders, solderers, and other metalworkers (eg, jewelry workers) who use cadmium-containing alloys are at risk of developing acute cadmium toxicity through the inhalation of cadmium oxide fumes. Other workers (such as in battery factories) who do not work with metals per se may develop significant chronic cadmium toxicity through exposure to cadmium-containing dust. A better understanding of the health effects of cadmium has led to improvements in working conditions and significantly decreased workplace cadmium exposure.

Hobby Exposure Hobbyists who are exposed to cadmium are generally exposed to cadmium oxide through metalwork with cadmium solders, similar to the exposures of occupational metalworkers. Significant cadmium toxicity in this population invariably results from metalworking in a closed space with inadequate ventilation and/or improper respiratory precautions.

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mium or the cadmium-metallothionein complex is the ultimate toxicant. It appears, however, that unbound cadmium mediates cellular damage26,36,58,61,80; metallothionein is unquestionably protective23,58 and functions as a natural chelating agent with a strong affinity for cadmium.19,53 Although metallothionein may play a role in proximal tubular concentration of cadmium, renal damage is reduced by metallothionein, as metallothionein-deficient mice demonstrate more toxicity after cadmium exposure than controls.58 The exact mechanism by which cadmium interferes with cellular function is poorly understood. Cadmium exerts at least some of its toxic effect via the binding of sulfhydryl groups and the subsequent denaturing of proteins and/or inactivation of enzymes. The mitochondrion is one of the organelles most effected by this process,1 which may result in a greater susceptibility to oxidative stress in cadmium-poisoned cells. Cadmium may also interfere with E-cadherin, an important protein in some cell-cell junctions68; this interference may play a role in the development of acute lung injury. The demonstrated interference of cadmium with calcium transport mechanisms89,90 might lead to intracellular hypercalcemia and, ultimately, to cell death.

TOXICOKINETICS

Specific Organ System Pathophysiology

The bioavailability of elemental cadmium (cadmium metal) is unknown. Cadmium salts are poorly (5–20%) bioavailable via the gastrointestinal (GI) route, but cadmium fumes (cadmium oxide) are readily bioavailable (up to 90%) via the pulmonary route.93 Because the only data on cadmium toxicokinetics come from work with cadmium salts, “cadmium” in this discussion should be construed as referring to inorganic cadmium salts unless otherwise noted. After exposure, cadmium is taken up into the bloodstream, where it is bound to
2-macroglobulin and albumin.95 It is then quickly and preferentially redistributed to the liver and kidney. Although other organs such as the pancreas, spleen, heart, lung, and testes can accumulate part of an acute cadmium load, they do so much less avidly.26 After it is incorporated in the liver and kidney, cadmium is complexed with metallothionein, an endogenous thiol-rich protein that is produced in both organs. Metallothionein binds and sequesters cadmium. Slowly, over time, hepatic stores of the cadmium-metallothionein complex (Cd-MT) are released. Circulating Cd-MT is then filtered by the glomerulus, and a significant amount is reabsorbed by, and concentrated in, the proximal tubule cells.79,80 Cadmium is renally concentrated by this mechanism, which is one of the reasons that the kidney is the principal target organ in cadmium toxicity. There is no evidence that cadmium ions are oxidized, reduced, methylated, or otherwise biotransformed. The volume of distribution (Vd) of cadmium is unknown, but is presumably quite large as a consequence of significant hepatic sequestration. Cadmium distribution and elimination are complex, and an eight-compartment kinetic model is proposed.52 The slow release of cadmium from metallothionein-complexed hepatic stores accounts for its very long half-life of 10 or more years.

Kidney. The pathophysiology of cadmium-related renal disease has been thoroughly studied and is well understood. Animals exposed to cadmium develop evidence of biochemical dysfunction and morphologic abnormalities of the kidney within 10 weeks when exposed to subcutaneous cadmium,26 and within 8 hours when given intraperitoneal cadmium.79 In humans, the renal damage caused by cadmium usually develops over years. Proteinuria is by far the most common renal abnormality caused by cadmium. Proteinuria usually begins with proximal tubular dysfunction, which manifests as urinary loss of low-molecular-weight proteins such as 2-microglobulin and retinol binding protein. This low-molecular-weight proteinuria is usually more significant than, and generally precedes glomerular dysfunction, which manifests as urinary loss of higher-molecular-weight proteins such as albumin and transferrin. Some cadmium-exposed workers, however, have predominantly glomerular proteinuria.7 There appears to be a dose-response relationship between total body cadmium burden and urinary dysfunction,12,45,46,64,88 although some authors refute such a relationship, especially at low doses.41 As noted earlier, proteinuria develops because of injury to the proximal convoluted tubule, which concentrates cadmium by reabsorbing the cadmium-metallothionein complex.79,80 Cadmium also appears to produce hypercalcuria,75 possibly via damage to the proximal tubule.

PATHOPHYSIOLOGY Cellular Pathophysiology Cadmium is very quickly and efficiently complexed to metallothionein in vivo, which raises the question of whether free cad-

Bone. Cadmium causes osteomalacia, probably through abnormalities of calcium and phosphate homeostasis. In one autopsy study, the severity of osteomalacia in a cadmium-exposed population correlated with a decline in the serum [calcium] × [phosphate] product.83 These electrolyte imbalances are, in turn, probably a result of renal proximal tubular dysfunction. Lung. The pathophysiology of acute cadmium pneumonitis is not well established. Human autopsy studies33,67,76,96 generally show degeneration of, and/or loss of, bronchial and bronchiolar epithelial cells; most patients also had proteinaceous pulmonary edema. The mechanism by which these findings develop is not clear.

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Gastrointestinal Tract. Based on case reports,9,97 cadmium salts appear to be caustic substances with the potential to induce significant GI symptoms (nausea, vomiting, and abdominal pain) and result in GI hemorrhage, necrosis, and perforation. In this respect, cadmium salts appear to be similar to mercuric chloride (HgCl2).

and pulmonary fibrosis.86 Patients may recover without apparent sequelae.98 Given the small number of patients, lack of controls, and lack of uniformity of care, the findings of long-term sequelae in case reports of patients with a history of acute cadmium pneumonitis should be considered associations at best.

Chronic Poisoning

CLINICAL MANIFESTATIONS Acute Poisoning Oral/Cadmium Salts. Although most acute cadmium exposures are pulmonary, acute oral exposures also occur. In one case,9 a 17year-old female ingested approximately 150 g of cadmium chloride and presented to the emergency department with hypotension and edema of the face, pharynx, and neck. Her condition quickly deteriorated, and she suffered a respiratory arrest. She was intubated, underwent orogastric lavage, chelation with an unspecified agent, and charcoal hemoperfusion. Multisystem organ failure ensued, and she died within 30 hours of presentation. At autopsy, the most significant finding was hemorrhagic necrosis of the upper GI tract, consistent with a caustic ingestion. Although her blood cadmium level was more than 2000 times normal, it is not clear whether her demise was related to the cellular effects of cadmium or to the caustic nature of the ingestion. In a second case,97 a 23-year-old male ingested approximately 5 g of cadmium iodide in a suicide attempt and presented with acute hemorrhagic gastroenteritis. His condition deteriorated, and despite treatment with ethylenediamine-tetraacetic acid (EDTA) and supportive measures, he died on hospital day 7. Autopsy did not reveal a specific cause of death. Pulmonary/Cadmium Fumes. Cadmium pneumonitis results from acute inhalation of cadmium oxide fumes during metalwork. The acute phase of cadmium pneumonitis may mimic metal fume fever (Chap. 95), but the two entities are distinctly different. Whereas metal fume fever is benign and self-limited, acute cadmium pneumonitis can progress to hypoxia, respiratory insufficiency, and death. Case reports of patients who develop acute cadmium pneumonitis4,5,33,67,76,86,96,98 are striking in their similar presentations. Patients were generally in good health until they began soldering or brazing with cadmium alloy in a closed space or without appropriate respiratory precautions. Within 6–12 hours, they developed constitutional symptoms, such as fever and chills, as well as a cough and respiratory distress, for which they sought care. On initial presentation to a healthcare provider, these patients may not appear ill; they may have a normal physical examination, oxygenation status, and chest radiograph. This apparent normalcy may lead to some confusion about the severity of the patient’s illness, and misdiagnosis (with metal-fume fever or some other nonspecific pulmonary ailment) is common. As the pneumonitis progresses to acute lung injury (ALI; Chap. 95), rales and rhonchi develop, oxygenation becomes impaired, and the chest radiograph develops a pattern consistent with pulmonary edema. Death despite aggressive supportive care is reported, and usually occurs within 3–5 days.33,67,76,96 Patients who survive an episode of acute cadmium pneumonitis are described as developing various chronic pulmonary ailments, including restrictive lung disease,4,5 diffusion abnormalities,4

Chronic cadmium poisoning generally occurs through occupational exposure, although instances of mass environmental exposure, such as occurred in Japan,29,62 are reported. Unfortunately, studies of chronic cadmium poisoning in humans are retrospective, and thus imperfectly controlled. In addition, especially in the industrial setting, cadmium exposure may serve simply as a marker for other exposures, such as toxic vapors, other heavy metals, or solvents, which may contribute to or cause the pathologic condition in question. Nonetheless, a great deal of data about the chronic toxicity of cadmium is available. Nephrotoxicity. The most common finding in chronic cadmium poisoning is proteinuria. This proteinuria is generally felt to be irreversible even after removal from exposure,40,50,71 although some small studies suggest a potential for clinical improvement.87 The question of whether renal dysfunction progresses after removal from exposure, however, is less clear. One large study of an environmentally exposed population found no progression of proteinuria or decrease in glomerular filtration rate (GFR) over time,40 whereas a study of a different environmentally exposed population showed slowly progressive renal dysfunction over a 10-year period.43 In an occupationally exposed cohort, followup studies showed a progressive decrease in GFR over time.70,71 It is important to note that the route and duration of exposure, as well as blood and urine cadmium concentrations, differ markedly within these studies, limiting the importance and breadth of applicability of any analysis. Occupational cadmium exposure is also associated with nephrolithiasis,44,74 quite likely because of hypercalcuria.75 Pulmonary Toxicity. Large studies of cadmium-exposed workers failed to demonstrate consistent results regarding chronic occupational cadmium exposure and chronic lung disease. In one study of 57 workers occupationally exposed to enough cadmium to produce renal dysfunction, there was no evidence of pulmonary dysfunction, even in those individuals with the greatest cadmium exposure.28 Conversely, other studies demonstrate both restrictive17 and obstructive22,73 changes on pulmonary function tests. Interestingly, a followup study of the group with restrictive lung disease showed improvements after cadmium exposure was reduced.16 The discrepancy in these results may be partly a result of markedly different degrees of exposure among the various groups. Cadmium may be associated with pulmonary neoplasia; the carcinogenicity of cadmium is discussed separately (below). Musculoskeletal Toxicity. Osteomalacia, one of the most prominent features of the itai-itai epidemic, is a condition in which inadequate mineralization of mature bone predisposes these bones to pathologic fractures. Interestingly, osteomalacia is generally not a prominent feature of most populations occupationally exposed to cadmium, although it is mentioned in case reports.10,50 The bias to-

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ward men in occupational cadmium studies (whereas the original itai-itai epidemic consisted largely of women), as well as differences in cumulative dosing, may account for some of this discrepancy. Hepatotoxicity. Although the liver stores as much cadmium as any other organ, hepatotoxicity is not a prominent feature of human cadmium exposure.42 The liver can certainly be a target organ, however, and hepatotoxicity is easily inducible in animals.1,26,27,69 Neurologic Toxicity. Evidence suggests that cadmium may be a neurotoxin. Cadmium exposure has been linked to olfactory disturbances,72,82 impaired higher cortical function,91 Parkinson syndrome,65,91 and sensory peripheral neuropathy.91,92 Other Organ Systems. Cadmium induces hypertension in rats,57 but human studies have not shown a convincing link.32,66 Although there is evidence that cadmium may cause immunosuppression affecting both humoral and cell-mediated immunity in animals,25 a single human study showed no overt immunopathology in an occupationally exposed cohort.49 The testes are clearly a target organ in animal exposures,56 but the testes are not considered a major target organ in humans. Cancer. Cadmium is capable of inducing tumors in multiple tissues in animals. These effects seem to be exacerbated by zinc deficiency.93 In humans, the only well-established site of carcinogenicity is the lung, and even those studies demonstrating an increased rate of lung cancer have methodologic flaws, such as coexposure to arsenic, a known pulmonary carcinogen.11,51 The preponderance of evidence, however, indicates that cadmium is a human carcinogen, and it is designated as such by the International Agency for Research on Cancer and the US National Toxicology Program.

DIAGNOSTIC TESTING Other than to confirm exposure, cadmium levels have limited utility in the management of the acutely exposed patient. Diagnosis and treatment are based on the patient’s history, physical examination, and symptoms. Ancillary tests, such as arterial blood gas analysis and chest radiograph in a patient exposed to cadmium oxide fumes, are more useful than cadmium levels. In the patient chronically exposed to cadmium, both cadmium levels and ancillary testing may prove helpful. Workers at high risk for cadmium toxicity should undergo regular urinalysis for proteinuria, and the development of proteinuria should prompt a reassignment to a low-exposure or no-exposure area. In the asymptomatic patient, the acceptable level for cadmium-exposed workers without proteinuria is 15 µg Cd/g urinary creatinine, although renal dysfunction has occurred at levels as low as 5 µg Cd/g urinary creatinine.21,45 Urinary cadmium levels, which reflect the slow, steady-state turnover and release of metallothioneinbound cadmium from the liver, are a better reflection of total body cadmium burden than blood levels. It is for this reason that urine cadmium levels are used for occupational monitoring.

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MANAGEMENT Acute Exposure Oral/Cadmium Salts. After airway, breathing, and circulation have been assessed, attention can be given to gastrointestinal decontamination. Although oral exposures are rare, they can prove fatal.9,97 In light of this, even in the absence of any evidence, gastric lavage seems appropriate. A small nasogastric tube should suffice, as inorganic cadmium salts are powders, not pills. There are no data regarding the use of activated charcoal in acute oral cadmium toxicity; however, activated charcoal is a relatively benign intervention and is clearly indicated in the treatment of ingestion of some metals, such as thallium and mercury (Chap. 82). In light of this, activated charcoal should be given in the absence of any contraindications (such as known perforation or pending endoscopy). Given the lack of experience with acute oral cadmium poisoning, all patients should be admitted to the hospital for supportive care, monitoring of renal and hepatic function, and consideration of evaluation of the gastrointestinal tract for evidence of caustic damage. Suggestions for the evaluation of a patient with a potential caustic injury are found elsewhere in this text (Chap. 87). Although it seems logical to chelate any patient with an acute life-threatening ingestion of a metal compound, the benefit of chelation in acute cadmium exposure is unproven. Multiple chelating agents have been tried, all in animal models, and frequently with conflicting results. The ideal chelating agent for treatment of oral cadmium toxicity would be well tolerated, would decrease gastrointestinal absorption of cadmium, would decrease the concentration of cadmium in organs such as the kidney and liver, and would not lead to increased cadmium levels in other critical organs such as the brain. Of the chelating agents studied for cadmium toxicity thus far, 2,3-dimercaptosuccinic acid (DMSA, succimer) comes closest to fulfilling these criteria. In models of acute oral cadmium toxicity, DMSA decreases the gastrointestinal absorption of cadmium3,6 and improves survival6,48 without increasing cadmium burdens in target organs.2,6 In a patient thought to have ingested potentially lethal amounts of cadmium (5 g is the lowest reported human toxic dose), treatment with DMSA would be reasonable given the low toxicity and apparent efficacy of this agent. It must be stressed, however, that the data supporting the use of DMSA are promising but not definitive, and are only derived from animal models. Furthermore, the Food and Drug Administration has not approved DMSA for this indication. It would be reasonable to use doses of DMSA that are well tolerated (10 mg/kg/dose three times a day), although dosing in human exposures is completely unstudied. Other chelating agents that may have some benefit in treating cadmium toxicity, but for which further investigation is warranted, include diethylenetriaminepentaacetic acid (DTPA)6,14 and 2,3dimercaptopropane sulfonate (DMPS),14,48 both of which reduce tissue burdens and increase survival. Many other chelating agents have been studied for treatment of acute cadmium toxicity and were found to be ineffective or detrimental. 2,3-Dimercaptopropanol (British Anti-Lewisite, BAL) increases whole-body cadmium excretion,47 but may increase renal tissue levels.14,47 BAL probably reduces acute toxicity modestly, but at the expense of potentiating chronic toxicity.20 Penicillamine does not appear to increase cadmium excretion or reduce tissue levels and may increase renal cadmium levels,14 as well as speed

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the development of nephrotoxicity.59 Cyclic tetramines (such as CYCLAM and TACPD, which have shown promise in nickel chelation) are theoretically beneficial in cadmium toxicity,37 but have yielded discouraging results thus far.81 Detergent formula chelating agents such as sodium tripolyphosphate (STPP) and nitrilotriacetic acid (NTA) appear to enhance both tissue uptake and lethality of cadmium as compared to controls.30,31 Data regarding calcium disodium EDTA are conflicting; although both mortality39 and renal concentrations14 were reduced in some models, there is also evidence that EDTA may potentiate toxicity.60 Dithiocarbamates decrease renal and hepatic concentrations,77,94 although some members of this class promote the uptake of cadmium into the CNS.3,34 The ability to draw conclusions about the above chelating agents in acute toxicity is difficult, for a number of reasons. Although some agents, such as EDTA and some dithiocarbamates, show promise, these agents may potentially prove harmful by redistributing cadmium to target organs. Furthermore, multiple models of acute cadmium exposure (oral, subcutaneous, intraperitoneal, and intravenous), multiple routes of administration of the chelating agent (oral, intraperitoneal, and intravenous), and multiple animal models (mouse, rat, and toad) are employed by various authors. Comparisons between studies are thus difficult, if not impossible. In addition, there is no evidence that the animal models being used are of any significance with regard to human toxicokinetics or toxicodynamics. Perhaps most significantly, most of the studies in question administer chelating agents within 30 minutes of exposure, which is an unrealistic time frame for the management of most human cadmium poisonings. The issue of rapidity of initiation of treatment is crucial, because cadmium is so rapidly cleared from the blood and redistributed to target organs that small delays may render chelating agents ineffective. One important study established that a variety of chelating agents (including EDTA, DTPA, and a dithiocarbamate) were effective in promoting cadmium excretion and reducing critical organ levels of cadmium when given immediately after cadmium exposure. However, in the second part of this study, when administration of these agents was delayed by only 2 hours, excretion fell by 90%, and concentrations of cadmium in target organs were indistinguishable from the control group.15 In summary, DMSA appears to have the most benefit in preventing morbidity and mortality in animal models of acute cadmium toxicity. DTPA and DMPS have also been shown to be effective, but the data are less convincing than for DMSA. Studies examining other agents, such as BAL, penicillamine, cyclic tetramines (CYCLAM and TACPD), detergent formula chelating agents (STPP and NTA), EDTA, and some dithiocarbamates, have found that these agents either have a mixed safety profile or are outright deleterious. Pulmonary/Cadmium Fumes. The patient who is ill after exposure to cadmium fumes (generally cadmium oxide) will invariably present with respiratory complaints and, usually, with constitutional symptoms as well. The patient should be removed from the exposure; the airway should then be assessed and appropriate oxygenation assured, although hypoxia may not be a problem acutely. Steroids are frequently used, but there are no studies to prove their efficacy. Because cadmium inhalation injuries are neither benign nor self-limited, all patients with acute inhalational exposures to cadmium should be admitted to the hospital for observation and

supportive care until respiratory symptoms have resolved. All such patients should have long-term followup arranged with a pulmonologist to assess the possibility of chronic lung injury, even in instances of single exposures. Chelation should never be entertained as an option for patients acutely exposed to cadmium fumes. Although large studies are lacking, these patients do not appear to be at risk for extrapulmonary injury.4,5,86,98

Chronic Exposure Patients chronically exposed to cadmium frequently come to attention during routine screening, as cadmium is a known industrial toxin and most patients who work with cadmium are under close medical surveillance. Usually, patients have developed proteinuria or less commonly, chronic pulmonary complaints. The management of such patients is challenging. Reduction (and preferably elimination) of cadmium exposure is the first intervention. However, as mentioned earlier, chronic cadmiuminduced renal and pulmonary changes may have a largely irreversible component. Chelation of patients with chronic cadmium toxicity is not currently recommended for a number of reasons. First, there is no evidence that chelation of chronically poisoned animals improves long-term outcomes, although some agents may lessen short-term organ dysfunction.55 Second, the majority of cadmium in a chronically exposed patient is bound to intracellular metallothionein, which greatly reduces its toxicity. Any attempt to remove cadmium from these deposits risks redistributing cadmium to other organs, possibly exacerbating toxicity; for instance, BAL may potentiate nephrotoxicity.24 Finally, many typical chelating agents (such as DMSA and DTPA35) do not remove significant amounts of cadmium, possibly because they cannot cross cell membranes to access the intracellular cadmium or because these agents do not have a high enough affinity for cadmium to dislodge it from metallothionein. Of all chelating agents tested thus far in animal models of chronic cadmium toxicity, the dithiocarbamates have shown the most success in reducing total body cadmium burdens in chronically poisoned animals. Unfortunately, the most effective agents, which are highly lipophilic, also tend to cause redistribution of cadmium to the brain; their lipophilicity allows them to cross cell membranes into hepatocytes, but also promotes their uptake into the lipid-rich central nervous system.35 Numerous dithiocarbamates have been synthesized and studied with regard to cadmium decorporation, however, and several species effectively reduce whole-body, renal, and hepatic cadmium levels without an increase in CNS cadmium.55,78 At this time, there are no FDAapproved dithiocarbamate preparations. Further research into the subject of chelation for chronic cadmium poisoning is ongoing, and may in the future suggest an agent which is not only safe, but reduces the risk of exacerbating end-organ toxicity. However, there is insufficient evidence at this time to justify the use of any chelating agent in the treatment of chronic cadmium toxicity.

SUMMARY Cadmium is a potent toxin with different effects based on the time course and route of exposure. In the acute oral exposure, gastrointestinal injury may predominate; in acute inhalation, a severe

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chemical pneumonitis may ensue. In chronic environmental or occupational exposure, nephrotoxicity (usually manifest by proteinuria) is the most significant finding, although other organ systems, such as the lungs, can be affected. Treatment for all patients with suspected cadmium poisoning, acute or chronic, consists of removal from the source, decontamination if possible, and supportive care. In the rare instance of acute cadmium salt ingestion, treatment with DMSA may be warranted; there is insufficient evidence to recommend chelation in the chronically cadmium poisoned patient at this time.

REFERENCES 1. Al-Nasser IA: Cadmium hepatotoxicity and alterations of the mitochondrial function. J Toxicol Clin Toxicol 2000;38:407–413. 2. Andersen O, Nielsen JB: Oral cadmium chloride intoxication in mice: Effects of penicillamine, dimercaptosuccinic acid and related compounds. Pharmacol Toxicol 1988;63:386–389. 3. Anderson O, Nielsen JB, Svendsen P: Oral cadmium chloride intoxication in mice: Diethyldithiocarbamate enhances rather than alleviates acute toxicity. Toxicology 1988;52:331–342. 4. Anthony JS, Zamel N, Aberman A: Abnormalities in pulmonary function after brief exposure to toxic metal fumes. Can Med Assoc J 1978;119:586–588. 5. Barnhart S, Rosenstock L: Cadmium chemical pneumonitis. Chest 1984;86:791. 6. Basinger MA, Jones MM, Hoscher MA, et al: Antagonists for acute oral cadmium chloride intoxication. J Toxicol Environ Health 1988; 23:77–89. 7. Bernard A, Roels H, Hubermont G, et al: Characterization of the proteinuria of cadmium-exposed workers. Int Arch Occup Environ Health 1976;38:19–30. 8. Bernard A, Roels H, Thielemans N, et al: Assessment of the causality of the cadmium-protein relationships in the urine of the general population with reference to the Cadmibel study. IARC Sci Publ 1992; 118:341–346. 9. Buckler HM, Smith WD, Rees WD: Self-poisoning with oral cadmium chloride. Br Med J 1986;292:1559–1560. 10. Blainey JD, Adams RG, Brewer DB, et al: Cadmium-induced osteomalacia. Br J Ind Med 1980;37:278–284. 11. Bofetta P: Methodological aspects of the epidemiological association between cadmium and cancer in humans. IARC Sci Publ 1992;118: 425–434. 12. Buchet JP, Lauwerys R, Roels H, et al: Renal effects of cadmium body burden of the general population. Lancet 1990;336:699–702. 13. Budavari S, O’Neil MJ, Smith A, et al, eds: The Merck Index. Whithouse Station, NJ, Merck & Company, 1996, p. 1665. 14. Cantilena LR, Klaassen CD: Comparison of the effectiveness of several chelators after single administration on the toxicity, excretion, and distribution of cadmium. Toxicol Appl Pharmacol 1981;58: 452–460. 15. Cantilena LR, Klaassen CD: Decreased effectiveness of chelation therapy with time after acute cadmium poisoning. Toxicol Appl Pharmacol 1982;63:173–180. 16. Chan OY, Poh SC, Lee HS, et al: Respiratory function in cadmium battery workers—A follow-up study. Ann Acad Med Singapore 1988; 17:283–287. 17. Chan OY, Poh SC, Tan KT, Kwok SF: Respiratory function in cadmium battery workers. Singapore Med J 1986;27:108–119. 18. Cherian MG: Chelation of cadmium with BAL and DTPA in rats. Nature 1980;287:871–872. 19. Cherian MG, Goyer RA, Delaquerriere-Richardson L: Cadmium-metallothionein-induced nephropathy. Toxicol Appl Pharmacol 1976;38: 399–408.

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20. Cherian, MG, Rodgers K: Chelation of cadmium from metallothionein in vivo and its excretion in rats repeatedly injected with cadmium chloride. J Pharmacol Exp Ther 1982;222:699–703. 21. Chia KS, Tan AL, Chia SE, et al: Renal tubular function of cadmium exposed workers. Ann Acad Med Singapore 1992;21:756–759. 22. Cortona G, Apostoli P, Toffoletto F, et al: Occupational exposure to cadmium and lung function. IARC Sci Publ 1992;118:205–210. 23. Coyle P, Niezing G, Shelton TL, et al: Tolerance to cadmium toxicity by metallothionein and zinc: In vivo and in vitro studies with MT-null mice. Toxicology 2000;150:53–67. 24. Dalhamn T, Friberg L: Dimercaprol (2,3-dimercaptopropanol) in chronic cadmium poisoning. Acta Pharmacol Toxicol 1955;11: 68–71. 25. Dan G, Lall SB, Rao DN: Humoral and cell-mediated immune response to cadmium in mice. Drug Chem Toxicol 2000;23:349–360. 26. Dudley RE, Gammal LM, Klaassen CD: Cadmium-induced hepatic and renal injury in chronically exposed rats: Likely role of hepatic cadmium-metallothionein in nephrotoxicity. Toxicol Appl Pharmacol 1985;77:414–426. 27. Dudley RE, Svoboda DJ, Klaassen CD: Acute exposure to cadmium causes severe liver injury in rats. Toxicol Appl Pharmacol 1982; 65:302–313. 28. Edling C, Elinder CG, Randma E: Lung function in workers using cadmium containing solder. Br J Ind Med 1986;43:657–662. 29. Emmerson BT: “Ouch-ouch” disease: The osteomalacia of cadmium nephropathy. Ann Intern Med 1970;73:854. 30. Engstrom B: Influence of chelating agents on toxicity and distribution of cadmium among proteins of mouse liver and kidney following oral or subcutaneous exposure. Acta Pharmacol Toxicol 1981;48: 108–117. 31. Engstrom B, Nordberg GF: Effects of detergent formula chelating agents on the metabolism and toxicity of cadmium in mice. Acta Pharmacol Toxicol 1978;43:387–397. 32. Engvall J, Perk J: Prevalence of hypertension among cadmiumexposed workers. Arch Environ Health 1985;40:185–190. 33. Fuortes L, Leo A, Ellerbeck PG, Friell LA: Acute respiratory fatality associated with exposure to sheet metal and cadmium fumes. J Toxicol Clin Toxicol 1991;29:279–283. 34. Gale GR, Atkins LM, Walker EM, et al: Comparative effects of diethyldithiocarbamate, dimercaptosuccinate, and diethylenetri-aminepentaacetate on organ distribution and excretion of cadmium. Ann Clin Lab Sci 1983;13:33–44. 35. Gale GR, Atkins LM, Walker EM, et al: Mechanism of diethyldithiocarbamate, dihydroxyethyldithiocarbamate, and dicarboxymethyldithiocarbamate action on distribution and excretion of cadmium. Ann Clin Lab Sci 1983;13:474–481. 36. Goyer RA, et al: Non-metallothionein-bound cadmium in the pathogenesis of cadmium nephrotoxicity in the rat. Toxicol Appl Pharmacol 1989;101:232–244. 37. Gulumian M, Casimiro E, Linder PW, et al: Evaluation of a new chelating agent for cadmium: A preliminary report. Hum Exp Toxicol 1993;12:247–251. 38. Hammond, CR: Cadmium. In: Lide DR, ed: CRC Handbook of Chemistry and Physics, 80th ed. Boca Raton, FL, CRC Press, 1989, pp. 4–8. 39. Hilmy AM, El-Domaity N, Daabees AY: Toxicity of cadmium administration to the toad and the treatment of its poisoning with EDTA. Comp Biochem Physiol C 1986;85:249–252. 40. Hotz P, Buchet JP, Bernard A, et al: Renal effects of low-level environmental cadmium exposure: 5-year follow-up of a subcohort from the Cadmibel study. Lancet 1999;354:1508–1513. 41. Ikeda M, Moon CS, Zhang ZW, et al: Urinary alpha1-microglobulin, beta2-microglobulin, and retinol-binding protein levels in general populations in Japan with references to cadmium in urine, blood, and 24-hour food duplicates. Environ Res 1995;70:35–46. 42. Ikeda M, Watanabe T, Zhang Z-W, et al: The integrity of the liver among people environmentally exposed to cadmium at various levels. Int Arch Occup Environ Health 1997;69:379–385.

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43. Iwata K, Saito H, Moriyama M, Nakano A: Renal tubular function after reduction of environmental cadmium exposure: A ten-year follow-up. Arch Environ Health 1993;48:157–163. 44. Jarup L, Elinder CG: Incidence of renal stones among cadmium exposed battery workers. Br J Ind Med 1993;50:598–602. 45. Jarup L, Elinder CG: Dose-response relations between urinary cadmium and tubular proteinuria in cadmium-exposed workers. Am J Ind Med 1994;26:759–769. 46. Jarup L, Hellstrom L, Alfven T, et al: Low level exposure to cadmium and early kidney damage: The OSCAR study. Occup Environ Med 2000;57:668–672. 47. Jones MM, Cherian MG, Singh PK, et al: A comparative study on the influence of vicinal dithiols and a dithiocarbamate on the biliary excretion of cadmium in rat. Toxicol Appl Pharmacol 1991;110: 241–250. 48. Jones MM, Weater AD, Weller WL: The relative effectiveness of some chelating agents as antidotes in acute cadmium poisoning. Res Commun Chem Pathol Pharmacol 1978;22:581–588. 49. Karakaya A, Yucesoy B, Sardas OS: An immunological study on workers occupationally exposed to cadmium. Hum Exp Toxicol 1994; 13:73–75. 50. Kazantis G: Renal tubular dysfunction and abnormalities of calcium metabolism in cadmium workers. Environ Health Perspect 1979;28: 155–159. 51. Kazantis G, Blanks RG, Sullivan KR: Is cadmium a human carcinogen? IARC Sci Publ 1992;118:435–446. 52. Kjellstrom T, Nordberg GF: A kinetic model of cadmium metabolism in the human being. Environ Res 1978;16:248–269. 53. Klaassen CD, Liu J, Choudhuri S: Metallothionein: An intracellular protein to protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 1999;39:267–294. 54. Kojima S, Kaminaka K, Kiyozumi M, et al: Comparative effects of three chelating agents on distribution and excretion of cadmium in rats. Toxicol Appl Pharmacol 1986;83:516–524. 55. Kojima S, Ono H, Kiyozumi M, et al: Effect of N-benzyl-D-glucamine dithiocarbamate on the renal toxicity produced by subacute exposure to cadmium in rats. Toxicol Applied Pharmacol 1989;98:39–48. 56. Kojima S, Sugimura Y, Hirukawa H, et al: Effects of dithiocarbamates on testicular toxicity in rats caused by acute exposure to cadmium. Toxicol Appl Pharmacol 1992;116:24–29. 57. Lall SB, Das N, Rama R, et al: Cadmium-induced nephrotoxicity in rats. Indian J Exp Biol 1997;35(2):151–154. 58. Liu J, Liu Y, Habeebu SS, Klaassen CD: Susceptibility of MT null mice to chronic CdCl2-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex. Toxicol Sci 1998; 46:197–203. 59. Lyle WH, Green JN, Gore V, et al: Enhancement of cadmium nephrotoxicity by penicillamine in the rat. Postgrad Med J 1968;Suppl: 18–21. 60. McGivern J, Mason J: The effect of chelation on the fate of intravenously administered cadmium in rats. J Comp Pathol 1979;89:1–9. 61. Min K-S, Onosaka S, Tanaka K: Renal accumulation of cadmium and nephropathy following long-term administration of cadmium-metallothionein. Toxicol Appl Pharmacol 1996;141:102–109. 62. Murata I, Hirono T, Saeki Y, et al: Cadmium enteropathy, renal osteomalacia (“itai itai” disease in Japan). Bull Soc Int Chir 1970;29: 34–42. 63. Nishio H, Hayashi C, Lee MJ, et al: Itai-itai disease is not associated with polymorphisms of the estrogen receptor alpha gene. Arch Toxicol 1999;73:496–498. 64. Nogawa K, Kido T, Shaikh ZA: Dose-response relationship for renal dysfunction in a population environmentally exposed to cadmium. IARC Sci Publ 1992;118:311–318. 65. Okuda B, Iwamoto Y, Tachibana H, Sugita M: Parkinsonism after acute cadmium poisoning. Clin Neurol Neurosurg 1997;99:263–265. 66. Ostergaard K: Cadmium and hypertension. Lancet 1977;8013: 677–678.

67. Patwardhan JR, Finckh ES: Fatal cadmium-fume pneumonitis. Med J Aust 1976;1(25):962–966. 68. Prozialec WC: Evidence that e-cadherin may be a target for cadmium toxicity in epithelial cells. Toxicol Appl Pharmacol 2000;164: 231–249. 69. Rikans LE, Yamano T: Mechanisms of cadmium-mediated acute hepatotoxicity. J Biochem Mol Toxicol 2000;14:110–117. 70. Roels H, Djubgang J, Buchet JT, et al: Evolution of cadmium-induced renal dysfunction in workers removed from exposure. Scand J Work Environ Health 1982;8:191–200. 71. Roels HA, Lauwerys RR, Buchet JP, et al: Health significance of cadmium-induced renal dysfunction: A five-year follow-up. Br J Ind Med 1989;46:755–764. 72. Rose CS, Heywood PG, Costanzo RM: Olfactory impairment after chronic occupational cadmium exposure. J Occup Med 1992;34: 600–605. 73. Sakurai H, Omae K, Toyama T, et al: Cross-sectional study of pulmonary function in cadmium alloy workers. Scand J Work Environ Health 1982;8S1:122–130. 74. Scott R, Cunningham C, McLelland A, et al: The importance of cadmium as a factor in calcified upper urinary tract stone disease—A prospective 7-year study. Br J Urol 1982;54:584–589. 75. Scott R, Patterson PJ, Burns R, et al: Hypercalciuria related to cadmium exposure. Urology 1978;11:462–465. 76. Seidal K, Jorgensen N, Elinder CG, et al: Fatal cadmium-induced pneumonitis. Scand J Work Environ Health 1993;19:429–431. 77. Shimada H, Funakoshi T, Kiyozumi M, et al: Comparison of the effectiveness of dithiocarbamates on the excretion and distribution of cadmium in mice. Res Commun Chem Pathol Pharmacol 1991;73: 249–252. 78. Singh PK, Jones SG, Gale GR, et al: Selective removal of cadmium from aged hepatic and renal deposits: N-substituted talooctamine dithiocarbamates as cadmium mobilizing agent. Chem Biol Interact 1990;74:79–91. 79. Squibb KS, Pritchard JB, Fowler BA: Cadmium-metallothionein nephropathy: Relationships between ultrastructural/biochemical alterations and intracellular cadmium binding. J Pharmacol Exp Ther 1984;229:311–321. 80. Squibb KS, Ridlington JW, Carmichael NG, Fowler BA: Early cellular effects of circulating cadmium-thionein on kidney proximal tubules. Environ Health Perspect 1979;28:287–296. 81. Srivasta RC, Gupta S, Ahmad N, et al: Comparative evaluation of chelating agents on the mobilization of cadmium: A mechanistic approach. J Toxicology Environ Health 1996;47:173–182. 82. Surunda AJ: Measuring olfactory dysfunction from cadmium in an occupational and environmental medicine office practice. J Occup Environ Med 2000;42:337. 83. Takebayashi S, Jimi S, Segawaa M, Kiyoshi Y: Cadmium induces osteomalacia mediated by proximal tubular atrophy and disturbances of phosphate reabsorption. A study of 11 autopsies. Pathol Res Pract 2000;196:653–663. 84. Telisman S, Jurasovic J, Pizent A, et al: Cadmium in the blood and seminal fluid of nonoccupationally exposed adult male subjects with regard to smoking habits. Int Arch Occup Environ Health 1997; 70:243–248. 85. Thun MJ, et al: Nephropathy in cadmium workers: Assessment of risk from airborne occupational exposure to cadmium. Br J Ind Med 1989;46:689–697. 86. Townshend RH: Acute cadmium pneumonitis: A 17-year follow up. Br J Ind Med 1982;39:411–412. 87. Tsychya K: Proteinuria of cadmium workers. J Occup Med 1976; 18:463–466. 88. van Sittert NJ, Ribbens PH, Huisman B, Lugtengurg D: A nine-year follow-up study of renal effects in workers exposed to cadmium in a zinc ore refinery. Br J Ind Med 1993;50:603–612. 89. Verbost PM, Filk G, Pang PKT, et al: Cadmium inhibition of the erythrocyte Ca2+ pump. J Biol Chem 1989;264:5613–5615.

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90. Verbost PM, Senden MHMN, van Os CH: Nanomolar concentrations of Cd2+ inhibit Ca2+ transport systems in plasma membranes and intracellular Ca2+ stores in intestinal epithelium. Biochem Biophys Acta 1987;902:247–252. 91. Viaene, MK, Masschelein R, Leenders J, et al: Neurobehavioural effects of occupational exposure to cadmium: A cross-sectional epidemiological study. Occup Environ Med 2000;57:19–27. 92. Viaene, MK, Roels HA, Leenders J, et al: Cadmium: A possible etiological factor in peripheral polyneuropathy. Neurotoxicology 1999; 20:7–16. 93. Waalkes MP: Cadmium carcinogenesis in review. J Inorg Biochem 2000;79:241–244.

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94. Wang, C, Fany Y, Peng S, et al: Synthesis of novel chelating agents and their effect on cadmium decorporation. Chem Res Toxicol 1999; 12:331–334. 95. Watkins SR, Hodge RM, Cowman DC, Wickham PP: Cadmiumbinding serum protein. Biochem Biophys Res Commun 1977;74: 1403–1410. 96. Winston RM: Cadmium fume poisoning. Br Med J 1971;758:401. 97. Wisniewska-Knypl JM, Jablonska J, Myslak Z: Binding of cadmium on metallothionein in man: An analysis of a fatal poisoning by cadmium iodide. Arch Toxicol 1971;28:46–55. 98. Yates DH, Goldman KP: Acute cadmium poisoning in a foreman plant welder. Br J Ind Med 1990;47:429–431.

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82C

COPPER Lewis S. Nelson

Copper MW = 63.5 daltons Normal Levels Blood, total = 70–140 µg/dL (11–22µmol/L) Serum, total = 120–145 µg/dL (18.9–22.8 µmol/L) Serum free = 4–7 µg/dL (0.63–1.1 µmol/L) Urine = 30–50 µg/L (0.47–0.79 µmol/L) Ceruloplasmin = 25–50 µg/dL Action Levels Blood = 100 µg/dL (15.7 µmol/L) Values greater than or equal to the action level necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical condition of the patient.

A 16-year-old boy presented to the hospital 3 days after reportedly ingesting 1 tablespoon of K77 Root Killer in an attempt to gain needed attention from his aunt. The patient denied suicidality and stated that he did not know that the granules, which were in his home to halt the growth of tree roots into the home’s septic system, were toxic. Immediately after ingesting the product, he was given milk by his aunt. According to the patient this prompted four episodes of blue-colored emesis, containing crystals of the ingested substance. Although he had abdominal pain for the next 72 hours, the patient did not seek medical care because he assumed these symptoms would be transient. There was no suggestion that this was indeed a suicide attempt. Ultimately, the patient presented to the hospital because he developed dark brown discoloration of his urine, yellowing of his eyes, and worsening abdominal pain. He denied throat discomfort, hematemesis, or melena. His presenting vital signs were blood pressure, 102/52 mmHg; pulse, 86 beats/min; respirations, 18 breaths/min; and he was afebrile. His physical examination was significant for the presence of scleral and sublingual icterus, although dermal jaundice was not appreciated. His oropharynx was normal and his chest was clear. On abdominal examination there was moderate tenderness over the left upper quadrant and left costovertebral angle. There was no involuntary guarding or rebound. Stool obtained by rectal examination was guaiac negative. The patient’s neurologic examination was normal. A chest radiograph was normal. His initial laboratory assessment was remarkable for a hematocrit of 20%, and normal chemistries (anion gap, 5) and renal function (blood urea nitrogen (BUN), 15 mg/dL; creatinine, 0.8 mg/dL). Hepatic profiling revealed an aspartate aminotransferase (AST) of 54 IU/L, alkaline phosphatase of 77 IU/L, and a total bilirubin of 5.2 mg/dL with an indirect bilirubin of 0.2 mg/dL. The patient was started on D-penicillamine, 500 mg every 6 hours orally, and was hydrated aggressively with intravenous 0.9% sodium chloride. His clinical status improved over the next 72 hours and no blood transfusion was required.

Copper is among the more frequently reported metals with which patients are poisoned. It routinely ranks third, behind lead and arsenic, in nonmedicinal metal exposures (such as iron or lithium) reported to US Poison Control Centers (Chap. 116). Still, acute symptomatic poisoning remains relatively rare in this country. In India, copper sulfate ingestion is a leading cause of suicide.23,67 In that country, copper sulfate poisoning is reportedly responsible for nearly a third of all poisonings requiring hemodialysis, and is the most common nephrotoxic indication for dialysis.6,21 The dramatic clinical presentations and potential for poor outcome without appropriate treatment highlight the toxicologic significance of copper. Copper, in its various forms, is still used intensively in our society. As the metal, it is extensively used in both wiring and plumbing. Its use in coinage, at least in the United States, fell dramatically with its replacement by zinc in the penny. Copper salts, alternatively, are widely used in fungicides, algicides, and plant growth regulators (Table 82–3). They are also important as catalysts, particularly in the petroleum industry. Throughout this chapter, unless otherwise noted, discussion of toxicologically important aspects of copper refers to inorganic, or ionic, copper.

HISTORY AND EPIDEMIOLOGY Copper is available naturally, either as native copper or as one of its sulfide or oxide ores. Important ores include malachite (CuCO3 (OH)2), chalcocite (Cu2S), cuprite (Cu2O), and chalcopyrite (CuFeS2 or Cu2S Fe2S3). Chalcopyrite, a yellow sulfide ore, is the source of 80% of the world’s copper production. The smelting of copper ores began about 7000 years ago; copper metal gradually assumed its current level of importance at the start of the Bronze Age around 3000 BC. Smelting, or the separation of the ore components, begins with roasting to dry the ore concentrate, which is then further purified by electrolysis to a 99.5% level of purity. The sulfide ores have a naturally high arsenic content that is released

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TABLE 82–3.

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Important Copper Products

Chemical Name

Chemical Structure

Common Name

Notes

Chalcopyrite

CuFeS2

Copper iron sulfide

Chromated cupric arsenate

1% copper oxide 47% chromium oxide 34% arsenic pentoxide Cu((HOCH2CH2)3N)2

CCA

Copper ore; source of 80% of world’s copper Wood preservative 34

Chelated copper

Algicide

Cu(C2H3O2)2.3Cu(AsO2)2

Paris or Vienna green

Cupric arsenite

CuHAsO3

Swedish or Scheele green

Insecticide, wood preservative, pigment* Wood preservative insecticide*

Cupric hydroxide Cupric chloride Cupric chloride, basic Copper octanoate

Cu(OH)2 CuCI2 CuCI2 + CuO

Cupric oxide

CuO

Cupric sulfate

CuSO4

Cupric sulfate, basic Cuprous cyanide Cuprous oxide

CuSO4 + CuO CuCN Cu2O

Copper triethanolamine complex Cupric acetoarsenite

Basic copper chloride; copper oxychloride Copper soap Black copper oxide; tenorite Roman vitriol, blue vitriol, bluestone, hydrocyanite Bordeaux solution Cupricin Red copper oxide, cuprite

Fungicide Catalyst in petrochemical industry Fungicide Fungicide in paint, rot-proof rope, and roofing Glass pigment, flux, polishing agent Fungicide, plant growth regulator, whitewash, home-grown crystals Fungicide Electroplating solutions Antifouling paint

*No longer used in United States.

during the extraction process, posing a risk for those who perform copper smelting. Although, as noted, acute copper poisoning is uncommon in the United States, copper’s historical role as a pharmacotherapeutic agent remains noteworthy. Copper sulfate was used in burn wound débridement until cases of systemic poisoning were reported.35 Interestingly, in one report, each wound débridement procedure was associated with a fall in the child’s hematocrit by 8–10%. In the 1960s, copper sulfate (250-mg dose, containing 100 mg copper ion) was ironically a recommended emetic agent, typically for use in children, following potentially toxic exposures.40 It was recognized for its rapid onset and effectiveness, and it compared favorably with syrup of ipecac. However, this was rapidly identified to be a highly dangerous practice and its use was discontinued.36,72 Copper salts are still administered in religious rituals as a green-colored “spiritual water,” containing 100–150 g/L of copper sulfate as an emetic to expel one’s sins.7,71 Acute or chronic copper poisoning occurs when copper ions are leached from copper pipes or copper containers. This occurs most frequently when carbon dioxide gas, used for postmix soft drink carbonation, backflows into the tubing transporting water to the soda dispensers, creating an acidic solution of carbonic acid.83 Similarly, storage of acidic potable substances, such as orange or lemon juice, in copper vessels may cause copper poisoning.84 A particularly dangerous situation occurs when acidic water is inadvertently used for hemodialysis.26,48 In this circumstance, the leached copper avoids the normal gastrointestinal barrier and is delivered directly to the patient’s circulation. In one reported se-

ries, the copper level in the dialysis water was 650 µg/L, causing several poisonings and the death of a patient with a whole-blood copper level of 2095 µg/L.26 Similarly, stagnant water or hot water,63 even if not highly acidic, may accumulate copper ions and cause poisoning.8,27 Metallic copper is ideal for electrical wiring because it is highly malleable, can be drawn into fine wire, and has an electrical conductivity only exceeded by silver. Similarly, its excellent heat conductivity accounts for its widespread use in cookware. Although the metal is reactive with air, it forms a resistant layer of insoluble copper carbonate on its surface. It is this water- and airresistant compound that accounts for the green coloration of ornamental roofing and statues. Because copper is a soft metal it must be strengthened prior to use in structural applications or as a coinage metal. This is most commonly done by the creation of copper alloys. Brass is an alloy of copper compounded with as much as 35% zinc. Similarly, bronze contains copper combined with up to 14% zinc. Gunmetal is an alloy that contains 88% copper, 10% tin, and 2% zinc. Sterling silver and white gold also contain copper.

CHEMICAL PRINCIPLES Metallic copper (Cu0) has an oxidation state of zero and, although not in itself poisonous, it may release copper ions in acidic environments. The copper intrauterine device (IUD) for contraception derives its efficacy from the effects of the local release of copper

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ions.12 Similarly, metallic copper bracelets, worn by patients with rheumatoid arthritis, purportedly derive their far-reaching antiinflammatory effect through dermal copper ion absorption and distribution to affected tissues.80 Ingestion of large amounts of metallic copper, for example as coins, may rarely produce acute copper poisoning.86 Poisoning in this situation is caused by release of large amounts of copper ion from copper alloy by the acidic gastric content. Also, finely divided metallic copper dust or bronze powder used in industry and for gilding, although not systemically bioavailable, may produce life-threatening bronchopulmonary irritation, presumably as a consequence of the local release of ions.33 As noted, most patients who are suffering from acute copper poisoning are exposed to ionic copper. In copper (II) sulfate, also known as cupric sulfate, the copper atom is in the +2 oxidation state. Copper sulfate is used as a fungicide and algicide and to eradicate tree roots that invade septic or sewage systems. Copper sulfate is the most readily available form and that which is involved in the majority of nonindustrial copper salt exposures. Copper sulfate was a favorite ingredient in many home chemistry sets because of its brilliant blue color when dissolved in water. Although serious poisoning, particularly in children,81 led regulatory agencies in the United States to restrict its use, it still accounts for most chemistry set–related exposures in other countries.53 Homegrown copper sulfate crystals kits are occasionally responsible for fatal poisonings.30 Cuprous salts, containing copper in the +1 oxidation state, are unstable in water and readily oxidize to the cupric form. Regardless of oxidation state, there are numerous copper salts used in industry and agriculture (Table 82–3), many of which are not poisonous. Because those salts that are water soluble are more likely to be toxic, it is important to determine the nature of the implicated copper product in poisoned patients. Analogously, when examining the medical literature, it is critical to discern which form of copper is involved in the experiment or case report before understanding and application of the results can occur.

PHARMACOLOGY/PHYSIOLOGY Copper is one of eight essential metals that our body stores in milligram amounts (100–150 mg). Daily requirements of copper are approximately 50 µg/kg in infants and 30 µg/kg in adults. The daily requirement is satisfied by nuts, fish, and green vegetables such as legumes, although our largest source is generally from drinking water. Although most natural water contains a small quantity (4–10 µg/L), most copper is tightly bound to organic matter and therefore not orally bioavailable. Copper pipes typically add about 1 mg of copper to the daily intake of an adult. The Environmental Protection Agency guidelines permit up to 1.3 mg/L of copper in drinking water, although in some areas concentrations may intermittently be as high as 60 mg/L. Copper in water may be tasted at concentrations of 1–5 mg/L and a blue-green discoloration is imparted when the levels are greater than 5 mg/L. Acute gastrointestinal symptoms occur when water contains more than 25 mg/L, although levels as low as 3 mg/L are often considered “toxic” by regulatory agencies. Copper deficiency is exceedingly rare even in the poorest communities and is most frequently a result of excessive zinc intake or to a genetic aberration such as Menkes disease. Copper is absorbed by an active process involving a Cu-ATPase in the small intestinal mucosal cell membrane, also known as

the Menkes ATPase (see below). Although the gastrointestinal absorption varies with the copper intake and is as low as 12% in patients with high copper intake, in the presence of damaged mucosa, such as following acute overdose, the fractional absorption is likely to be significantly higher. Once absorbed, copper is rapidly bound to albumin and amino acids, such as histidine, for transport to the liver and other tissues. Its half-life in the plasma is approximately 15 minutes. Copper uptake by the hepatic cells occurs via a specific uptake pump after being released locally in the reduced state from its carrier (albumin or ceruloplasmin). This process, which is facilitated by the reducing agent ascorbic acid, provides a potential window, however brief, for detoxification of the ion by chelating agents. In the hepatocyte complex, trafficking systems exist involving ceruloplasmin, metallothionein, and other metallochaperones within the cytoplasm to prevent copper toxicity and to aid delivery to the appropriate enzymes.18 A distinct Cu-ATPase, located on certain subcellular organelles such as the trans-Golgi network or pericanalicular lysosomes, assists in the appropriate localization and elimination, respectively, of the metal.18 By this mechanism, copper is either incorporated into enzymes or released, as a metallothionein-copper complex, directly into the biliary system for fecal elimination. Some copper is released from the liver bound primarily to ceruloplasmin, an
2-sialoglycoprotein with a molecular weight of 132,000 daltons. Ceruloplasmin-bound copper accounts for approximately 90–95% of serum copper. Ceruloplasmin is a multifunctional protein that binds six atoms of copper per molecule, and copper bound to this carrier has a plasma half-life of approximately 24 hours. Ceruloplasmin is also involved in the mobilization of iron from its storage sites and it serves an analogous role as a ferrioxidase during the ferrous-ferric conversion. Copper (I) is oxidized directly by ceruloplasmin, thereby avoiding the generation of reactive oxygen species. About 5–10% of serum copper is bound to albumin under normal conditions, but following acute poisoning, the majority of the excess copper binds to albumin. The albumin-copper complex represents the “free” or toxicologically active copper. The amount of unbound copper in the blood under normal circumstances is well below 1%. The volume of distribution of copper is 2.0 L/kg and the half-life of erythrocyte copper is 26 days. There are several important copper-containing enzymes in humans (Table 82–4). The common link among these enzymes is their participation in redox reactions in which a molecule, typically oxygen, donates or shares its electrons with another com-

TABLE 82–4. Important Copper-Containing Enzymes and Their Functions Enzyme

Function

Alcohol dehydrogenase Catalase Ceruloplasmin Cytochrome c oxidase Dopamine -hydroxylase Factor V Lysyl oxidase Monoamine oxidase Superoxide dismutase Tyrosinase

Metabolism of alcohols Detoxifies peroxide Copper transport, ferrioxidase Electron transport chain Converts dopamine to norepinephrine Coagulation cascade Cross-links collagen and elastin Deamination of primary amines Detoxifies free radicals Melanin production

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pound. In this respect, the physiology, chemistry, and toxicology of copper are most similar to those of iron. In fact, “blue-blooded” animals, such as octopi and spiders, use copper in hemocyanin, a blue pigment, in a manner analogous to how “red-blooded” animals use iron in hemoglobin. When all of the various roles of copper are compiled, it is understandable why a genetic defect in intestinal copper absorption, or Menkes “kinky hair” syndrome, is characterized by mental retardation, thermoregulatory dysfunction, hypopigmentation, connective tissue abnormalities, and pili torti (kinky hair). The elimination of copper occurs predominantly through biliary excretion following complexation with ceruloplasmin. Biliary excretion approximates gastrointestinal absorption, and averages 1000 µg/24h (35–305 µg/L).5 Renal elimination under normal conditions is trivial, accounting for approximately 5–25 µg/24h (2.7–30 µg/L).5

TOXICOLOGY/PATHOPHYSIOLOGY Redox Chemistry In acute overdose, a high fraction of the serum copper remains bound to low-affinity proteins, such as albumin, and thus is biologically active. Because, as a transition metal, copper is capable of assuming one of several different oxidation, or valence, states, it is an active participant in reduction-oxidation, or redox, reactions. In particular, participation in the Fenton reaction and HaberWeiss cycle explains the toxicologic effects of copper as a generator of oxidative stress and inhibitor of several key metabolic enzymes (Chap. 12). In particular, the mitochondrial electron transport chain and lipid membranes serve as ready sources of electrons for copper reduction, establishing a chain of events that ultimately leads to mitochondrial or membrane dysfunction, respectively.55

Erythrocytes Copper (II) ion inhibits sulfhydryl groups on enzymes in important antioxidant systems, including glucose-6-phosphate dehydrogenase and glutathione reductase.76 While support for these effects is only indirect, intraerythrocytic levels of reduced glutathione fall following copper exposure. This effect is presumably part of the protective role that glutathione, a nucleophile or reducing agent, normally has on oxidants, in this case, either cupric ions50 or the reactive oxygen species they generate.49,77 Thus, in the setting of copper poisoning, in which excessive quantities of oxidants are produced, the depletion of glutathione presumably allows peroxidative membrane damage. In the presence of sulfhydryl-rich cell membranes, such as those on erythrocytes, cupric ions are reduced to cuprous ions, which are capable of generating superoxide radicals in the presence of oxygen.44 This one electron reduction of oxygen regenerates the cupric ion, allowing redox cycling and continuous generation of reactive oxygen species (Fig. 82–1). The importance of hemoglobin-derived reactive oxygen species is demonstrated by the lack of hemolysis in the presence of anaerobic conditions or in an environment saturated with carbon monoxide.10 The in vitro hemolytic activity of copper sulfate is reduced by albumin and several sulfhydryl-containing compounds, including D-penicillamine and succimer.1 Interestingly, dimercaptopropane sulfonate (DMPS), another sulfhydryl-containing compound that is often

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Figure 82–1. Copper, in the cupric or Cu2+ state, is reduced by sulfhydrylcontaining compounds, such as glutathione (GSH) or dimercaptopropane sulfonate (DMPS), to its cuprous form (Cu+); in the process, disulfide links are formed. Oxidized glutathione (GSSG) is subsequently enzymatically re· duced by glutathione reductase to regenerate GSH. Superoxide anions (O2¯), formed when molecular oxygen (O2) acquires an additional electron, are continually generated by mitochondria. Both the Fenton and the HaberWeiss reactions use the cuprous form of copper as a catalyst to convert the superoxide radical into the more biologically consequential hydroxyl radical (OH•).14,73

used as a chelator, worsens copper-induced hemolysis. This paradoxical effect is variably ascribed to concomitant inhibition of superoxide dismutase, an important antioxidant enzyme, or to its ability to efficiently reduce either membrane dithiols to thiols or cupric to cuprous ion, in either case increasing the generation of superoxide.2 Hemolysis frequently occurs within the first 24 hours in patients with acute copper poisoning.68 This time of onset differs markedly from hemolysis that follows most other oxidant stressors and is likely a consequence of the differing nature of the erythrocyte insult. That is, the hemolysis following most oxidant exposures is caused by precipitation of hemoglobin as Heinz bodies and subsequent erythrocyte destruction by the reticuloendothelial system. This may occur in the setting of acute copper poisoning, particularly following less substantial exposure. More consequently, and accounting for the early hemolysis, copper also directly oxidizes the erythrocyte membrane, thereby initiating red cell lysis independently of the reticuloendothelial system. Oxidant-induced disulfide cross-links in the erythrocyte membrane reduce its stability and flexibility, thereby predisposing to early cell rupture.4,62

Liver Although most of the accumulated copper in hepatocytes is rapidly complexed with metallothionein or otherwise used, failure to completely sequester copper ions allows their participation in redox reactions. Hepatic cells are protected from copper toxicity in vitro by prior induction of metallothionein with zinc or cadmium or by the infusion of metallothionein. These hepatic protective effects support the toxicologic significance of free intracellular copper ions. These findings also explain the therapeutic use of zinc acetate in patients suffering from Wilson disease,16 because copper itself is not a good inducer of metallothionein in humans. Copper ions also generate hydroxyl radicals, which are potent inducers of lipid peroxidation, as well as other reactive oxygen

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species. Lipid peroxidation is confirmed in hepatocytes by the measurement of increased production of lipid-conjugated dienes and other products.69 The peroxidative effects on biologic membranes are worse in animals deficient in vitamin E and are prevented by vitamin E replacement, presumably because of its role as a membrane-localized free radical scavenger.39,69 These effects are most pronounced in mitochondria, perhaps because of the reduction of cupric to cuprous ion in these organelles.29,70 Copper ions also accumulate in the cellular nuclei, where localized production of hydroxyl radicals may form DNA adducts and cause apoptosis.61 Histologically, liver damage follows a centrilobular pattern of necrosis. The sequelae of copper’s potent hepatotoxic effects are not isolated to the liver. After liver necrosis occurs, typically at liver concentrations greater than 50 mg/g dry weight, massive release of copper into the blood occurs, which may be of sufficient magnitude to cause hemolysis. This sequence of events is common during the crises of Wilson disease, and may allow for an understanding of a delayed secondary episode of hemolysis that occurs in some copper-poisoned patients.

Kidney The kidneys bioaccumulate copper. Although primarily bound to metallothionein, when available, copper is otherwise free to participate in oxidant-generating reactions in a manner analogous to iron. Thus, reactive oxygen species are probably responsible for the nephrotoxic effects of copper. Pathologic analysis of the kidneys of oliguric or anuric patients typically reveals tubular necrosis, and some demonstrate hemoglobin casts. These findings suggest that renal failure may result indirectly from the hemoglobinuria induced by the massive release of free extracellular hemoglobin. The urinary hemoglobin, like myoglobin, may undergo conversion to ferriheme or its release of iron, either of which results in oxidative stress on the renal tubular epithelial cell.87 Additionally, free intravascular hemoglobin, through the local scavenging of nitric oxide within the renal arterioles, may cause renal vasoconstriction.79

Central Nervous System Although charged entities such as copper ions do not readily cross the blood-brain barrier, elevated cerebrospinal fluid copper concentrations are characteristic of chronic copper overload conditions such as Wilson disease.74 This accumulation is accomplished through carrier-mediated transport of albumin-bound, not ceruloplasmin-bound, copper into the central nervous system.

CLINICAL MANIFESTATIONS Acute Copper Salt Poisoning Gastrointestinal irritation is the most common initial manifestation of copper salt poisoning. This syndrome includes the rapid onset of emesis and abdominal pain, possibly followed by gastroduodenal ulceration, hemorrhage, or perforation.23,46 Blue coloration of the vomitus may occur following the ingestion of certain copper salts, particularly copper sulfate.30,65,81 Blue vomitus is not, however, pathognomonic for copper poisoning, and also occurs in patients who ingest boric acid, methylene blue, or food dyes. Other common symptoms include retrosternal chest pain and a metallic

taste. The lethal dose of copper sulfate is suggested to be 0.15–0.3 g/kg, but this is unverified. Intravenous injection of copper sulfate reportedly produces a clinical syndrome identical to that following ingestion.58 Given its location and function within the gastrointestinal tract, the liver receives the initial and most substantial exposure to any ingested copper product. Hepatotoxicity is therefore a frequent, although rarely an isolated,37 manifestation of acute copper sulfate poisoning, typically occurring in the patients with more severe poisoning. Jaundice, while among the common clinical and biochemical findings following overdose, may be hepatocellular or hemolytic.9 Hemolysis is more common than hepatotoxicity, and is present in most patients with liver damage.51,68 As noted, copper-induced hemolysis occurs earlier and may be more severe than hemolysis induced by conventional toxins (see “Pathophysiology” earlier in this chapter). Additionally, copper-induced oxidation of the heme iron within the erythrocyte produces methemoglobinemia.54 In most reported cases, the discovery of significant methemoglobinemia occurs early in the patient’s clinical course and is rapidly followed by hemolysis.20 Because the methemoglobin is released within the plasma, methylene blue should not be expected to reduce the ferric iron because this reaction requires an intact erythrocyte. Because free methemoglobin is filterable, methemoglobinuria may occur, although it cannot be differentiated from other heme forms in the urine without specialized testing. In addition, many reports document an abnormal glucose-6-phosphate dehydrogenase (G-6-PD) activity, suggesting causation for methemoglobinemia or hemolysis. However, interpretation of this test result is difficult because high levels of copper interfere with the measurement of G-6-PD. Renal and pulmonary toxicity occur occasionally and represent extraerythrocytic manifestations of the oxidative effects of the copper ions. In spite of massive intravascular hemolysis,22 hemoglobinuric renal failure is uncommon in patients who receive adequate volume replacement therapy. Hypotension and cardiovascular collapse occur in patients with the most severe poisoning and are likely multifactorial in origin. Undoubtedly, intravascular volume depletion from vomiting and diarrhea is involved. However, the poor patient outcome despite appropriate volume loading suggests that direct effects of copper on vascular and cardiac cells are present. Sepsis due to transmucosal invasion may also be partially responsible.24 Depressed mental status, ranging from lethargy to coma, or seizures following acute poisoning are likely epiphenomena related to damage to other organ systems. These findings are particularly common in patients with hepatic failure, and are comparable to those of hepatic encephalopathy from other causes. In patients with chronic poisoning, such as Wilson disease, neurologic manifestations are prominent (see below) and typically involve movement disorders. Although not strictly a form of copper poisoning, inhalation of copper oxide fumes, generated during welding or other industrial processes, may produce metal fume fever, a syndrome historically called “brass chills” or “foundry workers’ ague.” Patients with this syndrome present with cough, chills, chest pain, or fever that are most likely immunologic and not toxicologic in origin (Chap. 95). However, copper oxide formation, unlike zinc oxide, only occurs at extremely high temperatures, accounting for the relative infrequency of the copper-induced metal fume fever.

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Chronic Copper Poisoning Although hepatolenticular degeneration, known as Wilson disease, is a condition of chronic copper overload, there are qualitative similarities to acute copper poisoning. Wilson disease is an inherited, autosomal-recessive disorder of copper metabolism affecting approximately 1/40,000 persons. The gene implicated in this disease (ATP7B) codes for a hepatocyte membrane-bound copperbinding protein that is required for the maturation of ceruloplasmin and the biliary excretion of copper. The resultant increase in hepatic copper concentrations produces continuing oxidative stress on the hepatocyte and cellular necrosis with the inevitable development of cirrhosis. Patients undergo periodic fluctuations in the extent of their copper-induced hepatitis, and episodes of severe hepatitis are frequently associated with hemolysis as stored copper is released from dying hepatocytes. The adverse effects of copper on the lenticular nucleus in the basal ganglia causes movement disorders such as ataxia, tremor, parkinsonism, dysphagia, and dystonia.56 None of the other forms of copper poisoning are associated with substantial or direct neurotoxicity. Psychiatric manifestations, such as behavioral changes or mood disorders, may also occur.16 Accumulation of copper within the cornea accounts for the characteristic green-brown KayserFleischer rings. Although patients’ serum copper levels are decreased, they typically have a reduced ceruloplasmin concentration caused by the failure of copper incorporation into ceruloplasmin and release from the liver and an elevated urinary copper concentration.16 Treatment involves lifelong therapy with D-penicillamine, trientine (triethylene tetramine), or molybdenum salts; if patients are D-penicillamine sensitive they can receive either trientine or molybdenum salts. Zinc acetate, FDA approved as a maintenance therapy, induces the formation of intestinal metallothionein and thereby blocks copper absorption by effecting intestinal mucosal cell sequestration. Chronic exogenous copper poisoning is uncommon in adults, but is reported following the use of copper-containing dietary supplements.57 However, chronic exposure is common in children in some parts of the world. This condition, commonly called childhood cirrhosis in India or idiopathic copper toxicosis elsewhere, generally occurs in the setting of excessive dietary intake of copper because of copper-contaminated water or from brass vessels used to store milk. In these children, there may be a genetic predisposition to copper accumulation as signs of chronic liver disease develop by several months of age and progress rapidly.64,66 Both serum copper and ceruloplasmin levels are markedly elevated, which differentiates this disease from Wilson disease. The incidence of the disease has fallen dramatically, probably as a consequence of improved nutrition and replacement of copper utensils and storage containers with those made of steel. “Vineyard sprayers lung,” first described in 1969, refers to the occupational pulmonary disease that occurred among Portuguese vineyard workers applying Bordeaux solution, a 1–2% copper sulfate solution neutralized with hydrated lime (Ca(OH)2).59 The patients developed interstitial pulmonary fibrosis, which included histiocytic granulomas containing copper. Many of these workers also developed lung adenocarcinoma, hepatic angiosarcoma, and micronodular cirrhosis, raising the possibility of a carcinogenic effect of chronic copper exposure. There is also a suggestion of an increased incidence of pulmonary adenocarcinoma among smelters, who are, however, exposed to many other toxins, includ-

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ing arsenic, a known carcinogen.47 Copper is not on the list of suspected carcinogens compiled by the International Agency of Research on Cancer (IARC). Ocular effects of copper salts, primarily following occupational exposure, include irritation of the corneal, conjunctival, or adnexal structures. Chronic ocular exposure to particulate elemental copper or one of its alloys may result in chalcosis lentis, from the Greek word chalkos, or copper. This chronic exposure manifests as a green-brown discoloration of the lens or cornea similar to Kayser-Fleischer rings.

DIAGNOSTIC TESTING Real-time testing for copper is impractical and almost all management decisions must be based on clinical criteria. Copper levels are often obtained for confirmatory or investigative purposes. Although never adequately studied, whole-blood copper levels may better correlate with clinical findings than serum copper concentrations.23 The rapid movement of copper from serum into the erythrocyte presumably explains this finding. However, while there is a statistical relationship between the whole-blood copper levels and the severity of poisoning, there is little correlation between clinical findings at any given copper concentration regardless of what biologic tissue is measured.23,77 Similarly, other than at extremely high or low values, there is no defined value at which the prognosis may be established with certainty. Reported serum copper concentrations in patients with hemolysis range from 96 to 747 µg/dL, and those following severe poisoning include values of 6600 µg/dL30 and 8267 µg/dL.20 Serum copper levels in 11 patients with copper-induced acute renal failure ranged from 115 to 390 µg/dL.21 The normal urinary copper value is approximately 25 µg/24h, and is reportedly as high as 628 µg/24h in patients with copper poisoning.28 Occasionally, serum copper levels reveal a secondary rise, likely because of release during hepatocellular necrosis. This secondary rise typically occurs only in patients with life-threatening poisoning, and clinical evaluation is far more practical than serial copper levels.68 Elevated copper levels are also noted in patients with inflammatory conditions, biliary cirrhosis, and pregnancy. These conditions are associated with an elevated ceruloplasmin, and the fraction of bound copper in the serum remains normal. Although the hepatic copper content of patients with Wilson disease is elevated, their serum copper levels are generally below normal unless hepatic necrosis is occurring. Although serum ceruloplasmin levels rise in patients with acute copper poisoning,78 presumably reflecting increased hepatic synthesis, the ceruloplasmin cannot be used to define the patients’ prognosis. Metallothionein levels may also rise rapidly,46 but the implications of this finding are not defined. Routine laboratory testing following acute copper salt poisoning should include an assessment for both hemolysis and hepatotoxicity. Differentiation of these etiologies as a cause for jaundice is made by standard methodology, such as comparison of the bilirubin fractions. That is, indirect bilirubin is proportionally elevated in patients with hemolysis, whereas the direct fraction rises in patients with hepatocellular necrosis. An assessment of the patients’ electrolyte and hydration status is warranted. The international normalized ratio (INR) may be prolonged in the absence of

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liver injury or diffuse intravascular coagulation (DIC), and may be a result of a direct effect of free copper ions on the coagulation cascade.54 The utility of radiographs to identify copper solutions is unstudied. However, even though copper metal embedded in the skin is clearly visible, topically applied copper salts are not visualized.13 The diagnostic implications of these findings following copper salt ingestion are undefined. Thus, obtaining an abdominal radiograph, while probably of low clinical yield, may be justified if it occasionally alters management.

MANAGEMENT Optimal and aggressive supportive care is the cornerstone to the effective management of patients with acute copper poisoning. Attention to antiemetic therapy, fluid and electrolyte correction, and normalization of vital signs is the critical first step before consideration of chelation therapy. Gastrointestinal decontamination is of limited concern because the onset of emesis is generally within minutes of ingestion. A dose of oral activated charcoal, while of unproved benefit, is unlikely to be harmful and may have potential adsorptive capacity for copper. Advanced therapy for patients with renal failure may include hemodialysis, and liver transplantation may be needed for patients with life-threatening hepatic failure.

Chelation Therapy Chelation therapy should be initiated when hepatic or hematologic complications are present or the patient is severely poisoned. Studies on the efficacy of chelation therapy following acute copper salt poisoning are limited. Even when administered early and appropriately, organ damage and death still occur. Application of the data from the existing literature is complex because of the lack of controlled therapeutic studies of human copper poisoning. Although experimental animal models and uncontrolled human data exist, the results are frequently contradictory. Three agents are clinically available, and most dosing and efficacy data derive either from their use in the treatment of patients with Wilson disease or from their effects on copper elimination during chelation of other metals. Most patients with copper poisoning are initially treated with intramuscular BAL.75,81 Although BAL may be less effective than D-penicillamine its use is probably appropriate in patients in whom vomiting or gastrointestinal injury prevents oral D-penicillamine administration. Furthermore, because the BAL-copper complex primarily undergoes biliary elimination, it is useful in patients with renal failure. When tolerated, D-penicillamine therapy should be started simultaneously or shortly after the initiation of therapy with BAL. Calcium disodium ethylenediamine tetraacetate (CaNa2EDTA) reduces the oxidative damage induced by copper ions in experimental models.85 However, when used for the chelation of other metals, it does not greatly enhance the elimination of copper.76 In addition, even with short-term use CaNa2-EDTA inactivates dopamine -hydroxylase in humans, presumably by chelating its copper moiety.25 However, because the in vivo activity of this enzyme is restored upon the addition of exogenous copper, the detrimental effect on the formation of neuronal

norepinephrine during the treatment of acute poisoning is debatable. D-Penicillamine (D---dimethylcysteine, Cuprimine), a structurally distinct metabolite of penicillin, is an orally bioavailable monothiol chelating agent. It is used in the treatment of lead, mercury, and copper toxicity, as well as in the management of rheumatoid arthritis and scleroderma. D-Penicillamine is effective in preventing copper-induced hemolysis in patients with Wilson disease and in reducing hepatotoxicity in those with Indian childhood cirrhosis.11 Its protective mechanism is primarily mediated through chelation of unbound copper ions, rendering them unable to participate in redox reactions.42 The D-penicillamine-copper complex undergoes rapid renal clearance in patients with competent kidneys. The use of D-penicillamine is not formally studied in patients with acute copper salt poisoning, but case studies suggest that copper elimination is enhanced.35 The recommended dose is 1–2 g/d in adults and 20–30 mg/kg in children, in both cases given orally in four divided doses.11 Although D-penicillamine appears effective, it is associated with several significant complications. For example, D-penicillamine is associated with a worsening of neurologic findings in nearly 50% of patients treated for Wilson disease.15 Subacute toxicities of D-penicillamine include aplastic anemia, agranulocytosis, and renal and pulmonary disease. Long-term use of D-penicillamine is also associated with various cutaneous lesions and immune system dysfunction. However, in the brief treatment necessary for acutely poisoned patients, the major risk is the potential for hypersensitivity reactions that occur in 25% of patients who are penicillin allergic. This hypersensitivity reaction is likely related to contamination of the pharmaceutical preparation with penicillin rather than immunologic cross-reactivity. The use of Dpenicillamine during pregnancy is associated with congenital abnormalities, although all of the data are derived from women with Wilson disease who had long-term therapy. Succimer, or dimercaptosuccinic acid, is sometimes described as being an ineffective copper chelator, although it is able to triple the baseline copper elimination in a murine model.19 Given its ease of use, relative safety, and benefit in experimental models, succimer may be used in lieu of D-penicillamine in patients with mild or moderate poisoning. Under these circumstances, the use of standard lead poisoning dosing regimens is warranted. Dimercaptopropane sulfonate (DMPS), an experimental chelating agent that is gaining popularity for the treatment of lead poisoning, prevents acute tubular necrosis in copper-poisoned mice.52 DMPS proved to be the most effective of a panel of chelators in a murine model of copper sulfate poisoning.38 However, DMPS, unlike D-penicillamine, forms intramolecular disulfide bridges, each of which liberates an electron. This property, which accounts for its potency as a reducing agent, also probably explains its propensity to worsen copper-induced hemolysis in vitro.1,3 Because an adequate analysis of risk versus benefit is unavailable, DMPS should probably not be used to chelate copper-poisoned patients. Trientine, an orally bioavailable agent, is the second-line agent for patients with Wilson disease. As with zinc therapy, which is also of proven efficacy in Wilson disease, these agents have no known role in acute copper poisoning. Although unstudied in such patients, the need for several weeks of zinc therapy prior to realizing full efficacy makes its acute therapeutic use questionable. Although large oral doses of zinc salts may limit the absorption of

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copper ion, the concomitant gastrointestinal corrosive effects of zinc ion make this therapy impractical.32

Extracorporeal Elimination Limited data exist regarding the extent to which copper ion is eliminated by various extracorporeal means. Exchange transfusion, a conceptually beneficial method of copper removal from the body, is of undefined, but probably limited, benefit in acute copper sulfate poisoning.24 Hemodialysis membranes undoubtedly allow copper ion to cross based upon the recognized association of hemodialysis actually resulting in copper poisoning.26 Although copper should be similarly cleared by hemodialysis, its relatively large volume of distribution makes this unlikely. Furthermore, copper ions are highly protein bound, and the dialyzable concentration (ie, albumin bound) is less than 1 pmol/L, suggesting that hemodialysis would have little clinical utility. This fact is supported by case reports in which serum or dialysate concentrations of copper are assessed.58 Furthermore, given the propensity of hemodialysis to lyse erythrocytes, which may release stored copper and worsen toxicity, hemodialysis is not recommended.31 Peritoneal dialysis is not useful in patients with fulminant Wilson disease.45 Peritoneal dialysis removed less than 0.7 mg in a copper sulfate-poisoned child whose copper concentration was 207 µg/dL.31 However, in the same patient, the addition of albumin to the dwell removed 9 mg of copper at a time when the child’s serum copper concentration was lower.24 Recently, continuous hemofiltration (CVVH) using albumin dialysis or plasma exchange enhanced the elimination of copper in patients with fulminant Wilson disease.41,43 Copper removal averaged 17 mg and 7 mg per treatment, respectively, but it is unclear whether this removal would be beneficial following an ingestion of a substantial gram quantity of copper sulfate. Management of the hepatic toxicity requires little more than standard supportive care. The potential benefit of N-acetylcysteine is unstudied, although it is used in many forms of fulminant hepatic failure. Liver transplantation should be considered, but specific criteria for transfer to a specialized liver unit or for transplant, other than those that are applicable for Wilson disease60 or other more common, noncopper etiologies, are undefined. There are no controlled data on the treatment of acute copper poisoning in pregnancy. The available data on pregnant women with Wilson disease document that D-penicillamine is teratogenic and that zinc may be the preferred agent.17

SUMMARY Acute copper poisoning is rare in the United States, but it is associated with dramatic toxicologic effects, primarily hemolysis and hepatitis. Copper’s toxicologic effects are primarily mediated by oxidative stress on the erythrocyte and hepatocyte, and this similarity to iron salt poisoning adds a framework for the conceptual understanding of the disease. The infrequency of acute copper poisoning severely limits our ability to perform controlled studies on its management. Fortunately, exhaustive research into diseases of copper metabolism, particularly Wilson disease, which has periodic exacerbations similar to acute copper poisoning, provides insight into managing patients with acute copper salt poisoning.

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REFERENCES 1. Aaseth J, Skaug V, Alexander J: Haemolytic activity of copper as influenced by chelating agents, albumine and chromium. Acta Pharmacol Toxicol 1984;54:304–310. 2. Aaseth J, Ribarov S, Bochev P: The interaction of copper (Cu2+) with the erythrocyte membrane and 2,3-dimercaptopropanesulphonate in vitro: A source of activated oxygen species. Pharmacol Toxicol 1987; 61:250–253. 3. Aaseth J, Benov L, Ribarov S: Mercaptodextran—A new copper chelator and scavenger of oxygen radicals. Acta Pharmacol Sinica 1990;11:363–367. 4. Adams KF, Johnson G, Hornowski E, et al: The effect of copper on erythrocyte deformability. A possible mechanism of hemolysis in acute copper intoxication. Biochem Biophys Acta 1979;550:279–287. 5. Adelstein SJ, Vallee BL: Copper metabolism in man. N Engl J Med 1961;265:892–897. 6. Agarwal SK, Tiwari SC, Dash SC: Spectrum of poisoning requiring haemodialysis in a tertiary care hospital in India. Int J Artif Organs 1993;16:20–22. 7. Akintonwa A, Mabadeje AFB, Odutola TA: Fatal poisoning by copper sulfate ingested from “Spiritual Water.” Vet Hum Toxicol 1989; 31:453–454. 8. Arens P: Factors to be considered concerning the corrosion of copper tubes. Eur J Med Res 1999;28:243–245. 9. Ashraf I: Hepatic derangements (biochemical) in acute copper sulphate poisoning. J Indian Med Assoc 1970;55:341–342. 10. Barnes G, Frieden E: Oxygen requirement for cupric ion-induced hemolysis. Biochem Biophys Res Commun 1983;115:680–684. 11. Bavdekar AR, Bhave SA, Pradhan AM, et al: Long-term survival in Indian childhood cirrhosis treated with D-penicillamine. Arch Dis Child 1996;74:32–35. 12. Beltran-Garcia MJ, Espinosa A, Herrera N, et al: Formation of copper oxychloride and reactive oxygen species as causes of uterine injury during copper oxidation of Cu-IUD. Contraception 2000;61:99–103. 13. Bentur Y, Koren G, McGuigan M, Speilberg SP: An unusual exposure to copper: Clinical and pharmacokinetic evaluation. J Toxicol Clin Toxicol 1988;26:371–380. 14. Bergendi L, Benes L, Durackova Z, et al: Chemistry, physiology and pathology of free radicals. Life Sci 1999;65:1865–1874. 15. Brewer GJ, Terry CA, Aisen AM, Hill GM: Worsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy. Arch Neurol 1987;44:490–493. 16. Brewer GJ: Recognition, diagnosis and management of Wilson’s disease. Proc Soc Exp Biol Med 2000;223:39–46. 17. Brewer GJ, Johnson VD, Dick RD, et al: Treatment of Wilson’s disease with zinc. XVII: Treatment during pregnancy. Hepatology 2000; 31:364–370. 18. Camakaris J, Voskoboinik I, Mercer JF: Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun 1999;261: 225–232. 19. Cantilena LR, Klaassen CD: The effect of chelating agents on the excretion of endogenous metals. Toxicol Appl Pharmacol 1982;63: 344–350. 20. Chugh KS, Singhal PC, Sharma BK: Methemoglobinemia in acute copper sulfate poisoning. Ann Intern Med 1975;82:226–227. 21. Chugh KS, Sharma BK, Singhal PC, et al: Acute renal failure following copper sulphate intoxication. Postgrad Med J 1977;53:18–23. 22. Chugh KS, Singhal PC, Sharma BK, et al: Acute renal failure due to intravascular hemolysis in the North Indian patients. Am J Med Sci 1977;274:139–146. 23. Chuttani HK, Gupta PS, Gulati S, et al: Acute copper sulfate poisoning. Am J Med 1965;39:849–854. 24. Cole DEC, Lirenman DS: Role of albumin-enriched peritoneal dialysate in acute copper poisoning. J Pediatr 1978;92:955–957.

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25. De Paris P, Caroldi S: In vivo inhibition of serum dopamine-betahydroxylase by CaNa2 EDTA injection. Hum Exp Toxicol 1994;13: 253–256. 26. Eastwood JB, Phillips ME, Minty P, et al: Heparin inactivation, acidosis and copper poisoning due to presumed acid contamination of water in a hemodialysis unit. Clin Nephrol 1983;20:197–201. 27. Eife R, Weiss M, Muller-Hocker M, et al: Chronic poisoning by copper in tap water: II. Copper intoxications with predominantly systemic symptoms. Eur J Med Res 1999;28:224–228. 28. Fairbanks VF: Copper sulfate-induced hemolytic anemia. Arch Intern Med 1967;120:428–432. 29. Gu M, Cooper JM, Butler P, et al: Oxidative-phosphorylation defects in liver of patients with Wilson’s disease. Lancet 2000;356:469–474. 30. Gulliver JM: A fatal copper sulfate poisoning. J Anal Toxicol 1991; 15:341–342. 31. Hamlyn AN, Gollan JL, Douglas AP, et al: Fulminant Wilson’s disease with haemolysis and renal failure: Copper studies and assessment of dialysis regimens. Br Med J 1977;2:660–663. 32. Hantson P, Lievens M, Mahieu P: Accidental ingestion of a zinc and copper sulfate preparation. J Toxicol Clin Toxicol 1996;34:725–730. 33. Harris GBC, Haggarty RJ: Toxic hazards: Bronze-powder inhalation. N Engl J Med 1957;256:40–41. 34. Hay E, Derazon H, Eisenberg Y, et al: Suicide by ingestion of a CCA wood preservative. J Emerg Med 2000;19:159–163. 35. Holtzman NA, Elliot DA, Heller RH: Copper intoxication: Report of a case with observations on ceruloplasmin. N Engl J Med 1966;275: 347–352. 36. Holtzman NA, Haslam RHA: Elevation of serum copper following copper sulfate as an emetic. Pediatrics 1968;42:189–193. 37. Jantsch W, Kulig K, Rumack BH: Massive copper sulfate ingestion resulting in hepatotoxicity. J Toxicol Clin Toxicol 1984;85: 585–588. 38. Jones MM, Basinger MA, Tarka MP: The relative effectiveness of some chelating agents in acute copper intoxication in the mouse. Res Commun Chem Pathol Pharmacol 1980;27:571–577. 39. Kadiiska MB, Hanna PM, Jordan SJ, Mason RP: Electron spin resonance evidence for free radical generation in copper treated vitamin E and selenium-deficient rats: In vivo spin-trapping investigation. Mol Pharmacol 1993;44:222–227. 40. Karlsson B, Noren L: Ipecacuanha and copper sulphate as emetics in intoxications in children. Acta Paediatrica Scand 1965;54:331–335. 41. Kiss JE, Berman D, Van Thiel D: Effective removal of copper by plasma exchange in fulminant Wilson’s disease. Transfusion 1998;38: 327–331. 42. Klein D, Lichtmannegger J, Heinzmann U, et al: Dissolution of copper-rich granules in hepatic lysosomes by D-penicillamine prevents the development of fulminant hepatitis in Long-Evans cinnamon rats. J Hepatol 2000;32:193–201. 43. Kreymann B, Seige M, Schweigart U: Albumin dialysis: Effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation. J Hepatol 1999;31: 1080–1085. 44. Kumar SK, Rowse C, Hochstein P: Copper-induced generation of superoxide in human red cell membrane. Biochem Biophys Res Commun 1978;83:587–592. 45. Kuno T, Hitomi T, Zaitu M, et al: Severely decompensated abdominal Wilson disease treated with peritoneal dialysis: A case report. Acta Paediatr Jpn 1998;40:85–87. 46. Kurisaki E, Kuroda Y, Sato M: Copper-binding protein in acute copper poisoning. Forensic Sci Int 1988;38:3–11. 47. Lubin JH, Pottern LM, Stone BJ, et al: Respiratory cancer in a cohort of copper smelter workers: Results from more than 50 years of follow-up. Am J Epidemiol 2000;151:554–565. 48. Manzler AD, Schreiner AW: Copper-induced acute hemolytic anemia. A new complication of hemodialysis. Ann Intern Med 1970;73: 409–412. 49. Metz EN, Sagone AL: The effect of copper on the erythrocyte hexose monophosphate shunt pathway. J Lab Clin Med 1972;80:405–413.

50. Milne L, Nicotera P, Orrenius S, et al: Effects of glutathione and chelating agents on copper-mediated DNA oxidation: Pro-oxidant and antioxidant properties of glutathione. Arch Biochem Biophys 1993; 304:102–109. 51. Mital VP, Wahal PK, Bansal OP: Study of erythrocytic glutathione in acute copper sulphate poisoning. Indian J Pathol Bacteriol 1966;9: 155–162. 52. Mitchell WM, Basinger MA, Jones MM: Antagonism of acute copper (II)-induced renal lesions by sodium 2,3-dimercaptopropanesulfonate. Johns Hopkins Med J 1982;151:283–285. 53. Mucklow ES: Chemistry set poisoning. Int J Clin Pract 1997;51: 321–323. 54. Nagaraj MV, Rao PV, Susarala S: Copper sulphate poisoning, hemolysis and methemoglobinemia. J Assoc Physcians India 1985;33: 308–309. 55. Nakatani T, Spolter L, Kobayashi K: Redox state in liver mitochondria in acute copper sulfate poisoning. Life Sci 1994;54:967–974. 56. Oder W, Prayer L, Grimm G, et al: Wilson’s disease: Evidence of subgroups derived from clinical findings and brain lesions. Neurology 1993;43:120–124. 57. O’Donohue J, Reid M, Varghese A, et al: A case of adult chronic copper self-intoxication resulting in cirrhosis. Eur J Med Res 1999;28: 252. 58. Oldenquist G, Salem M: Parenteral copper sulfate poisoning causing acute renal failure. Nephrol Dial Transplant 1999;14:441–443. 59. Pimentel JC, Marques F: “Vineyard sprayer’s lung”: A new occupational disease. Thorax 1969;24:678–688. 60. Robles R, Parrilla P, Sicilia J, et al: Indications and results of liver transplants in Wilson’s disease. Transplant Proc 1999;31:2453–2454. 61. Sagripanti JL, Goering PL, Lamanna A: Interaction of copper with DNA and antagonism by other metals. Toxicol Appl Pharmacol 1991; 110:477–485. 62. Salhany JM, Swanson JC, Cordes KA, et al: Evidence suggesting direct oxidation of human erythrocyte membrane sulfhydryls by copper. Biochem Biophys Res Commun 1978;82:1294–1298. 63. Salmon MA, Wright T: Chronic copper poisoning presenting as pink disease. Arch Dis Child 1971;46:108–110. 64. Scheinberg IH, Sternlieb I: Is non-Indian childhood cirrhosis caused by excess dietary copper? Lancet 1994;344:1002–1004. 65. Schwartz E, Schmidt E: Refractory shock secondary to copper sulfate ingestion. Ann Emerg Med 1986;15:952–954. 66. Sethi S, Grover S, Khodaskar MB: Role of copper in Indian childhood cirrhosis. Ann Trop Paediatr 1993;13:3–5. 67. Singh S, Sharma BK, Wahi PL, et al: Spectrum of acute poisoning in adults (10-year experience). J Assoc Physicians India 1984;32: 561–563. 68. Singh MM, Singh G: Biochemical changes in blood in cases of acute copper sulphate poisoning. J Indian Med Assoc 1968;50:549–555. 69. Sokol RJ, Devereaux M, Mierau GW, et al: Oxidant injury to hepatic mitochondrial lipids in rats with dietary copper overload. Gastroenterology 1990;90:1061–1071. 70. Sokol RJ, Devereaux M, O’Brien K, et al: Abnormal hepatic mitochondrial respiration and cytochrome c oxidase activity in rats with long-term copper overload. Gastroenterology 1993;105:178–187. 71. Sontz E, Schwieger J: The “Green Water” syndrome: Copper-induced hemolysis and subsequent acute renal failure as a consequence of a religious ritual. Am J Med 1995;98:311–315. 72. Stein RS, Jenkins D, Korns ME: Death after use of cupric sulfate as emetic. JAMA 1976;235:801. 73. Stohs SJ, Bagchi D: Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 1995;18:321–336. 74. Stuerenburg HJ: CSF copper concentrations, blood-brain barrier function, and coeruloplasmin synthesis during the treatment of Wilson’s disease. J Neural Transm 2000;107:321–329. 75. Takeda T, Yukioka T, Shimazaki S: Cupric sulfate intoxication with rhabdomyolysis, treated with chelating agents and blood purification. Intern Med 2000;39:253–255.

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76. Thomas DJ, Chisolm J: Lead, zinc and copper decorporation during calcium disodium ethylenediamine tetraacetate treatment of lead-poisoned children. J Pharmacol Exp Ther 1986;239:829–835. 77. Wahal PK, Mehrotra MP, Patney NL, et al: A study of haemolytic jaundice in acute copper sulphate poisoning. J Assoc Physicians India 1976;24:103–108. 78. Wahal PK, Mehrotra MP, Kishore B, et al: A study of serum ceruloplasmin levels in acute copper sulphate poisoning. J Assoc Physicians India 1978;26:983–987. 79. Wakabayashi Y, Kikawada R: Effect of L-arginine on myoglobininduced acute renal failure in the rabbit. Am J Physiol 1996;270: F784–F789. 80. Walker WR, Keats DM: An investigation of the therapeutic value of the “copper bracelet”—Dermal assimilation of copper in arthritic/ rheumatoid conditions. Agents Actions 1976;6:454–459. 81. Walsh FM, Crosson FJ, Bayley M, et al: Acute copper intoxication: Pathophysiology and therapy with a case report. Am J Dis Child 1977;131:149–151.

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82. Walshe JM: Penicillamine: A new oral therapy for Wilson’s disease. Am J Med 1956;21:487–495. 83. Witherell LE: Outbreak of acute copper poisoning due to soft drink dispenser [letter]. Am J Public Health 1980;70:1115. 84. Wyllie J: Copper poisoning at a cocktail party. Am J Public Health 1957;47:617. 85. Yamamoto H, Hirose K, Hayasaki Y, et al: Mechanism of enhanced lipid peroxidation in the liver of Long-Evans cinnamon (LEC) rats. Arch Toxicol 1999;73:457–464. 86. Yelin G, Taff ML, Sadowski GE: Copper toxicity following massive ingestion of coins. Am J Forensic Med Pathol 1987;8:78–85. 87. Zager RA, Burkhart KM, Conrad DS, et al: Iron, heme oxygenase, and glutathione: Effects on myohemoglobinuric proximal tubular injury. Kidney Int 1995;48:1624–1634.

CHAPTER

83

THALLIUM Maria Mercurio / Robert S. Hoffman

Thallium MW Normal Levels Blood Urine

=

204.39 daltons

= =

0.980 µmol/L)

Values greater than or equal to the action level necessitate clinical intervention. Values below this level may necessitate intervention based on the clinical condition of the patient.

A 21-year-old female college student developed mild, but persistent abdominal pain with intermittent severe colicky pain. Three days after the initial painful episode, her hair began to fall out. She became constipated, and noted a delay in the onset of her menses. Within 5 days of her initial symptoms, she was completely bald. On day 18, she was hospitalized, where routine physical examination only revealed horizontal white (Mees) lines on her fingernails. Her routine blood chemistries and several special studies for autoimmune disease were all normal. Her overall condition responded to nutritional support, her symptoms gradually resolved, her hair regrew, and she was discharged almost 2 months after the onset of symptoms, but without a clear diagnosis. The patient returned to school. One month later, she felt pain in both her hands and feet, and developed difficulty speaking, dizziness, blurred vision, and vertigo. She was taken to the hospital once again. On admission, her blood pressure was 140/110 mm Hg; other vital signs were normal. Examination of her extremities showed good muscular strength in her legs but poor muscle coordination, and hyperesthesias in a stocking-and-glove distribution. Her deep-tendon reflexes were hypoactive in both legs, but normal in her upper extremities. Cranial nerve examination revealed horizontal and vertical nystagmus, and palsies of the abducens (VI) and facial (VII) cranial nerves. Routine chemistries and a lumbar puncture were normal. Four days later, still without a diagnosis, her symptoms of vertigo and tremulousness worsened. Her doctors noted that she was showing signs of oculogyric crisis, and her mental status deteriorated. Her alopecia returned. A magnetic resonance image (MRI) of her brain was interpreted as normal, and an electroencephalogram (EEG) was felt to be nondiagnostic. Her condition progressed very rapidly with the development of bulbar palsy, involuntary chewing movements of her mouth, and spastic clonus of both upper limbs. Her level of consciousness changed from mild agitation to lethargy. Tonic movements of both upper extremities and episodic oculogyric crisis were noted. Five days after her hospitalization, she became comatose. Investigative studies for arsenic, antinuclear antibody, antidoublestranded DNA antibody, rheumatoid factor, HIV, and Lyme disease

were negative. Routine urinalysis was normal. She was treated with several broad-spectrum antibiotics, antiviral agents, hormones, and intravenous injections of γ-globulin, none of which had any appreciable effect on her signs and symptoms. Because her spontaneous respiratory efforts became progressively weaker and irregular, a tracheostomy was performed and she was placed on a ventilator. At that point, the diagnosis of acute disseminated encephalomyelitis was considered. Plasmapheresis was initiated and seven exchanges, for a total of 10 L, were completed over the following 3 weeks. No change in her condition was noted. Ultimately, the diagnosis of thallium toxicity was considered. Blood, urine, and cerebrospinal fluid (CSF) thallium levels were reported as 275, 532, and 31 µg/L, respectively. Nail and hair levels were 22,824 and 532 µg/kg, respectively. The patient was started on a regimen of intravenous potassium (100 mEq/d), oral Prussian blue (250 mg/kg/d divided q4h in 50 mL of 15% mannitol), and daily hemodialysis. Her symptoms slowly improved. About 2 months after hospitalization she began to intermittently regain consciousness. One year after the initial event, her orientation and memory improved and her IQ was estimated at 128, with good mathematical and verbal abilities. The patient was able to sit in a wheelchair for a prolonged period of time and could move herself 20–30 meters. She still could not move her legs. Her vision remained poor, but periodically she was able to see clearly.

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1272

Thallium, a metal with atomic number 81, is located between mercury and lead on the periodic table. Thallium is a commonly found constituent of granite, shale, volcanic rock, and pyrites (which are used to make sulfuric acid), and is also recovered as flue dust from iron, lead, cadmium, and copper smelters. Thallium is a soft pliable metal-like lead that melts at 300°C (572°F), boils at 1482°C (2699.6°F), and is essentially nontoxic. However, thallium forms univalent thallous and trivalent thallic salts, which are highly toxic. It has been used in alloys as an anticorrosive, in optical

CHAPTER 83

lenses to increase the refractive index, in artists’ paints, in lamps to improve tungsten filaments, in imitation jewelry, as a catalyst, and in fireworks. In the early 1900s, thallium salts were used medicinally to treat syphilis, gonorrhea, tuberculosis, and ringworm of the scalp, and as a depilatory.4,56 Although the usual oral dose given for epilation in the treatment of ringworm of the scalp was 7–8 mg/kg, fatal doses ranged from 6 to 40 mg/kg.10,47 Many cases of severe thallium poisoning (thallotoxicosis) resulted from the treatment of ringworm, with one author summarizing nearly 700 cases and 46 deaths.58 Because thallium sulfate is odorless and tasteless, it was also successfully used as a rodenticide. Commercially available as Thalgrain, Echol’s Roach Powder, Mo-Go, Martin’s Rat Stop liquid, and Senco Corn Mix, thallium sulfate was very efficient at killing rats, prairie dogs, and other unwanted rodents. In response to numerous case reports of unintentional poisonings,59,68 its use as a household rodenticide was restricted in the United States in 1965. Ultimately, even the commercial use of thallium salts as a rodenticide was banned in the United States in 1975, because of continued reports of human toxicity. Unfortunately, life-threatening unintentional poisoning continues in other countries where thallium salts are still commonly used as rodenticides.66,85 Additional cases of thallium poisoning are reported in this and other countries as a result of its use as a homicidal agent,15,51,55,61 and through contamination of herbal products72 and illicit drugs such as heroin65 and cocaine.33 Although occupational exposures to consequential amounts of thallium salts are uncommon, toxicity is well described in this setting as well.28 Presently, trace amounts of thallium salts are used as a radioactive contrast agent to image tumors and to visualize cardiac function.56 The following discussion of thallium toxicity actuality refers to toxicity resulting from exposure to inorganic thallium salts, because this source represents virtually the entire literature on thallium poisoning.

TOXICOKINETICS Exposures usually occur via one of three routes: inhalation of dust, ingestion, and absorption through intact skin. Thallium is rapidly absorbed following all routes of exposure, distributed throughout most of the body following three-compartment toxicokinetics67 (Chap. 11), and eliminated slowly via the kidneys and gastrointestinal tract. The volume of distribution for thallium is very large, and is estimated to be about 3.6 L/kg.14 Although thallium is found in all organs, it is distributed unevenly, with higher concentrations found in the large and small intestine, liver, kidney, heart, brain, and muscles.4,43 The toxicokinetics of thallium can be described in the following three-phase model. In the first phase, which occurs rapidly in the 4 hours following exposure, thallium is distributed to a central compartment and to well-perfused peripheral organs such as the kidney, liver, and muscle. In the second phase, which can last between 4 and 48 hours, thallium is distributed into the central nervous system.67 Whereas traditional sources suggest that this distribution phase is generally completed within 24 hours of ingestion,67 a recent human case suggests slower distribution into the CNS as evidenced by increasing CSF levels days following exposure when blood levels were declining.75 The third, or elimination, phase starts about 24 hours after ingestion. The primary mecha-

THALLIUM

1273

nism of thallium elimination is secretion into the intestine, but enteral reabsorption of the thallium that was initially present in the bile subsequently reduces the fecal elimination.13,55 The duration of the elimination phase depends on the route of exposure, dose, and treatment. Unlike many other metals such as lead, thallium does not have a major anatomic reservoir. As such, reported elimination half-lives are as short as 1.7 days in humans with thallium poisoning.31 Thallium is excreted primarily via the feces (51.4%) and the urine (26.4%).46 It is glomerularly filtered, and approximately 50% is reabsorbed in the tubules. Furthermore, thallium is secreted into the tubular lumen in a manner similar to potassium.2

PATHOPHYSIOLOGY The mechanism of toxicity of thallium is not well established. In the body, thallium behaves biologically like potassium because of their similar ionic radii (0.147 nm for thallium and 0.133 nm for potassium). Because cell membranes cannot differentiate between thallium and potassium ions, thallous ions accumulate in areas with high potassium concentrations such as central and peripheral nervous, hepatic, and muscular tissues.53,85 This accumulation is the fundamental principle that governs the use of radioactive thallium in cardiac imaging studies. Thallium replaces potassium in the activation of potassium-dependent enzymes.53 In low concentrations, thallium stimulates these enzyme systems, but in high concentrations, it inhibits them.54 Thallium also inhibits several potassium-dependent systems. Pyruvate kinase, a magnesiumdependent glycolytic enzyme that requires potassium to achieve maximum activity, has 50 times greater affinity for thallous ions than potassium ions.38 Succinate dehydrogenase, an essential enzyme in the Krebs cycle, is inhibited by small doses of thallium in rats.26 Sodium-potassium ATPase, which is responsible for active transport of monovalent ions across cell membranes, can use thallous ions at extremely low concentrations because of an affinity that is 10-fold greater than that of potassium ions,6,21 but is inhibited by thallium at higher concentrations.34 Thallium also impairs depolarization of muscle fibers.56 Mitochondrial energy is decreased as a result of the inhibition of pyruvate kinase and succinate dehydrogenase, resulting in a decrease of adenosine triphosphate (ATP) generation via oxidative phosphorylation. Enzymatic destruction results in swelling and vacuolization of the mitochondria after exposure to thallium.76 At low levels, thallium can activate other potassium-dependent enzymes such as phosphatase, homoserine dehydrogenase, vitamin B12–dependent diol dehydrogenase, L-threonine dehydrogenase, and adenosine monophosphate (AMP) deaminase.56 Thallous ions have been used to isolate riboflavin from milk in the form of a reversible precipitate. Thallous ions may also form insoluble complexes and cause intracellular sequestration of riboflavin in vivo.8 Riboflavin is the vitamin precursor of the flavin coenzyme FAD (flavin adenine dinucleotide). Because of a decrease in riboflavin, metabolic reactions dependent upon flavoproteins will decrease, causing disruption of the electron transport chain and a subsequent further decrease or impairment in the generation of cellular energy.8 This decrease in cellular energy may lead to a decrease in mitotic activity and cessation of hair follicle formation resulting in the clinical sign of alopecia. Subsequent hair loss is the result of combined arrested formation and local destruction of hairshaft cells in the hair bulb.8,68 Unfortunately, ri-

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boflavin supplementation was ineffective in one animal model of thallium poisoning.3 Data also demonstrate that the dermatologic, neurologic, and cardiovascular effects of thallium toxicity mirror the side effects of thiamine deficiency (beri beri), highlighting the inhibitory effect of thallium on glycolytic enzymes.8,56 It is unclear whether thiamine administration has any beneficial effect in patients with thallium poisoning. Thallium, like many other metals, has a high affinity for sulfhydryl groups. Sulfhydryl groups, present in enzymes and other proteins, form complexes with thallium. Keratin, a structural protein, consists of many cysteine residues that cross-link and form disulfide bonds. These disulfide bonds add strength to keratin. Thallium interferes with the formation of disulfide bonds, which may lead to the development of alopecia and defects in nail growth resulting in Mees lines.23,56,61,71 Additionally, the complexation of sulfhydryl groups with thallium results in a decrease in glutathione production (secondarily to a decrease in cysteine). This results in the accumulation of lipid peroxides in the brain, specifically the cerebellum, which appear as dark, pigmented, lipofuscinlike areas.25 The complexity and presumable multifactorial nature of thallium poisoning are again highlighted by the inability of N-acetylcysteine–induced augmentation of glutathione stores to protect against toxicity in an animal model.3 Thallium also adversely affects protein synthesis in animals by damaging ribosomes, particularly the 60S subunit.32 Although ribosomes are primarily dependent on potassium and magnesium, thallium will be used if present. In an experimental model, low concentrations of thallium are protective against hypokalemiainduced ribosomal inactivation. As thallium concentrations increase, the protective effects diminish, resulting in progressive destabilization and destruction of the ribosomes. Ribosomal destruction can also be produced with exposure to potassium concentrations of 4.5–20 times higher than the thallium concentrations necessary to achieve the same effect.32 Pathologic studies of the central nervous system in patients with thallium poisoning reveal localized areas of edema found in the cerebral hemispheres and brainstem. Chromatolytic changes are prominent in neurons of the motor cortex, third-nerve nuclei, substantia nigra, and pyramidal cells of the globus pallidus. In chronic exposures, there are signs of edema of the pial and arachnoidal membranes, and changes in the ganglion cells of the ventral and dorsal horns of the spinal cord, consisting of chromatolysis, swelling, and fatty degeneration.4,68 The peripheral nervous system, which is usually clinically affected before the central nervous system, exhibits axonopathy in a classic dying back or wallerian degeneration pattern.4,17 Fragmentation and degeneration of associated myelin sheaths are accompanied by activation of Schwann cells.4,8,9 Because thallium affects the longer peripheral fibers—first sensory, then motor, and finally the shorter fibers—toxic effects occur initially in the lower extremities.

CLINICAL MANIFESTATIONS Many of the effects of thallium poisoning are somewhat nonspecific and occur over a variable time course.44 When combined, however, a clear toxidrome can be defined (Table 83–1). Alopecia and the painful ascending peripheral neuropathy are the most characteristic findings.19,55 Because of the delayed development of alopecia, the diagnosis of thallotoxicosis is often overlooked. In

fact, with acute exposures, a dose-dependent latent period of hours to days may precede initial symptoms.44,56 When death occurs, it is usually the result of coma, respiratory paralysis, and cardiac arrest. Unlike most other metal salt poisonings, in cases of thallium toxicity, gastrointestinal symptoms are usually modest or may even be absent.10 The most common symptom is abdominal pain, which is sometimes accompanied by vomiting and either diarrhea or constipation.15,44,41,54,71,86 Constipation may be a result of decreased intestinal motility and peristalsis caused by direct involvement of the vagus nerve.10,56 Rarely, severe symptoms, such as hematemesis, bloody diarrhea, or ulceration of the mucosal lining, can occur. Pleuritic chest pain was described in one small series of poisoned patients.51 Another patient was reported to have developed “chest tightness” shortly after drinking thallium-poisoned tea.55 No etiology for this finding has been proposed. Tachycardia and hypertension frequently occur in patients with thallotoxicosis and usually develop during the first or second week following an acute ingestion. A poor prognosis may be associated with a persistent and pronounced tachycardia. No exact mechanism has been determined for these cardiovascular effects of thallium toxicity. Some authors theorize that they result from autonomic neuropathic dysfunction directly related to vagus nerve involvement, but others have noted early electrocardiographic changes, such as T-wave flattening or inversion and nonspecific ST-segment abnormalities, which might suggest direct myocardial damage.5,9,54,56 Another theory suggests that a stimulating effect of thallium on ATPase in the chromaffin cells can lead to increased output of catecholamines, resulting in sinus tachycardia.2,55 Neurologic effects usually appear 2–5 days postexposure. Patients may present with severely painful, rapidly progressive ascending peripheral neuropathies.4,5,17,51 Pain and paresthesias are present in lower extremities (especially the soles of the feet), and although numbness is present in fingers and toes, there is also decreased sensation to pinprick, touch, temperature, vibration, and proprioception.5,72 The weight of the bedsheets on the lower extremities may be sufficient to cause excruciating pain.51 Motor weakness is always distal in distribution, with the lower limbs more affected than the upper limbs.9,56 Symptoms of confusion, delirium, psychosis, hallucinations, seizures, headache, insomnia, anxiety, tremor, ataxia, and choreoathetosis are common. Onset is variable, and most likely dependent on dose. Ataxia can develop within 48 hours after ingestion. Insomnia occurs in almost every patient and may progress to total reversal of sleep rhythm. Coma may occur, especially with larger exposures.9,44,56,71 All cranial nerves—with the possible exception of I, V, and VIII—can be affected by thallium. Third cranial nerve involvement, as evidenced by ptosis, is common, and may be present asymmetrically.9 Nystagmus, another common finding, demonstrates fourth and sixth cranial nerve involvement.9 Neuropsychologic findings may indicate focal injury, and have been reported to persist for months after exposure.49 Thallium is toxic to both the retinal fibers and the neural retina.73 In cases of a large single ingestion of thallium, approximately 25% of patients may develop severe lesions of the optic nerve.56,71 Optic neuropathies can lead to optic atrophy and a permanent decrease in visual acuity. In early stages, the optic disk shows signs of neuritis, which is red and poorly defined, and later develops pallor from resultant optic nerve atrophy. In patients exposed to multiple small doses, nearly 100% suffer optic injury.54 Visual complaints may be delayed in comparison to other neuro-

CHAPTER 83

TABLE 83–1.

THALLIUM

1275

Clinical Manifestations of Acute Thallium Poisoning

Organ System

Gastrointestinal Nausea Vomiting Diarrhea Constipation Cardiovascular Nonspecific ECG changes Hypertension Tachycardia Respiratory Pleuritic chest pain Respiratory depression Renal Albuminuria Renal insufficiency Dermatologic Dry skin Alopecia Mees lines Neurologic Painful ascending sensory neuropathy Motor neuropathy Cranial nerve abnormalities Altered mental status Seizures Optic neuritis Memory and cognitive deficits

Onset of Effects

Immediate (2 weeks)

†

† †

‡

† † †

‡ ‡

†

†

‡

† † † †

†

‡ ‡

† ‡ ‡

† = typical onset of symptoms. The time course outlined above may be accelerated with extremely large doses. When “†” appears in two adjacent columns, the time course is highly variable and may be dose-dependent. With small ingestions, many effects listed above may not be evident. ‡ = effects that may persist long after exposure, and possibly permanently.

logic findings,73 and can include decreased acuity and central scotomata. Other ophthalmic effects that have been described are noninflammatory keratitis, cataracts, and the color vision defect of tritanomaly (blue color defect).79,80 Renal function may remain normal in mild cases of thallium poisoning, even though the kidney bioaccumulates thallium more than any other organ. Changes in renal function in patients with severe thallotoxicosis include oliguria, diminished creatinine clearance, elevated blood urea nitrogen, and albuminuria.2,51,54,56 These findings correlate with morphologic studies in thalliumpoisoned rats, demonstrating abnormalities in the renal medulla, mainly in the thick ascending limb of the loop of Henle, that occur by the second day after exposure and resolve by the tenth day.2 Alopecia is the most common and classic manifestation of thallium toxicity.55,82 Typically occurring as the presenting symptom in patients with chronic exposures, following an acute exposure, epilation begins in approximately 10 days and total hair loss usually occurs within a month.19,55 Facial and axillary hair, especially the inner one-third of the eyebrows, may be spared, but in some cases, full beards, as well as all scalp hair, are lost.68 Microscopic studies show thallium deposition as dark brown or black pigmentation located in the roots of hair samples. These deposits can be

found within 3–5 days of initial exposure.7,54 In patients with chronic exposures, several bands may be noted on the hair shaft, demonstrating multiple exposures. Initial hair regrowth is very fine and unpigmented, but usually returns to normal following mild exposure.54 In patients with severe exposures, alopecia may be permanent. Dermatologic effects that have been observed include acne, palmar erythema, and dry scaly skin that results from damage to the sebaceous glands.82 Mees lines appear within 2–4 weeks after exposure.55,61,71 Other less common findings include hepatic injury33 and hypochloremic metabolic acidosis.71 Anemia and thrombocytopenia are occasionally reported.45,71

Special Concerns: Teratogenic Effects In animal models, thallium is teratogenic.22,24 One study evaluated 297 children born in an area in which thallium levels were higher than normal because of industrial contamination.16 Urine thallium levels in the exposed children were as high as 76.5 µg/L. Although these children had a slightly higher than expected incidence of congenital abnormalities, no causal relationship could be established with regard to thallium exposure.16

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There are few human reports of acute thallium poisoning during pregnancy. A comprehensive literature review demonstrated 25 cases, which included acute and chronic exposures that occurred during all trimesters.30 Thallium crosses the placenta, albeit slowly, and is able to cause characteristic fetal toxicity,18,60 which manifests initially as decreased fetal movement, possibly as a consequence of fetal paralysis. The classic adult signs and symptoms of thallium poisoning have been described in the neonate following delivery and the fetus following abortion.18,54,60,66 However, outcome of the pregnancy may be normal despite significant maternal toxicity.18,35 The only consistent finding is a trend toward prematurity and low birth weight, especially in those children exposed during the first trimester.30 At least one author recommends continuing the pregnancy as long as the mother is clinically improving.18 It is reasonable to conclude that a fetus exposed during organogenesis has the potential for permanent injury. Those exposed later in the pregnancy may recover without deficit if their exposures are limited and the mother recovers. If the exposure occurs closer to term, the child may be born with overt toxicity such as alopecia, dermatitis, nail growth disturbances, and permanent central nervous system lesions.54 Because thallium is eliminated in breast milk, nursing children have an additional risk of exposure.30 These few case reports and animal studies provide confusing and sometimes contradictory results. It seems that fetal outcome is determined both by the stage of pregnancy and the extent of maternal toxicity. However, because there are insufficient data to predict the outcome of pregnancy complicated by maternal thallium poisoning, all patients should receive individualized care.

Diagnostic Testing Radiographs of tampered food products51 and the abdomen23 can document the presence of a heavy metal such as thallium, which is radiopaque. Although abdominal radiography may be useful shortly after a suspected exposure, the sensitivity and specificity of this test is unknown. Similarly, the yield from other routine studies, such as the complete blood count, electrolytes, urine analysis, and ECG, is limited in that these other studies are often normal, or demonstrate nonspecific findings at best. Microscopic inspection of the hair reveals a diagnostic pattern of black pigmentation of the hair roots of the scalp in approximately of 95% of poisoned patients.7,55,71,82 However, to the untrained observer this test is likely to be inconclusive. The definitive clinical diagnosis of thallium poisoning can only be established by demonstrating elevated thallium levels. Thallium can be recovered in the hair, nails, feces, saliva, blood, and urine, and standard assays and normal values for most of these sources can be found.56 Urine spot tests notoriously give falsenegative results, require the use of dangerous materials that are not routinely available (20% nitric acid), and should therefore be avoided.71 The standard toxicologic method is to obtain a 24-hour urine sample for thallium to be assayed by atomic absorption spectroscopy.11,87 Normal urine values are below 5 µg/L. Some authors suggest a potassium mobilization test to enhance urinary elimination (similar to the ethylenediaminetetraacetic acid (EDTA) mobilization test) to assist in the diagnosis of thallium exposure.7,33,71 We advise against this practice because of its lack of proven utility and its potential to exacerbate neurologic toxicity (see the discussion of potassium in the next section of this chapter).

ASSESSMENT Most patients with acute and consequential thallium toxicity present to the Emergency Department soon after exposure with the alterations in gastrointestinal, cardiovascular, and neurologic function described previously. Establishing the correct diagnosis at this early stage is essential to assure a satisfactory outcome. Unfortunately, many patients with either smaller acute exposures or chronic thallium poisoning first present for healthcare days to weeks after their initial exposure, and diagnosis is often delayed. In these instances, obtaining valuable aspects of the exposure history may be difficult. Gastrointestinal symptoms may not have occurred, or may have been dismissed because of their mild and transient nature. Those patients with small acute or chronic exposures usually present for healthcare because of alopecia or the acute onset of neuropathy. The differential diagnosis of the neuropathy includes disorders such as poisoning by arsenic, colchicine, and vinca alkaloids; botulism; thiamine deficiency; and Guillain-Barré syndrome. Both the sensory neuropathy and the preservation of reflexes help differentiate thallium-induced neuropathy from Guillain-Barré syndrome and most other causes of acute neuropathy.9 When gastrointestinal symptoms are present along with neuropathy and other end-organ effects, poisoning with metal salts such as arsenic and mercury should be considered (Chaps. 79 and 81). The differential diagnosis of abrupt and complete alopecia is more restricted and includes arsenic, selenium, colchicine, and vinca alkaloid poisoning (Chap. 29). When Mees lines are present, they indicate past exposure to metals, mitotic inhibitors, or antimetabolites, and as such are nonspecific for thallium (Chaps. 29, 79, and 81).

MANAGEMENT The treatment goals for a patient with thallium poisoning are identical to those of all poisoned patients: initial stabilization, prevention of absorption, and enhanced elimination. Following the initial assessment and stabilization of the patient’s airway, breathing, and circulatory status, gastrointestinal decontamination should be instituted in patients with known thallium ingestions because of the significant morbidity and mortality associated with a significant exposure.

Decontamination Patients who present for healthcare shortly after ingestion should be considered candidates for ipecac-induced emesis or for orogastric lavage (Chap. 5). If the patient presents more than a few hours after ingestion, or has had considerable spontaneous emesis, these techniques should be avoided. Thallium salts are substantially adsorbed to activated charcoal in vitro.41,29 Additionally, because thallium undergoes enterohepatic recirculation, activated charcoal may be useful both to prevent absorption following a recent ingestion and to enhance elimination of thallium in patients who present in the postabsorptive phase.81 In fact, a rat model of thallium poisoning demonstrated that multiple-dose activated charcoal (given as 0.5 g/kg twice daily for 5 days) increased the fecal elimination of thallium by 82% and produced a substantial improvement in survival.46 Other data demonstrate that activated charcoal alone is superior to either forced diuresis or potassium chloride therapy.42 In patients with severe thallium toxicity constipation is common,

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such that the addition of mannitol48 or another cathartic to the first dose of activated charcoal seems logical. While no studies address the utility of whole-bowel irrigation with polyethylene glycol electrolyte lavage solution, this technique may prove useful, especially when radiopaque material is demonstrated in the gastrointestinal tract by an abdominal radiograph.

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in the central nervous system, potentially exacerbating neurologic symptoms.36,78 Because of the significant adverse effects of dithizone and the redistribution of thallium following dithiocarb use, neither agent is recommended in the treatment of patients with thallium toxicity.

Prussian Blue Potassium The similarities between the cellular handling of potassium and thallium ions led to the natural investigation of a role for potassium in the treatment of thallium poisoning. In humans, potassium administration is associated with an increase in urinary thallium elimination.10,20,62 The magnitude of this increase is reported to be on the order of 2–3-fold.62 This is supported by animal models that demonstrate some benefit in terms of either enhanced thallium elimination or survival.21,42,46 It is believed that potassium administration blocks tubular reabsorption of thallium and mobilizes thallium from tissue stores, thereby raising thallium levels available for glomerular filtration.57,71 However, it is this second mechanism that is of concern. Many authors report either the development of acute neurologic toxicity or the severe exacerbation of neurologic symptoms during potassium administration.5,20,51,62,70,83 Others cite data demonstrating that potassium’s augmentation of thallium elimination in humans is quite limited.39 Additionally, some animal models demonstrate that potassium loading enhances lethality50 and permits thallium redistribution into the CNS.26 For these reasons, the routine use of potassium should be considered potentially dangerous. Some authors recommend forced diuresis, especially in conjunction with potassium chloride.13,81 However, no convincing experimental evidence can support the use of forced diuresis with or without potassium at this time. Once again, the similarities between thallium and potassium might suggest a role for administration of sodium polystyrene sulfonate (SPS) as a sodium-thallium exchange resin. Although in vitro binding between thallium and SPS is excellent, it is unlikely to be clinically useful because of preferential binding between potassium and SPS.29

Chelation Thallium toxicity does not respond to traditional chelation therapy. Studies demonstrate that the use of EDTA and diethylenetriamine pentaacetic acid are without benefit.56,71 Dimercaprol (British Anti-Lewisite, BAL) and D-penicillamine also fail to enhance thallium excretion in experimental models.56,71 In one model in which D-penicillamine was able to enhance thallium elimination, it did so at the cost of substantial thallium redistribution into vital organs.69 Similarly, sulfur-containing compounds such as cysteine or N-acetyl cysteine (NAC) have not been demonstrated to be beneficial.46,52 Another chelator, diphenylthiocarbazone (dithizone), forms a minimally toxic complex with thallium, resulting in a 33% increase in fecal elimination of thallium in rats.74 Unfortunately, dithizone is goitrogenic and diabetogenic in animal studies.46,56,81 Dithiocarb (sodium diethyldithiocarbamate), an intermediate metabolite of tetraethylthiuram disulfide (disulfiram, or Antabuse) (Chap. 65), also increases the urinary excretion of thallium.74,78 Prior to thallium elimination, however, the formation of a lipophilic thallium-diethyldithiocarbamate complex can result in the redistribution of thallium into the central nervous system.36,78 After decomposition of the chelate complex, thallium may remain

Prussian blue is a crystal lattice of potassium ferric hexacyanoferrate (KFe(Fe(CN)6)) and can be used as a chelator for thallium toxicity.40 In vitro thallium is more effectively adsorbed to Prussian blue than to activated charcoal.29,37,40 When given orally, Prussian blue acts as an ion exchanger for univalent cations, with its affinity increasing as the ionic radius of the cation increases. As such, Prussian blue interferes with the enterohepatic circulation by exchanging potassium ions, from its lattice, for thallium ions in the gastrointestinal tract. This results in the formation of a concentration gradient causing an increased movement of thallium into the gut. Oral Prussian blue reduces the half-life of elimination of thallium in rats by 50%.67 Other animal studies overwhelmingly support both the safety and the superiority of Prussian blue as an antidote over all other agents in thallium poisoning.27,36,40,50,52,69 Humans with thallium poisoning are routinely given Prussian blue, which appears to result in clinical benefits, enhanced fecal elimination, and falling thallium concentrations.11,12,14,51,64,76,83,84,86 One series of 11 thallium-poisoned patients demonstrated both the safety of Prussian blue and its ability to substantially increase fecal thallium elimination.77 Unfortunately, because there are no controlled trials in humans that compare Prussian blue to other agents, and many of the patients reported above received multiple therapies, the true utility of Prussian blue is unknown. Reports suggest that Prussian blue is not absorbed from the gastrointestinal system,32,77 but our clinical experience demonstrates that prolonged therapy results in blue discoloration of the sweat and tears. Currently, Prussian blue is neither commercially available as a pharmaceutical agent, nor approved for use in the United States by the Food and Drug Administration. It is available from chemical supply companies, in various forms with varying degrees of efficacy.40,77 The colloidal, or soluble, form seems to be more efficacious than the insoluble form.77 The dose of Prussian blue is 250 mg/kg/d orally via a nasogastric tube in 2–4 divided doses per day.77 If patients are constipated, the Prussian blue may have greater utility if dissolved in 50 mL of 15% mannitol.81 Although any cathartic may be appropriate, most authors have used mannitol, possibly because of concerns regarding repeated magnesium use in patients with neurologic findings and sorbitol in patients with poor gastrointestinal mobility.

Extracorporeal Drug Removal Extracorporeal drug removal may have a limited beneficial role in patients with thallium toxicity, especially if begun shortly after the initial exposure while serum concentrations remain high prior to effective tissue distribution. A frequently quoted review attests to the benefits of hemodialysis.54 The actual data, however, show that hemodialysis at various stages of poisoning is no better than forced diuresis.12,63 Reported thallium removal rates by hemodialysis are trivial: 143 mg of thallium were removed by 120 hours,64 222.8 mg were removed by 121 hours,12 and 128 mg were removed by 54 hours of hemodialysis.12 These values can be placed

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in perspective knowing that the minimum lethal adult dose of thallium is estimated to be on the order of 1 g,56 and that many reported cases involve ingestions 10 times greater than the minimum lethal dose. Data from a more recent hemodialysis experience suggest that by using high blood flow rates (300 mL/min), clearances as high as 90–150 mL/min could be obtained.48 Although clearances seem encouraging, this must be kept in the perspective of thallium’s large volume of distribution. With lower blood flow rates, charcoal hemoperfusion may be 2–3 times more efficient than hemodialysis, providing clearance rates as high as 139 mL/min.12 Furthermore, combined hemoperfusion and hemodialysis were used in several cases1,12,14 and were reported to remove as much as 93 mg of thallium within 3 hours of therapy.1 While extracorporeal therapy alone is probably insufficient for patients with significant poisoning, and unnecessary in those with small exposures, it may have some utility in combination with other therapies, especially in patients with renal insufficiency or those with early massive and presumed lethal exposures. As is the case with other toxins, the use of peritoneal dialysis is probably ineffective in removing thallium.39 Table 83–2 summarizes the suggested therapy for thallium-poisoned patients.

SUMMARY The elimination of thallium salts from common use as depilatories and rodenticides substantially reduced the incidence of both intentional and unintentional thallium toxicity in the United States. Despite this fact, cases of significant poisoning still occur in countries in which thallium-containing rodenticides remain in use, and in this country as well, from attempted homicide and by intentional contamination of foods and illicit drugs. Early recognition of the thallium toxidrome and prompt initiation of safe and appropriate therapy will substantially improve the patient’s prognosis. When recognition and subsequent treatment are delayed, morbidity and mortality can be consequential.61

TABLE 83–2.

Treatment for Thallium Poisoning

Early (patients who present in the first hours postexposure) • Stabilize airway, breathing, and circulation if necessary • Consider ipecac-induced emesis or orogastric lavage if the patient has not vomited • Consider whole-bowel irrigation with polyethylene glycol electrolyte lavage solution for patients with large ingestions or the presence of radiopaque material on abdominal radiograph • Begin multiple-dose activated charcoal therapy; add a cathartic to the first dose if the patient does not have diarrhea • Give Prussian blue 250 mg/kg/d in 2 or 4 divided doses, dissolved in water, or 50 mL of 15% mannitol if the patient does not have diarrhea • Consider simultaneous charcoal hemoperfusion and hemodialysis, especially if the patient has renal insufficiency Late (patients who present more than 24 hours postexposure or with chronic toxicity) • Stabilize airway, breathing, and circulation if necessary • Begin multiple-dose activated charcoal therapy; add a cathartic to the first dose if the patient does not have diarrhea • Give Prussian blue 250 mg/kg/d in 2 or 4 divided doses, dissolved in water, or 50 mL of 15% mannitol if the patient does not have diarrhea

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86. Wainwright AP, Kox WJ, House IM, et al: Clinical features and therapy of acute thallium poisoning. Q J Med 1988;69:939–944. 87. Wakid NW, Cortas NK: Chemical and atomic absorption methods for thallium in urine compared [letter]. Clin Chem 1984;30:587–588.

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ANTISEPTICS, DISINFECTANTS, AND STERILANTS Paul M. Wax

A 60-year-old woman was brought to the Emergency Department (ED) from home 3 hours after drinking an unknown liquid. Apparently, the woman had ingested a few ounces of a liquid from an old liquor bottle that was stored in the garage. The patient had a past medical history that was significant for ethanol abuse. She was not taking any known medications. In the ED, the patient was unresponsive to voice but responded to deep pain. According to a family member, the patient had gone to the garage, looking for a bottle of rum. She was later discovered lying next to the bottle, having vomited several times. The bottle was also brought into the ED. Her vital signs were: blood pressure, 80/40 mm Hg; pulse, 130 beats/min and regular; respiratory rate, 14 breaths/min; and temperature, 98.6°F (37°C). The patient was disheveled but otherwise well appearing. An unusual, somewhat sweetish odor was noted on her breath. Examination of the head, eyes, ears, nose, and throat was otherwise unremarkable. The neck was supple. The chest was clear to auscultation bilaterally and cardiac examination revealed a rapid heart rate. Abdominal examination was soft and nontender, with normoactive bowel sounds. Rectal examination was negative for occult blood. Extremity examination was normal. Neurologically, the patient was comatose and had normal muscle tone and symmetric reflexes. Her initial electrocardiogram (ECG) showed sinus tachycardia with normal conduction and no evidence of ischemia. In the ED, the patient continued to vomit. She underwent endotracheal intubation for airway protection. The patient was treated with aggressive fluid resuscitation, including 3 L 0.9% NaCl, during the first 2 hours. Her blood pressure gradually improved, but she did exhibit episodes of atrial fibrillation and was given two intravenous doses of 0.25-mg digoxin. The patient was admitted to the intensive care unit (ICU). Pertinent initial laboratory studies revealed serum sodium, 134 mEq/L; potassium, 3.8 mEq/L; chloride, 98 mEq/L; bicarbonate, 18 mEq/L; blood urea nitrogen (BUN), 15 mg/dL; creatinine, 1.1 mg/dL; and glucose, 90 mg/dL. The arterial blood gas on room air showed pH 7.28; PCO2, 50 mm Hg; and PO2, 70 mm Hg. Urine toxicology screen was negative for drugs of abuse. Serum ethanol level was 30 mg/dL. The old liquor bottle that the patient had drunk from was noted to have a disinfectantlike odor that resembled formaldehyde. Given this formaldehydelike odor, the remaining liquid from the bottle was sent to the medical examiners office for a formaldehyde level. In the ICU, the patient remained comatose for the first 48 hours. Esophagogastroscopy revealed gastric inflammation, but no ulcerations or deep burns. There were no further dysrhythmias. The patient began to awaken during the third day of hospitalization and

was extubated and fully awake within 96 hours of the ingestion. The patient now admitted that she had run out of liquor in her house and had gone out to the garage, looking for other sources of ethanol. She believed that she had been drinking from an old rum bottle. A month after discharge, the medical examiner’s report of the analysis of the liquid from the old bottle revealed the presence of phenol. No formaldehyde, ethanol, or other chemicals were detected.

Antiseptics, disinfectants, and sterilants are a diverse group of antimicrobial agents used to prevent infection (Table 84–1). Although these terms are sometimes used interchangeably (and some of these agents are used for both antisepsis and disinfection), the distinguishing characteristics between the groups are important to emphasize. An antiseptic is a chemical agent that is applied to living tissue to kill or inhibit microorganisms. Iodophors, chlorhexidine, and the alcohols (ethanol and isopropanol) are commonly used antiseptics. A disinfectant is a chemical or physical agent that is applied to inanimate objects to kill microorganisms. Chlorine bleach (sodium hypochlorite), phenolic compounds, and formaldehyde are examples of currently used disinfectants. A sterilant is a chemical or physical agent that is applied to inanimate objects to kill all living organisms, including spores. Ethylene oxide and glutaraldehyde are examples of sterilants. Neither antiseptics nor disinfectants have complete sporicidal activity. Not surprisingly, many of these chemicals that are used to kill microbiologic organisms also demonstrate considerable human toxicity.20,64 Although sulfur, vinegar (acetic acid), and mercurial compounds were used as antiseptics as long as 2000 years ago, it was not until the 19th century that the use of antiseptics became commonplace. Some of the epochal figures in medicine were the first to extol the importance of antiseptics. Semmelweis implemented the practice of hand washing with chloride of lime as a means of preventing the dreaded puerperal fever. Lister experimented extensively with phenol as an antiseptic. Koch used mercury bichloride. Other agents introduced as antiseptics during the 19th century include tincture of iodine (used extensively during the Civil War), hydrogen peroxide, isopropanol, and ethanol.64 The use of these agents evolved during the 20th century as their toxicity and the principles of microbiology became better understood. Two of the more toxic antiseptics—iodine and phenol— were gradually replaced by the less toxic iodophors and substituted phenols. Mercury bichloride was superseded by the organic mercurials (eg, merbromin, thimerosal), which also proved

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TABLE 84–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Antiseptics, Disinfectants, Sterilants, and Related Compounds

Chemical Acids Boric acid

Alcohols (Chaps. 64,66) Ethanol Isopropyl alcohol

Aldehydes Formaldehyde

Glutaraldehyde Chlorhexidine Chlorinated Compounds Chlorine Chlorophors (Sodium Hypochlorite)

Commercial Product

Use

Toxic Effects

Therapeutics and Evaluation

Borax Sodium perborate Dobell’s solution

Antiseptic Mouthwash Eyewash Roach Killer

Blue-green emesis and diarrhea Boiled lobster appearance

GI decontamination Hemodialysis (rare)

Rubbing alcohol (70% ethanol) Rubbing alcohol (70% Isopropanol)

Antiseptic Disinfectant Antiseptic Disinfectant

CNS depression Respiratory depression CNS depression Respiratory depression Ketonemia, ketonuria GI irritation/bleeding Hemorrhagic tracheobronchitis

Supportive

Formalin (37% formaldehyde, 12–15% methanol) Cidex (2% glutaraldehyde) Hibiclens

Disinfectant Fixative Urea insulation Sterilant Antiseptic

Caustic gastroenteritis CNS depression

Gastric lavage Hemodialysis Sodium bicarbonate

Mucosal and dermal irritant GI irritation

Disinfectant Disinfectant

Irritant Mild GI irritation

Sterilant Plasticizer

Chlorine bleach (5% NaOCl) Dakin’s solution (1 part 5% NaOCl, 10 parts H2O)

Ethylene Oxide

Organic Mercurials (Chaps. 56, 81) Iodinated Compounds Iodine

Iodophors Iodide Oxidants Chlorates

Hydrogen peroxide

Subsitituted Quaternary Ammonium Compounds Benzalkonium chloride

Hemodialysis (rare)

Endoscopy (rare)

Merbromin 2% (Mercurchrome) Thimerosal (Merthiolate)

Antiseptic (obsolete)

Irritant CNS depression Peripheral neuropathy Carcinogen ? CNS Renal

Tincture of Iodine (2% I2, 24% NaI, 50% ethanol) Lugol’s solution (5% I2) Providone-iodine (Betadine) (0.001% I2) SSKI (100% KI)

Antiseptic

Caustic gastroenteritis

Milk, starch Sodium thiosulfate Endoscopy

Antiseptic

Limited

Same as iodine if symptomatic

Expectorant

Iodism

Steroids for significant salivary gland enlargement

Sodium chlorate Potassium chlorate

Antiseptic

Hemolytic anemia Methemoglobinemia Renal failure

Methylene blue? Exchange transfusion Hemodialysis

Oxygen emboli GI caustic

Lavage Radiographic evaluation Endoscopy Decontamination Endoscopy as needed

H2O2 3%—household H2O2 30%—industrial

Potassium permanganate Phenols Nonsubstituted

CNS; renal

Matches Herbicide Disinfectant

(Chap. 81)

Antiseptic

Oxidizing agent, caustic Manganese elevation

Phenol (carbolic acid)

Disinfectant

Decontamination: Polyethylene glycol or water Endoscopy as needed

Hexachlorophene

Disinfectant

Caustic gastroenteritis Dermal burns Cutaneous absorption CNS effects CNS disturbances

Zephiran

Disinfectant

GI caustic at high concentrations

Endoscopy if significant GI symptoms

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toxic. More recently, newer compounds, such as quaternary ammonium compounds, ethylene oxide, and glutaraldehyde, were introduced.

PHENOL Phenol, also known as carbolic acid, is one of the oldest antiseptic agents. Although at one time it was the standard antiseptic to which other antiseptics were compared and was used as a preoperative antiseptic and in wound dressings, phenol’s toxicity limited its usefulness. It is rarely used as an antiseptic today and has been replaced by the many phenolic derivatives. Currently, phenol is used as a disinfectant, chemical intermediary, and nail cauterizer. The last application uses a highly concentrated 89% solution. Phenol is also a component (0.1–4.5%) of various lotions, ointments, gels, gargles, lozenges, and throat sprays.64 Campho-Phenique and Chloraseptic contain 4.7% and 1.4% phenol, respectively. Although many cases of phenol poisoning were reported in the past, acute oral overdoses of phenol-containing solutions are relatively uncommon today.58 Phenol acts as a general protoplasmic poison. Toxicity is a result of its ability to cause cell wall disruption, protein denaturation, and coagulation necrosis. Intentional ingestion of concentrated phenol, ingestion of phenol-containing water, occupational exposure to aerosolized phenol, dermal contact, and parenteral administration may all result in symptomatic phenol poisoning. Phenol demonstrates excellent skin penetrance.16 Severe dermal burns from phenol with resultant phenol absorption have resulted in systemic toxicity, and even death within minutes to hours.16,99 Parenteral administration of phenol has also resulted in death.102 The lethal dose may be as little as 1 g.77 Clinical manifestations can be divided into local and systemic symptoms. Systemic symptoms from gastrointestinal (GI) or dermal absorption of phenol are usually more dangerous than the local effects and can result in significant morbidity and mortality. Manifestations of systemic toxicity include central nervous system (CNS) and cardiac symptoms. CNS effects include central stimulation, seizures, lethargy, and coma.60 In a study of patients who had ingested Creolin (26% phenol), CNS symptoms predominated.158 Nine of 52 patients evaluated at the hospital developed lethargy, and 2 patients developed coma. Seizures were not reported. Cardiac symptoms from phenol include tachycardia, bradycardia, and hypotension.60 Excessive dermal absorption of phenol during chemical peeling procedures was associated with dysrhythmias.179 Other systemic symptoms that may develop include pulmonary disturbances, hypothermia, metabolic acidosis, methemoglobinemia, and rabbit syndrome.14,77,86 “Phenol marasmus” was a term used in the 19th century to describe patients (usually physicians) who developed a typical characteristic syndrome after chronic exposure to aerosolized phenol. These symptoms included anorexia, weight loss, vertigo, headache, and salivation. A brown, or even black, discoloration of the urine was usually noted.111 Dark urine (bilirubin-negative) was also a prominent feature in a more recent case of occupational exposure to vaporized phenol.111 Local toxicity to the GI tract from the ingestion of phenol may result in nausea, vomiting, bloody diarrhea, and severe abdominal pain. Serious GI burns are uncommon, and strictures are rare.73,147 White patches in the oral cavity may be detected. In the Creolin study cited above, only 1 of 17 patients who underwent endoscopy

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had a significant esophageal burn.158 Ingestions of phenol-contaminated water are associated with the development of nausea, vomiting, diarrhea, burning sensation in the mouth, mouth sores, and dark urine.8,84 Dermal exposures to phenol usually result in a light brown staining of the skin. Markedly elevated blood and urine levels of phenol may be detected after ingestion, or dermal absorption, of phenol and phenolcontaining compounds (eg, Campho-Phenique).16,77,93 A variety of solutions have been suggested for dermal and gastric decontamination of phenol. Olive oil was recommended in the past as an irrigant fluid because it was thought to dissolve phenol and prevent absorption.55 Animal studies, however, show that systemic phenol absorption is actually increased when olive oil is used as a decontaminant.35 A study employing a rat model showed that cutaneous decontamination with a low-molecular-weight polyethylene glycol solution decreased mortality, systemic effects, and dermal burns.22 Although this study suggested that polyethylene glycol was superior to water as a decontamination agent, a subsequent study using a swine model could not demonstrate a difference between these two agents.135 Given the lack of definitive efficacy data, either low-molecular-weight polyethylene glycol (eg, PEG 300 or 400), if it is readily available in the ED, or water is currently recommended for dermal irrigation and careful gastric decontamination. Appropriate endoscopic evaluation, as needed to determine the extent of GI injury, and good supportive care are also recommended.

SUBSTITUTED PHENOLS AND OTHER RELATED COMPOUNDS

Substituted phenols are also used as antiseptic and disinfectant agents. Hexachlorophene (pHisoHex), a trichlorinated bis-phenol, is one of the best known substituted phenols. Hexachlorophene is considered generally less tissue-toxic than phenol. This agent was formerly used extensively as a detergent in hospitals. During the 1970s, an association was observed between repetitive wholebody washing of premature infants with 3% hexachlorophene and the development of vacuolar encephalopathy and cerebral edema.109 There were multiple reports of significant neurologic toxicity and death in children who became toxic after ingesting hexachlorophene.71 Fatalities also occurred after patients absorbed substantial amounts of hexachlorophene during the treatment of burn injuries.30 Since these reports, the use of hexachlorophene has declined significantly. pHisoDerm, another antiseptic agent with a similar sounding name to pHisoHex, contains sodium octylphenoxyethoxyethyl ether sulfonate and lanolin. These chemicals act as soaps and detergents. No reports of significant toxicity from pHisoDerm can be found in the literature. Irritative effects (nausea, vomiting, diar-

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rhea) would be the main problems to anticipate with oral exposure. In a study of poisoning admissions to Hong Kong hospitals, the ingestion of Dettol liquid, a household disinfectant that contains 4.8% chloroxylenol, 9% pine oil, and 12% isopropanol, accounted for 10% of admissions.28 Aspiration (perhaps, in part, because of the pine oil) occurred in 8% of these patients, resulting in upper airway obstruction, pneumonia, and acute respiratory distress syndrome. More common symptoms included nausea, vomiting, sore mouth, sore throat, drowsiness, abdominal pain, and fever. Dermal contact with Dettol may result in full-thickness chemical burns.41 Cresol, a mixture of three isomers of methylphenol, has better germicidal activity than phenol and is a commonly used disinfectant. Exposure to concentrated cresol may result in significant local tissue injury, hemolysis, renal injury, hepatic injury, and CNS and respiratory depression.41,65,186 Phenol levels, as well as cresol levels, serve as markers of exposure.186

FORMALDEHYDE Formaldehyde is a water-soluble, highly reactive gas at room temperature. Formalin consists of an aqueous solution of formaldehyde, usually containing about 37% formaldehyde and 12–15% methanol. Formaldehyde is quite irritating to the upper airways, and its odor is readily detectable at low concentrations. Lethality in adults begins to occur following ingestion of 1–2 ounces of formalin.46 Although formaldehyde was once widely used as a disinfectant and fumigant, its role as a disinfectant is now largely confined to the disinfection of hemodialysis machines. Nonetheless, formaldehyde has many other applications. Healthcare workers are probably most familiar with the use of formaldehyde as a tissue fixative and embalming agent. Formaldehyde is also used in the textile industry and in the production of resins and plastics. Formaldehyde is a major component of urea formaldehyde foam, used extensively for insulation.25 Formaldehyde is a protoplasmic poison and potent caustic. The acute ingestion of formaldehyde (as formalin) may result in both local and systemic symptoms. It causes coagulation necrosis, protein precipitation, and tissue fixation. Ingestions of formalin may result in significant gastric injury, including hemorrhage, diffuse necrosis, perforation, and stricture.4,11,143 The most extensive damage appears in the stomach, with only occasional involvement of the small intestine and colon.89 Chemical fixation of the stomach may occur.165 Esophageal involvement is not very prominent, and, if present, is usually limited to its distal segment.89 The most striking systemic manifestation of formaldehyde poisoning is acidosis, resulting from the conversion of formaldehyde to formic acid. This reaction occurs rapidly. On initial presentation, the patient may already have a profound acidemia, accompanied by a large anion gap. Although the methanol component of the formalin solution is readily absorbed and has resulted in methanol levels of 40 mg/dL,23,46 the rapid metabolism of formaldehyde to formic acid appears to be responsible for much of the acidosis (Chap. 66). The development of extensive tissue necrosis leading to lactate production may also be a factor. Blindness due to the accumulation of formate, a retinal toxin, is not reported. This is likely due to the lethality of the dose of formaldehyde necessary to cause retinal toxicity. Patients presenting after acute formaldehyde ingestions complain of the rapid onset of severe abdominal pain, which may be

accompanied by vomiting and diarrhea. Altered mental status and coma usually follow rapidly. Examination may demonstrate epigastric tenderness, hematemesis, cyanosis, hypotension, and tachypnea. Hypotension may be profound. Decreased myocardial contractility, as well as hypovolemic shock, contributes to the cardiovascular instability.72,167 Early endoscopic findings include ulceration, necrosis, perforation, and hemorrhage of the stomach, with little esophageal involvement. Acute intravascular hemolysis is described in hemodialysis patients whose dialysis equipment contained residual formaldehyde after undergoing routine cleaning.126,136 Occupational and environmental exposure to formaldehyde receives considerable attention. In particular, there is concern over the potential off-gassing of formaldehyde from the widely used urea formaldehyde building insulation, such as particle boards.124 Headache, nausea, skin rash, sore throat, nasal congestion, and eye irritation are associated with the use of these polymers.38 Formaldehyde, at concentrations as low as 1 ppm, may cause significant irritation to mucous membranes of the upper respiratory tract and conjunctivae.75,104 Formaldehyde is also a potential sensitizer for immune-mediated reversible bronchospasm.69 The exact immunologic mechanism is not yet elucidated, although it is likely that formaldehyde acts as a hapten. In addition, formaldehyde is thought to be a dermal sensitizer.156 Although both animal and human data suggest that formaldehyde exposure is associated with an increased incidence of nasopharyngeal carcinoma,3,142 its role in the pathogenesis of cancer in humans is unproven.1,128 Acute chemical pneumonitis occurs after significant inhalational exposure.134 Hepatotoxicity is also related to formaldehyde exposure.13 Membranous nephropathy is also associated with occupational or environmental formaldehyde exposure.21 Significant neurobehavioral impairment and seizures are also associated with long-term occupational exposure to formaldehyde (although phenol exposure may have contributed to the problems).87 The initial management of a patient with a significant formaldehyde exposure should include immediate dilution with water. Although such an approach may be useful in reducing the caustic effect, strong evidence for a beneficial result is lacking. Careful gastric aspiration with a small-bore nasogastric tube may limit systemic absorption. The role of activated charcoal is not studied and it probably should not be used if endoscopy is considered likely. Significant acidemia should be treated with sodium bicarbonate and folinic acid. Immediate hemodialysis may remove the accumulating formic acid, as well as the parent molecules: formaldehyde and methanol.46 An ethanol infusion or 4-methylpyrazole may block the metabolism of methanol, but neither of these agents will block the conversion of formaldehyde to formic acid (Chap. 66). Early endoscopy is recommended for all patients with significant GI symptoms to assess the degree of burn injury. Surgical intervention may be required for those with severe burns. Emergent gastrectomy, as well as late surgical intervention to relieve formaldehyde-induced gastric outlet obstruction, has sometimes been required.66,91

IODINE AND IODOPHORS Iodine usually refers to molecular iodine, also known as I2, free iodine, or elemental iodine. This chemical is the active ingredient of iodine-based antiseptics. The poor solubility of I2 in water is increased by adding iodide (I−). Alternatively, the use of ethanol as

CHAPTER 84

the solvent (eg, tincture of iodine) allows substantially more concentrated forms of I2 to be available. Iodophors are substances in which molecular iodine is compounded to a high-molecular-weight carrier or to a solubilizing agent. Povidone-iodine (Betadine), a commonly used iodophor, consists of iodine linked to polyvinylpyrrolidone (povidone). Problems associated with the use of iodine include unpleasant odor, skin irritation, allergic reactions, clothes staining, and poor stability. Iodophors, which limit the release of molecular iodine and are generally less toxic, are the standard iodine-based antiseptic preparations. Iodophor preparations are formulated as solutions, ointments, foams, surgical scrubs, wound-packing gauze, and vaginal preparations. The most common preparation is a 10% povidone-iodine solution that contains 1% “available” iodine (referring to all oxidizing iodine species), but only 0.001% free iodine (referring only to molecular iodine).20,64 Iodine is one of the oldest topical antiseptics. It is also used to disinfect medical equipment and drinking water. Iodine is an effective antiseptic against bacteria, viruses, protozoa, and fungi, and is used both prophylactically and therapeutically.43 Iodine is cytotoxic and an oxidant. It is thought to work by binding amino and heterocyclic nitrogen groups, oxidizing sulfhydryl groups, and saturating double bonds. Iodine also iodinates tyrosine groups.64 Iodine ingestions are much less common than in the past as a result of the change in antiseptic use from iodine to iodophor antiseptics.45 During the early part of the 20th century, however, iodine ingestions were quite routine. A study at Boston City Hospital from 1915 to 1936 revealed that iodine ingestions (usually tincture of iodine) were the most common cause of poisoning, accounting for 27% of all patients admitted for suicide attempts.115 Molecular iodine may cause severe caustic injury of the gastrointestinal (GI) tract, similar to what occurs following exposure to a strong alkali or acid (Chap. 87). A 1937 study reported 18 cases of oral iodine ingestions, usually involving tincture of iodine, that resulted in death.48 The amount ingested was recorded in 9 of these cases, and ranged from 30 to 250 mL (0.6–5.0 g of iodine). Symptoms consisted of vomiting, diarrhea, abdominal pain, GI bleeding, delirium, anuria, and vasomotor collapse. Death usually occurred within the first 48 hours after ingestion and resulted from gastrointestinal injury, hypovolemia, and circulatory collapse. Gastrointestinal strictures can also occur after the ingestion of tincture of iodine.182 There may be significant systemic absorption of iodine from topical iodine or iodophor preparations.129 Markedly elevated iodine levels do occur in patients who receive topical iodophor treatments to areas of dermal breakdown, such as burn injuries.96 Significant absorption occurs when iodophors are applied to the vagina, perianal fistulas, umbilical cords, and the skin of lowbirth-weight neonates.177 A fatality following intraoperative irrigation of a hip wound with povidone-iodine is reported.39 The serum iodine level, reported at necropsy, in this case, was 1000 times normal (normal, 5–8 µg/dL). Until recently, reports of adverse consequences from iodophor ingestions could not be found in the literature. In a recent single case report, however, a 9-week-old infant died within 3 hours of receiving povidone-iodine by mouth.92 In this unusual case, the child was administered 15 mL of povidone-iodine mixed with 135 mL of polyethylene glycol by nasogastric tube over a 3-hour period for the treatment of infantile colic. Postmortem examination showed an ulcerated and necrotic intestinal tract. A blood iodine level of 14,600 µg/dL was recorded. Significant toxicity from intentional ingestions of iodophors in adults is not documented.

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Acid-base disturbances are among the most significant abnormalities associated with iodine and iodophors. Metabolic acidosis occurred in several burn patients after receiving multiple applications of povidone-iodine ointment.96,131 These patients had elevated serum iodide concentrations and normal lactate levels. The exact etiology of the acidosis remains unclear. Postulated mechanisms for the acidosis have included the povidone-iodine itself (pH 2.43), bicarbonate consumption from the conversions of I2 to NaI, or decreased renal elimination of H+ as a consequence of iodine toxicity.131Metabolic acidosis associated with a high lactate level after iodine ingestion likely reflects tissue destruction.43 Electrolyte abnormalities may also occur following the absorption of iodine. A patient with decubitus ulcers who received prolonged wound care with povidone-iodine–soaked gauze developed metabolic acidosis, renal failure, hypernatremia, and hyperchloremia.43 The hyperchloremia was thought to be caused by a spurious elevation of measured chloride ions as a consequence of iodine’s interference with the chloride assay. This interference occurs on the Technicon STAT/ION autoanalyzer, but does not occur when the silver halide precipitation assay is used.43 Spurious hyperchloremia from iodine (or iodide) may result in the calculation of a low or negative anion gap (Chap. 24).26,49 Other problems associated with topical absorption of iodinecontaining preparations include hypothyroidism (particularly in neonates),26,155 hyperthyroidism, elevated liver enzymes, neutropenia, and hypoxemia.43 Because of the lack of consistency between iodine levels and symptomatology, and because many of these patients had significant secondary medical problems that may have accounted for their symptoms, the exact relationship between iodine absorption and the development of a specific clinical syndrome remains speculative. However, a recent clinical controlled trial that compared preterm infants exposed to either topical iodinated antiseptic agents or to chlorhexidine-containing antiseptics showed that the infants exposed to topical iodine–containing antiseptics were more likely to have higher thyrotropin levels and elevated urine iodine levels than was the chlorhexidine group.101 Contact dermatitis can result from repetitive applications of iodophors.108 A fatal case of exfoliative dermatitis from repeated local applications of tincture of iodine has also been described.148 The patient who ingests an iodine preparation requires expeditious evaluation, stabilization, and decontamination. Careful nasogastric aspiration and lavage may be performed to limit the caustic effect of the iodine if signs of perforation are absent. Irrigation with a starch solution will convert iodine to the much less toxic iodide, and, in the process, turn the gastric effluent dark blue-purple. This change in color may serve as a useful guide in determining when lavage can be terminated. If starch is not available, milk may be a useful alternative. Instillation of 100 mL of a solution of 1–3% sodium thiosulfate may also convert any remaining iodine to iodide. Activated charcoal binds iodine and may be useful.42 Whether any one of these suggested agents offers a distinct advantage over the others is not studied. Minimal GI absorption of iodine occurs because of its conversion to iodide in the GI tract.33 Early endoscopy may help assess the extent of the gastrointestinal injury. Judicious use of corticosteroids for circumferential seconddegree burn injuries may be helpful in preventing stricture formation (Chap. 87). Most patients with iodophor ingestion require only supportive management. The use of starch or sodium thiosulfate may be considered in symptomatic patients. Endoscopy is recommended in patients with persistent symptoms.

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IODIDES Iodide, as noted, refers to the reduced form of iodine, I
. Iodide is most commonly found in the salts, potassium iodide and sodium iodide. Potassium iodide is used as an expectorant and in the treatment of hyperthyroidism and radiation exposure. Saturated solution of potassium iodide (SSKI), containing 1 g/mL, is an example of a potassium iodide preparation. Sodium iodide is found as a dietary supplement in iodized table salt. Although iodides by themselves are not used as antiseptics, they are discussed in this section because iodine-containing antiseptic compounds may consist of a mixture of molecular iodine and an iodide salt. Lugol’s iodine solution, for instance, consists of 5% iodine and 10% potassium iodide. Tincture of iodine consists of 2% iodine, 2.4% sodium iodide, 47% alcohol, and water. Iodine is much more toxic than iodide because of its propensity to cause significant local tissue injury. Because iodide is not caustic, treatment of iodine ingestions includes conversion of iodine to the less toxic iodide. The organic iodides are another group of iodine-containing compounds. Radiologic contrast agents such as diatrizoate meglumine (Hypaque; 282 mg I2 /mL) are examples of commonly used organic iodides. Other iodine-containing compounds include the antidysrhythmic amiodarone (75 mg in a 200 mg tablet) and the antifungal Vioform (clioquinol; 12 mg in 1 gm of cream). Isotopes of iodine are another group of agents that contain iodine. The most commonly used isotope, I131, is employed in the diagnosis of thyroid disorders and treatment of hyperthyroidism. Iodism, first described in 1902, refers to a variety of reactions to iodides. The term has been used to describe both dose-dependent reactions and hypersensitivity reactions (“iodine idiosyncrasy”).24,78 The duration of exposure is most often chronic, but iodism may occur following acute exposures. The most noticeable manifestations of chronic dose-dependent iodide toxicity include skin eruptions (ioderma), salivary gland swelling, and goiter. Acute parotitis may be the most recognizable finding; hence, this syndrome is referred to as “iodide mumps.”24,62 Salivary swelling is thought to be caused by ductal inflammation and blockage. Significant salivary gland enlargement may result in dysphagia and possible airway obstruction.18 Other manifestations of iodism include metallic taste, gingivitis, sialorrhea, bronchorrhea, coryza, nausea, and vomiting.18,78 Druginduced fever is also attributed to iodide administration.171 Pure iodide ingestions do not produce GI injuries. Hypersensitivity reactions from the ingestion of small therapeutic doses of iodides may also occur. Manifestations of these idiosyncratic reactions include eosinophilia, lymphadenopathy, arthralgias, submucosal hemorrhages, arthritis, diverse cutaneous manifestations, hematuria, proteinuria, fever, and rapid onset of acute painful salivary gland swelling (sialoadenitis).24,62,180 A periarteritis nodosa type of reaction from iodide exposure is also described.138 Ioderma refers to the protean group of dermal lesions usually associated with chronic exposure to iodides. These skin eruptions are quite varied, ranging from pustular/bullous eruptions to generalized erythema and urticaria.148 Although ioderma is usually related to iodide exposure, it is also reported to occur as a systemic manifestation of povidone-iodine exposure from wound irrigation.19 Subacute and chronic exposure to excess iodides are also implicated in a variety of thyroid disorders, including goiter,184 thyrotoxicosis (Jod-Basedow phenomenon),50 and myxedema.116

Acute exposure to iodide in patients with normal thyroid glands generally results in blockade of thyroid hormone production (Wolff-Chaikoff effect). This is the basis for the administration of SSKI following exposure to radioactive fallout. Acute overdose of iodide medications is rare and typically of limited clinical consequence. In one case, a patient inadvertently ingested 15 g of potassium iodide and developed myocardial irritability and face, neck, and mouth swelling within 12 hours of ingestion.172 Subsequent recovery was uneventful. Reactions to intravenous iodinated radiologic contrast agents are well known.36 Anaphylactoid reactions are idiosyncratic in nature and not dose dependent. Salivary gland swelling is also described as a sequela to intravenous urography using these agents.168 The use of iodides, such as radiologic contrast media in early pregnancy, is potentially teratogenic and may lead to cretinism. Management of acute iodide ingestions is basically supportive. Activated charcoal may be considered in patients with large ingestions. Because absorbed iodide competes with chloride in the proximal tubule, sodium chloride diuresis may enhance the elimination of iodide. As a result of the conversion of iodine to iodide, patients treated for iodine ingestions may be at risk for subsequent iodide toxicity. Systemic corticosteroids have been used with success in the management of iodide-induced sialoadenitis180 and ioderma.5

CHLORHEXIDINE

Chlorhexidine is another commonly used antiseptic agent that is especially useful as a dental antiseptic. This cationic biguanide compound has been in use since the early 1950s. It is found in a variety of skin cleansers, usually as a 4% emulsion (eg, Hibiclens), and may also be found in mouthwash. Chlorhexidine is reported to have low toxicity. Few cases of deliberate oral ingestion of chlorhexidine can be found in the literature. Symptoms are usually mild and gastrointestinal irritation is the most likely effect after oral ingestion.27 Chlorhexidine has poor enteral absorption. In one case, ingestion of 150 mL of a 20% chlorhexidine gluconate solution resulted in oral cavity edema and significant irritant injury of the esophagus.110 In the same case, liver function tests rose to 30 times normal on the fifth day after ingestion. Liver biopsy showed lobular necrosis and fatty degeneration. Subsequently, the liver function tests normalized. In another case, the ingestion of 30 mL of a 4% solution by an 89-year-old woman did not result in any GI injury.47 Intravenous administration of chlorhexidine is associated with hemolysis, although this may be caused by the hypotonicity of the injected solution.29 Inhalation of vaporized chlorhexidine is reported to cause methemoglobinemia due to the conversion of chlorhexidine to p-chloraniline.175 The rectal administration of 4% chlorhexidine resulted in one patient in acute ulcerative colitis.63 Topical absorption of chlorhexidine is negligible. Contact dermatitis is reported in up to 8% of patients who received repetitive

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topical applications of chlorhexidine.64 More ominously, anaphylactic reactions, including shock, are associated with dermal application.7,123 Eye exposure may result in corneal damage.169 Treatment guidelines for chlorhexidine exposure are similar to those for other potentially caustic agents. Patients with significant symptoms may require endoscopy, but the need for such extensive evaluation is quite uncommon.

THE ALCOHOLS Isopropanol and ethanol are commonly used as skin antiseptics. Sold as rubbing alcohol, the standard concentration for these solutions is usually 70%. Their antiseptic action is thought to be a result of their ability to coagulate proteins. Isopropanol is slightly more germicidal than ethanol.64 These agents have limited efficacy against viruses or spores. Isopropanol tends to be more irritating than ethanol and may cause more pronounced central nervous system depression.178 The greater toxicity of isopropanol has caused some emergency departments to switch rubbing alcohol formulations from isopropanol to ethanol (Chaps. 64 and 66).

CHLORINE AND CHLOROPHORS Chlorine, one of the first antiseptics, is still used in the treatment of the community water supply and in swimming pools. Chlorine is a potent pulmonary irritant and may cause severe bronchospasm and pulmonary edema. Chapter 95 further discusses chlorine. Sodium hypochlorite, found in chlorine bleach (eg, Clorox) and Dakin solution, remains a commonly used disinfectant. First used in the late 1700s to bleach clothes, its utility arises from its oxidizing capability, measured as “available chlorine,” and its ability to release hypochlorous acid slowly. It is used to clean blood spills and to sterilize certain medical instruments. Toxicity from hypochlorite is mainly a result of its irritant effects. The ingestion of large amounts of household liquid bleach (5% sodium hypochlorite) on rare occasions can result in esophageal burns with subsequent stricture formation.51 In a cat model of bleach ingestion, a high incidence of mucosal injury and stricture formation was noted.181 However, the vast majority of household bleach ingestions in humans do not cause significant GI injuries.94,132 Accordingly, aggressive evaluation with endoscopy is usually not warranted when assessing most patients with household liquid bleach ingestions. The ingestion of a more concentrated “industrial strength” bleach preparation increases the likelihood of local tissue injury and should be managed accordingly (Chap. 87). Although direct inhalation of sodium hypochlorite vapors is usually not problematic, the erroneous mixing of sodium hypochlorite bleach with ammonia or acids can lead to the production of toxic vapors resulting in significant pulmonary symptomatology. Mixing sodium hypochlorite (NaOCl) with ammonium hydroxide (NH3OH) produces chloramine; mixing sodium hypochlorite with acid-containing toilet bowl cleaners (eg, hydrochloric acid, phosphoric acid) produces chlorine. When chloramine comes in contact with the moist mucous membranes of the pulmonary tree, hypochlorous acid (HOCl) and oxygen free radicals are produced. Hypochlorous acid subsequently decomposes to hydrochloric acid and oxygen. Chlorine contact with moist airway tissues also produces hypochlorous acid, hydrochloric acid, and oxygen (Chap. 95).

ANTISEPTICS, DISINFECTANTS, AND STERILANTS

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QUATERNARY AMMONIUM COMPOUNDS Quaternary ammonium compounds are a type of cationic surfactant (surface-active agent) used as disinfectants, detergents, and sanitizers. Chemically, the quaternary ammonium compounds are synthetic derivatives of ammonium chloride. They are structurally similar to other quaternary ammonium derivatives, such as the cholinesterase inhibitors (eg, neostigmine) and the neuromuscular blockers (eg, succinylcholine). Other cationic surfactants include the pyridinium compounds and the quinolinium compounds. Benzalkonium chloride (Zephiran) was one of the most commonly employed quaternary ammonium compounds in the past, but with the development of many newer quaternary ammonium compounds over the years, its use has substantially decreased. However, nebulized solutions used for the treatment of asthma, including albuterol and ipratropium bromide, may contain small amounts of benzalkonium chloride. Newer quaternary ammonium compounds are currently used as hospital disinfectants, including Coverage 256, which contains 6% alkyl dimethyl ammonium chloride and 5% octyldecyldimethyl ammonium chloride, and Render, which contains 5% alkyl dimethyl benzyl ammonium chloride. Quaternary ammonium compounds generally have a low order of toxicity as compared to phenol or formaldehyde. Of the infrequent complications that are described, most result from ingestions of benzalkonium chloride. Complications of these ingestions include burns to the mouth and esophagus, CNS depression, elevated liver enzymes, metabolic acidosis, and hypotension.2,174,183 Muscle paralysis is also occasionally described as a complication of these ingestions and is presumably a result of cholinesterase inhibition at the neuromuscular junction.58 Chronic inhalational exposure is associated with occupational asthma.17 Topical use of the quaternary ammonium compounds can cause contact dermatitis.151 Few data are available on the toxicity of the newer quaternary ammonium compound ingestions. Ingestions of other cationic surface-active agents, such as the pyridinium agent cetrimonium bromide (Cetrimide), are associated with caustic burns to the mouth, lips, and tongue.117 Peritoneal irrigation with cetrimonium bromide can produce metabolic abnormalities, hypotension, and methemoglobinemia.9,114 Treatment recommendations following the ingestion of the quaternary ammonium compounds and other cationic surfaceactive agents are similar to those for other potentially caustic ingestions. Emergency department evaluation should be considered for all patients who ingest more than a taste of a dilute (less than 1%) solution. Therapy is mainly supportive. Endoscopy may be warranted if symptoms suggest the possibility of a burn injury.

POTASSIUM PERMANGANATE Potassium permanganate (KMn04) is a violet water-soluble compound that is usually sold as crystals or tablets. Historically, it was used as an abortifacient, urethral irrigant, lavage fluid for alkaloid poisoning, and snakebite remedy. Currently, potassium permanganate is most often used a dermal antiseptic, particularly for patients with eczema. Potassium permanganate is a strong oxidizing agent and poisoning may result in local and systemic toxicity.157 Upon contact with mucous membranes, potassium permanganate reacts with

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

water to form manganese dioxide, potassium hydroxide, and molecular oxygen. Local tissue injury is the result of contact with the nascent oxygen, as well as the caustic effect of potassium hydroxide. A brown-black staining of the tissues occurs from the manganese dioxide. Following ingestion, initial symptoms include nausea and vomiting. Laryngeal edema and ulceration of the mouth, esophagus, and, to a lesser extent, the stomach may result from the caustic effects. Fatal gastrointestinal perforation and hemorrhage may occur.113,125 Esophageal strictures and pyloric stenosis may be late complications. Although potassium permanganate is not well absorbed from the GI tract, systemic absorption may occur, resulting in lifethreatening toxicity. Systemic effects include hepatotoxicity, renal damage, methemoglobinemia, hemolysis, hemorrhagic pancreatitis, acute respiratory distress syndrome, disseminated intravascular coagulation, and cardiovascular collapse.107,113,125 Elevation in blood or serum manganese concentration may also occur, confirming systemic absorption (normal levels: blood manganese 3.9–15.0 µg/L, serum manganese 0.9–2.9 µg/L). Chronic ingestion of potassium permanganate may result in classic manganese poisoning (manganism). A 66-year-old man who mistakenly ingested 10 g of potassium permanganate over a 4-week period (because of medication mislabeling) developed impaired concentration and autonomic and visual symptoms. He also developed abdominal pain, gastric ulceration, and alopecia. Serum manganese was elevated. Nine months later, the patient’s neurologic examination displayed extrapyramidal signs consistent with parkinsonism (Chap. 19).76 Since the consequential effects of KMn04 ingestion are due to its liberation of strong alkalis, the initial treatment of such a patient should include assessment for evidence of airway compromise. For similar reasons, syrup of ipecac–induced emesis is not recommended. Dilution with milk or water may be useful. The use of neutralizing agents, such as egg whites or sodium hypochlorite, is reported but unproved.157 The efficacy of activated charcoal is unknown. Patients with symptoms consistent with caustic injury should undergo early endoscopy. Corticosteroid agents along with antibiotics may be warranted in some cases, especially if laryngeal edema is present. Liver enzymes, BUN, creatinine, amylase, serum manganese, and methemoglobin levels should be performed when systemic toxicity is suspected. Methemoglobinemia should be treated with methylene blue. Dermal irrigation with dilute oxalic acid may be successful in removing cutaneous staining.157

HYDROGEN PEROXIDE Hydrogen peroxide, an oxidizing agent with weak antiseptic properties, has been used for many years as an antiseptic and a disinfectant. This agent is generally available in two strengths: dilute hydrogen peroxide, with a concentration of 3–9% by weight (usually 3%), sold for home use; and concentrated hydrogen peroxide, with a concentration greater than 10%, used primarily for industrial purposes. Commercial-strength hydrogen peroxide is most commonly found as a 27.5–70% solution. Home uses for dilute hydrogen peroxide include ear cerumen removal, mouth gargle, vaginal douche, enema, and hair bleaching. Dilute hydrogen peroxide is also sometimes used as a veterinary emetic. Commercial

uses of the more concentrated solutions include bleaching and cleansing textiles and wool, and producing foam rubber and rocket fuel. In the last few years, 35% hydrogen peroxide became available to the general public in health food stores and is sold as “hyperoxygenation therapy.” This potentially dangerous therapy is touted as a treatment for a variety of conditions, including AIDS and cancer.79 Hydrogen peroxide has two main mechanisms of toxicity: local tissue injury and gas formation. The extent of local tissue injury is determined by the strength of the hydrogen peroxide. Dilute hydrogen peroxide is an irritant and concentrated hydrogen peroxide is a caustic. Gas formation results when hydrogen peroxide interacts with tissue catalase, liberating molecular oxygen and water. While 1 mL of 3% hydrogen peroxide liberates 10 mL of oxygen at standard temperature and pressure, 1 mL of the more concentrated 35% hydrogen peroxide liberates more than 100 mL of oxygen. Gas formation can result in life-threatening embolization. Gas embolization may be due to dissection of gas under pressure into the tissues or may result from liberation of gas in the tissue or blood following absorption. The use of hydrogen peroxide in closed spaces, such as operative wounds, or its use under pressure during wound irrigation, increases the likelihood of embolization. Symptoms consistent with sudden oxygen embolization include rapid deterioration in mental status, cyanosis, acute respiratory failure, seizures, and ischemic ECG changes.52 A 2-year-old boy died after ingesting 4–6 oz (120–180 mL) of 35% hydrogen peroxide.31 Antemortem chest radiograph showed gas in the right ventricle, mediastinum, and portal venous system. Portal vein gas is also a prominent feature in other cases.106 Arterialization of gas oxygen embolization may result in cerebral infarction.150 Bilateral hemispheric infarctions detected by MRI imaging may occur after ingestion of concentrated hydrogen peroxide.80 The combination of local tissue injury and gas formation from the ingestion of concentrated hydrogen peroxide may cause GI disturbances, such as vomiting, hematemesis, abdominal pain, and abdominal bloating.79,106 Endoscopy may show significant gastric mucosal erosions; esophageal injury is usually minimal. Airway compromise manifested by stridor, drooling, apneic episodes, and radiographic evidence of subepiglottic narrowing may occur.44 Death from intravenous injection of 35% hydrogen peroxide is also reported.98 Clinical sequelae from the ingestion of dilute hydrogen peroxide are usually much more benign.44,70 Nausea and vomiting are the most common symptoms.44 A whitish discoloration may be noted in the oral cavity. Gastrointestinal injury is usually limited to superficial mucosal irritation, but multiple gastric and duodenal ulcers, accompanied by hematemesis, are reported.70 Portal venous gas embolization may occur as a result of the ingestion of 3% hydrogen peroxide.32,137 The use of 3% hydrogen peroxide for wound irrigation may result in significant complications. Extensive subcutaneous emphysema occurred after a dog bite to a human’s face was irrigated under pressure with 60 mL of 3% hydrogen peroxide.154 Systemic oxygen embolism, causing hypotension, ischemic ECG changes, and coma, resulted from the intraoperative irrigation of an infected herniorrhaphy wound.12 Gas embolism, resulting in intestinal gangrene, was reported to occur following colonic lavage with 1% hydrogen peroxide during surgical treatment of meconium ileus.149 Multiple cases of acute colitis are reported as a complication of administering 3% hydrogen peroxide enemas.112 The use of 3%

CHAPTER 84

hydrogen peroxide as a mouth rinse is associated with the development of oral ulcerations.139 Ocular exposures may result in conjunctival injection, burning pain, and blurry vision.44 A careful examination should be performed to detect any evidence of gas formation. A chest radiograph may reveal gas in the cardiac chambers, mediastinum, or pleural space. An abdominal radiograph may show gas in the GI tract or portal system and define the extent of bowel distension. MRI and computed tomography (CT) scan may be useful to detect brain lesions secondary to gas embolism.6,80 Endoscopic evaluation may be necessary in patients who ingest concentrated hydrogen peroxide to determine the extent of burn injury. The treatment of patients with hydrogen peroxide ingestions depends to a large degree on whether the patient has ingested a dilute or concentrated solution. Those with ingestions of concentrated solutions require expeditious evaluation. Dilution with milk or water, although unstudied, is unlikely to be helpful. Careful nasogastric aspiration of hydrogen peroxide may be helpful if the patient presents immediately after ingestion. Syrup of ipecac– induced emesis is contraindicated and activated charcoal offers no antidotal benefit. Patients with abdominal distension from gas formation should be treated with nasogastric suctioning. Those with clinical or radiographic evidence of gas in the heart should be placed in the Trendelenburg position to prevent gas from blocking the right ventricular outflow tract. Careful aspiration of intracardiac air through a central venous line may be attempted in patients in extremis.31 Although randomized controlled trials are not available, case reports suggest that hyperbaric therapy may be useful in cases of life-threatening gas embolization after hydrogen peroxide ingestion.106,118 Asymptomatic patients who unintentionally ingest small amounts of 3% hydrogen peroxide can be safely watched at home.

BORIC ACID Boric acid is an odorless, transparent crystal although it is most commonly available as a finely ground white powder. It is also commonly found as a 2.5–5% aqueous solution. Boric acid (H3PO3), prepared from borax (sodium borate; Na2 B4O7•10 H2O), was first used as an antiseptic agent by Lister in the late 19th century. Although used extensively over the years for antisepsis and irrigation, boric acid is only weakly bacteriostatic. As a result of its germicidal limitations and its inherent toxicity, boric acid is obsolete in modern antiseptic therapy. Nonetheless, it continues to be used as an antimicrobial to treat such conditions as vulvovaginal candidiasis.176 Boric acid is also employed in the treatment of cockroach infestation and as a soap, contact lens solution, toothpaste, and food preservative. Boric acid is readily absorbed through the GI tract, wounds, abraded skin, and serous cavities. Absorption does not occur through intact skin. Boric acid is predominantly eliminated unchanged by the kidney. Small amounts are also excreted into sweat, saliva, and feces.53 Boric acid is concentrated in the brain and liver. The exact mechanism of action of boric acid’s toxicity remains unclear. Although it is an inorganic acid, it does not behave as a caustic agent. Local effects are limited to tissue irritation. Over the years, boric acid has developed a reputation as an exceptionally potent toxin. This reputation was derived in great part

ANTISEPTICS, DISINFECTANTS, AND STERILANTS

1289

from a series of reports involving neonatal exposures to boric acid resulting in high morbidity and mortality. Life-threatening toxicity resulted from the repetitive topical application of boric acid for the treatment of diaper rash or the use of infant formulas unintentionally contaminated with boric acid.53,185 Fatality rates greater than 50% were reported in some series.185 Although infants appear to be the most sensitive to the toxic effects of boric acid, many cases of significant adult toxicity are also reported. These cases date predominantly from the time when boric acid was widely used as an irrigant. Routes of exposure to boric acid, resulting in fatalities, include wound irrigation, pleural irrigation, rectal washing, bladder irrigation, and vaginal packing.130,173 Classic boric acid poisoning, as described in these reports, usually involved multiple exposures over a period of days. Gastrointestinal, dermal, CNS, and renal manifestations predominate. The initial symptoms—nausea, vomiting, diarrhea, and occasionally crampy abdominal pain—may be confused with an acute gastroenteritis. At times, the emesis and diarrhea are greenish blue.185 Following the onset of GI symptoms, the majority of patients develop a characteristic intense generalized erythroderma.185 This rash, described as producing a “boiled lobster” appearance, may appear indistinguishable from toxic epidermal necrolysis or staphylococcal scalded skin syndrome in the neonate.144 The rash may be especially noticeable on the palms, soles, and buttocks.53 Typically, extensive desquamation takes place within 1–2 days. At times, prominent mucous membrane involvement of the oral cavity and conjunctivae is also apparent.185 At about the time of the development of the erythroderma, patients, particularly young infants, may develop prominent signs of CNS irritability, resembling meningeal irritation. Seizures, delirium, and coma can occur.53 Renal injury is common, a result of the renal elimination of this compound and prerenal azotemia from GI losses.53 Other complications of boric acid poisoning include hepatic injury, hyperthermia, and cardiovascular collapse.The abandonment of boric acid as an irrigant and particularly its removal from the nursery setting have led to a marked decrease in the incidence of significant boric acid poisoning. Two retrospective studies on boric acid ingestions suggest that a single acute ingestion of boric acid is generally quite benign.100,103 In these studies, 79–88% of patients remained asymptomatic. Symptoms, when present, primarily consist of GI irritative symptoms, such as nausea and vomiting. None of the 1184 patients in these two studies manifested the generalized erythroderma so commonly described in previous reports. Central nervous system manifestations of acute overdose were infrequent and limited to occasional lethargy and headache. Renal toxicity did not occur following single acute ingestions. Several reports suggest, however, that significant toxicity from massive acute ingestion of boric acid can occur. Fatality resulted from a single ingestion of two cups (280 g) of boric acid crystals by a 45-year-old man.140 Symptoms on presentation (two days after ingestion) included nausea, vomiting, green diarrhea, lethargy, hypotension, renal failure, and a prominent “boiled lobster” rash on his trunk and extremities. In another case, the ingestion of 30 g of boric acid by a 77-year-old man resulted in similar symptoms and death 63 hours postingestion, despite hemodialysis.81 Long-term chronic exposure to boric acid results in alopecia in adults and seizures in children.56,127,166 A 32-year-old woman who chronically ingested mouthwash containing boric acid over a

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7-month period developed progressive hair loss.166 The chronic application of a borax and honey mixture to pacifiers resulted in the development of recurrent seizures in nine infants, which resolved after the mixture was withheld.56,127 The diagnoses of boric acid poisoning can be confirmed with the measurement of blood or serum boric acid levels (nl = 1.4 nmol/mL), but this test is not routinely available. Treatment of boric acid toxicity is mainly supportive. Activated charcoal is not recommended because of its relatively poor adsorptive capacity for boric acid.42 In cases of massive oral overdose or renal failure, hemodialysis, or perhaps exchange transfusion in infants, may be helpful in shortening the half-life of boric acid.103,170,185

MERCURIALS Both inorganic mercurials, such as mercury bichloride, and organic mercurials, such as merbromin (Mercurochrome) or thimerosal (Merthiolate), were used in the past as topical antiseptic agents. Thimerosal contains 49% mercury. Their relatively weak bacteriostatic properties, along with the many problems associated with mercury toxicity, significantly limit their usefulness (Chap. 81). Repeated application of topical mercurials may result in significant absorption and systemic toxicity.119,141, The use of high-dose hepatitis B immunoglobulin (HBIG) may cause mercury toxicity because of the use of thimerosal as a preservative in the HBIG preparation.105 In one case, a 44-year-old male patient received 250 mL of HBIG (containing about 30 mg thimerosal) over 9 days following liver transplantation.150 He developed speech difficulties, tremor, and chorea. His blood mercury level was 104 µg/L (normal 450

80 111 144(o), 139(m), 138(p)

31 28 28

40 77 87 121

27 30 27 28

*Direct values for kinematic viscosity in Saybolt seconds universal (SSU) were not available for the following compounds: napththa, xylene, methylene chloride, carbon tetrachloride, trichloroethylene, perchloroethylene, and toluene. SSU was calculated by converting from available measurements in centipoise viscosity and/or centistokes viscosity using the following conversions: the value in centistokes is estimated by dividing centipoise by density at 20°C; SSU is approximated from centistokes using y = 3.2533x + 26.08 (R2 = 0.9998). Centipoise viscosity for naptha was estimated from the value for butylbenzene. Centipoise viscosity for xylene is the average of o-, m-, and p-xlylene.

CHAPTER 86

dustry and in household products. Their toxicities are discussed in Chaps. 64 and 66. Ethers contain an oxygen bound on either side by a carbon atom. Acute toxicity tends to mirror that of the corresponding alcohols. Aldehydes and ketones contain a single carbonoxygen double bond (C=O)—the former at the terminal carbon, the latter somewhere in the middle. Organic acids, esters, amides, and acyl halides represent more oxidized states of carbon; human toxicity is agent specific. Phenols consist of benzene rings with an attached hydroxyl (alcohol) group. The parent compound, phenol, has only one hydroxyl group attached to benzene. The toxicity of phenol can be dramatically altered by addition of other functional groups to the benzene ring (Chap. 84). Cresols, catechols, and salicylate are examples of substituted phenols. A variety of organic amines, amides, nitroso, and nitro compounds, as well as phosphates, sulfites, and sulfates, are used commercially and in industry. The addition of these functional groups to hydrocarbons dramatically alters the toxicity of the compound. Figure 86–1 and Chap. 12 present the chemical structures of some of the more commonly encountered hydrocarbons.

BACKGROUND AND EPIDEMIOLOGY The process of obtaining hydrocarbons from coal involves distillation of bituminous (soft) coal to remove coal gas, which can then be separated into a variety of natural gases. A large amount of distillant residue from the heating process remains as coal tar, which can be separated into kerosene and a variety of other hydrocarbon mixtures. The principal commercial source of hydrocarbons today involves distillation of crude oil. Petroleum is heated to fixed tem-

Figure 86–1.

Basic hydrocarbon structures.

HYDROCARBONS

1305

peratures in a large-scale distillation procedure, allowing separation of hydrocarbons into distillation fractions by vapor (boiling) point. Because of the relationship between boiling point and molecular weight, this process roughly divides substances into likesized mixtures. The most volatile fractions come off early, as gas, and are used primarily for heating. The least volatile fractions (larger than about 10 carbons) are used chiefly for fuel and/or lubricants, paraffins, petroleum jelly, and asphalt. The remaining volatile hydrocarbon fractions (C5 to C10) form the fractions most commonly used as solvents. Longer alkanes are often submitted to an industrial process known as cracking in which they are superheated in a chamber, with catalytic pyrolysis, into shorter-chain alkanes and alkenes. Refineries then typically employ processes such as catalytic isomerization, to increase the amount of branching in the hydrocarbon chain (which increases the “octane” of the fuel), and catalytic reforming, which converts alkanes and cycloalkanes into aromatic compounds.157 Occupations at risk for solvent exposure include petrochemical workers, plastics and rubber workers, printers, laboratory workers, painters, and hazardous waste workers. But exposures are ubiquitous in many occupations, and even in everyday life. In fact, the Occupational Safety and Health Administration estimates nearly 238,000 American workers are exposed annually to significant concentrations of benzene alone.106 Hydrocarbons are so common in our society that exposures and illnesses are typically hidden in databases according to the product implicated, and not merely as “hydrocarbon” or “solvent” exposure. This makes the epidemiology of hydrocarbon exposure and hydrocarbon-related illness particularly difficult to analyze. Because a common property of organic solvents is their volatility, inhalational exposure and even dermal exposure and absorption may occur.94 Most exposure does not involve ingestion—it may range from pumping your own gasoline to painting one’s home or applying or removing fingernail polish. Tables 86–1 and 86–2 list frequently encountered hydrocarbon-containing compounds. In the years 1995–1999, an average of 65,804 annual human exposures to hydrocarbon compounds were reported to American poison centers that contribute to the Toxic Exposures Surveillance System (TESS) database of the American Association of Poison Control Centers (AAPCC). These exposures resulted in an average of 13 deaths per year over the same period, and accounted for 3% of the total human exposures reported to AAPCC. The incidence of both exposures and deaths has not changed dramatically in this database since the first AAPCC report in 1983. Reliably, 40–50% of exposures are unintentional exposures in children younger than 6 years of age. The overwhelming majority of exposures in this age group are categorized as unintentional (page xx and Chap. 116). However, even within the TESS database, many thousands of hydrocarbon exposures are not listed as such, but are ascribed to “chemicals, pesticides, personal care products, cleaning substances, paints, automotive products,” and the like. Certainly these numbers dramatically underestimate North American exposures. Of greater concern is the trend toward increased intentional abuse of volatile solvents by young people. Data from the Monitoring the Future (MTF) study for the National Institute on Drug Abuse (NIDA) indicate that children in 8th to 12th grades have steadily increased their volatile inhalant use since the 1970s. Although this trend has leveled since 1995, as many as 10.3% of 8th graders and 5.6% of 12th graders have tried inhalants. Five percent of 8th graders say they have abused inhalants in the past

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

month. This survey almost certainly underestimates true use patterns, as high school dropouts are not surveyed.116 Similarly, the 1999 National Household Survey on Drug Abuse (NHSDA) estimates that 17 million Americans (7.8%) have abused inhalants at least once. The highest incidence of use is among 12–17-yearolds; but even among adults age 18–25 years, the rate of first use more than doubled between 1990 and 1998 (from 4.6 to 11.2 per 1000 potential new users). Overall, there was an increase of nearly a million new inhalant users in 1998, an increase of 154% over 1990.212 Medical examiner data reported to the Drug Abuse Warning Network (DAWN) from 1993–1998 implicate inhalants, solvents, and aerosols in an average of 135 drug-related deaths per year. These constitute 1.4–1.5% of the annual drug-related deaths reported into this system. While DAWN is biased in receiving the bulk of its reports from the large metropolitan areas, the problem permeates nonurban areas as well.113,202 As is the case in other datasets, children demonstrate particular risk: Although decedents age 6–17 years accounted for only 0.8% of drug mentions, this age group had 6% of mentions of inhalants/solvents/aerosols.225 The only Western nation that routinely tracks deaths from inhalant abuse (Great Britain) documents two deaths per week.175 In summary, three populations appear to be at risk for hydrocarbon-related illness: children with unintentional exposures, often ingestions; workers with occupational exposures, often dermal and inhalational; and adolescents/young adults who intentionally abuse solvents through inhalation.

PHARMACOLOGY Hydrocarbon use has a colorful history in medicine. Essential oils (or volatile oils) are typically fragrant hydrocarbon plant extracts. Examples are menthol, eucalyptus oil, clove oil, sassafras oil, and pennyroyal oil, among others. These oils have been used from antiquity for a variety of medicinal reasons, and are enjoying a resurgence with recent popularity of herbal supplements (Chap. 77). Mineral oil, castor oil, and glycerin are commonly used as laxatives. Hydrocarbon-based ointments, petroleum jelly, and camphor are used topically on skin and mucous membranes. Phenol and substituted phenols are common medical disinfectants (Chap. 84). Diethyl ether and halogenated hydrocarbon compounds such as chloroform were among the first general anesthetics; they were used more than 150 years ago.143,190 Cyclopropane and TCE have been widely used as general anesthetics.143 The toxicity of inhaled hydrocarbon solvent vapors relates primarily to their ability to alter consciousness. In fact, acute central nervous system (CNS) toxicity of solvent vapors in the settings of occupational overexposure or inhalational abuse can be predicted with analogy to the pharmacology of inhaled general anesthetics.198 The concentration of a volatile anesthetic that will produce loss of nociception in 50% of patients is defined as the minimum alveolar concentration (MAC) required to induce anesthesia. Inhaled solvent vapor similarly produces unconsciousness when the agent’s partial pressure in the lung reaches its ED50. Essentially all patients are anesthetized when the partial pressure is increased 30% above the MAC (MAC × 1.3). The dose-response curves suggest that essentially no individual is rendered unconscious by an inhaled dose 30% below the MAC. However, acute impairment of

cognitive and motor function may occur at much lower exposures.24 Lipid-soluble solvents, such as aromatic, aliphatic, or chlorinated hydrocarbons, are more likely to cause both acute and chronic CNS effects than are water-soluble hydrocarbons such as alcohols, ketones, and esters.138 The property of an inhaled anesthetic that correlates most closely with its ability to extinguish nociception is its lipid solubility.95 The Meyer-Overton hypothesis, proposed more than 100 years ago, implies that an anesthetic agent dissolves into some crucial lipid compartment of the CNS, causing inhibition of neuronal transmission.143 Unfortunately, this hypothesis really correlates agent characteristics with efficacy more than it elucidates a mechanism of action. This relationship may simply reflect delivery of the agent to its effector site(s), and may have little bearing on the therapeutic or toxic mechanism within the CNS. On the other hand, the lack of specific structural similarities or functional groups between various hydrocarbons, all of which induce similar clinical CNS effects, implies a non-receptor-mediated mechanism of action. Nonspecific inhibition of neuronal transmission through membrane or membrane protein conformational changes may occur.187,195 At least some hydrocarbons may have specific cellular sites of action within the CNS.17 Volatile anesthetics, for example, can affect ligand-gated ion channels. They interact with acetylcholine receptors to increase neurotransmitter binding75 and to potentiate nicotinic blockade.30 They stimulate γ-amino butyrate (GABAA) activity,135,154 as do toluene and trichloroethane (TCE),22 and they inhibit GABA catabolism.48 Some agents stimulate glutamate release.103 Toluene, on the other hand, inhibits neurotransmission at glutamate N-methyl-D-aspartate receptors. Toluene and TCE enhance glycine receptor function. Prolonged exposure to toluene can perturb dopaminergic transmission.22 General anesthetic effects are modulated by adenosine192 and by central 2-adrenergic agonism.191 This line of mechanistic research suggests that the Meyer-Overton hypothesis may be too simplistic to explain the differences in pharmacologic profiles observed with this wide class of specific chemicals.

TOXICOKINETICS Human toxicokinetic data are lacking for most hydrocarbons, and much of our understanding of the kinetics of this large family of chemicals comes from animal studies. Hydrocarbons are variably absorbed through ingestion, inhalation, or dermal routes of exposure, depending on their structure and chemical properties. Partition coefficients, in particular, are useful predictors of the rate and extent of the absorption and distribution of hydrocarbons into tissues. A partition coefficient for a given chemical is the ratio of concentrations achieved between two different media at equilibrium. The blood:air and tissue:air or tissue:blood coefficients directly relate to the pulmonary uptake and distribution of hydrocarbons. The tissue:blood partition coefficient is commonly determined by dividing the tissue:air coefficient by the blood:air coefficient.81,172 Table 86–3 presents partition coefficients for commonly encountered hydrocarbons. Where human data are limited, rat data are presented in the table. However, human and rat data correlate closely.172 Inhalation is a major route of exposure for most volatile hydrocarbons. The dose through the respiratory route is determined by

CHAPTER 86

TABLE 86–3.

HYDROCARBONS

1307

Kinetic Parameters of Selected Hydrocarbons

Agent

Aliphatics n-Hexane Paraffin/tar Aromatics Benzene

Partition Coefficients Blood/Air

Fat/Air

2.29*

159*

t 1⁄2


11 min

99 min

8h

90 h

18.0*

1021*

4–5 h

15–72 h

34.9

1877*

30–60 min

20–30 h

8.94

120*

Apparent t1/2 of COHb 13 h

40 min

Carbon tetrachloride

2.73

359*

84–91 min*

91–496 min*

TCE

8.11

554*

3h

30 h

2.53 10.3

263* 1638*

44 min 160 min

53 h 33 h

1, 1, 1- Trichloroethane Tetrachloroethylene

10–20% exhaled; liver metabolism by P450

2–Hexanol, 2, 5-hexanedione, -valerolactone

12% exhaled; liver metabolism to phenol Extensive liver extraction and metabolism Liver P450 oxidation

Phenol, catechol, hydroquinone, and conjugates 80% metab. to benzyl alchol; 70% renally excreted as hippuric acid Toluic acid, methyl hippuric acid

Not absorbed or metabolized 499*

o-Xylene Halogenated Methylene chloride

Relevant Metabolites



8.19

Toluene

Elimination

92% exhaled unchanged. (a) P4502E1 to CO and CO2 Low doses metabolized; (b) Glutathione transferase to CO2, high doses exhaled. formaldehyde, formic acid Two liver metabolic pathways Liver P450, some lung Trichloromethyl radical, trichloromethyl exhalation (doseperoxy radical, phosgene dependent) Liver P450—epoxide intermediate; trichloroethanol is glucuronidated and excreted 91% exhaled; liver P450 80% exhaled; liver P450

Chloral hydrate, trichloroethanol, trichloroacetate

Trichloroacetate, trichloroethanol Trichloroacetate, trichloroethanol

*Noted: Fat/blood partition coefficient is obtained by dividing the fat/air coefficient by the blood/air coefficient. As determined in rat models. All coefficients are determined at 37°C (98.6°F).

the air concentration, duration of exposure, minute ventilation, and the blood:air partition coefficient. Most hydrocarbons cross the alveolus through passive diffusion. The driving force for passive diffusion across the alveolus is the difference in vapor concentration between the alveolus and the blood. Hydrocarbons that are highly soluble in blood and tissues are readily absorbed through inhalation, and blood concentrations rise rapidly following inhalation exposure. Although aromatic hydrocarbons are generally well absorbed through inhalation, for aliphatic hydrocarbons, absorption through inhalation varies by molecular weight; aliphatic hydrocarbons with between 5 and 16 carbons are readily absorbed, whereas those with more than 16 carbons are not as readily absorbed.3 Absorption of aliphatic hydrocarbons through ingestion is inversely related to molecular weight, ranging from complete absorption at lower molecular weights to about 60% for C14 hydrocarbons, 5% for C28 hydrocarbons, and essentially no absorption for aliphatic hydrocarbons with >32 carbons.3 Oral absorption of aromatic hydrocarbons with between 5 and 9 carbons ranges from 80% to 97%. Oral absorption data for aromatic hydrocarbons with greater than 9 carbons are limited. While some hydrocarbons can be absorbed from the gastrointestinal tract in amounts sufficient to produce systemic toxicity, it is imperative to weigh the oral toxicity (oral LD50) of the hydrocarbon against the aspiration hazard (intratracheal LD50) when considering gastric decontamination.

While the skin is a common area of contact with solvents, for most hydrocarbons the dose received from dermal exposure is a small fraction of the dose received through other routes, such as inhalation. The skin is composed of both hydrophilic (proteinaceous portion of cells) and lipophilic (cell membranes) regions. While many hydrocarbons can remove lipids from the stratum corneum, permeability is not simply a result of lipid removal; permeability is also increased with hydration of the skin. When compounds have near equality in the water/lipid partition coefficient, their rate of skin absorption is increased. Solvents that contain both hydrophobic and hydrophilic moieties (eg, glycol ethers, dimethylformamide, dimethylsulfoxide) are particularly well absorbed.138 Other factors, in addition to the partition coefficient and permeability constant, that determine penetration across the skin include the thickness of the skin layer, the difference in concentration of the solvent on both sides of the epithelium, the diffusion constant, and skin integrity (ie, normal vs cut or abraded). The dose received via skin absorption also depends on the surface area of the skin exposed and the duration of contact. Although highly volatile compounds may have a short duration of skin contact because of evaporation, skin absorption can also occur from contact with hydrocarbon vapor. In studies with human volunteers exposed to varying concentrations of hydrocarbon vapors, the dermal dose accounted for only 0.1–2% of the inhalation dose. With massive exposure (eg, immersion), dermal absorption may contribute significantly to toxicity.94 Significant absorption

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with resultant toxicity has been described with carbon tetrachloride,115 tetrachloroethylene,94 and phenol.134 After they are absorbed into the central compartment, hydrocarbons are distributed to target and storage organs based on their tissue:blood partition coefficients and on the rate of perfusion of the tissue with blood. During the onset of systemic exposure, hydrocarbons accumulate in tissues, such as fat, that have coefficients between tissue and blood that are greater than 1 (eg, for toluene, the fat:blood partition coefficient is 60). Table 86–3 presents the distribution half-lives of selected hydrocarbons. Hydrocarbons can be eliminated from the body unchanged, eg, through expired air, or can be metabolized to more polar compounds, which are then excreted through urine or bile. Table 86–3 presents the blood elimination half-lives (for first-order elimination processes) and metabolites of selected hydrocarbons. Some hydrocarbons are metabolized to toxic metabolites (eg, methylene chloride, carbon tetrachloride, n-hexane, methyl-n-butyl ketone). The specific toxicities of these metabolites are discussed under “Special Cases,” later in this chapter.

PATHOPHYSIOLOGY Pulmonary For years, the medical literature held the stage for debate over the pathogenesis of lung injury after hydrocarbon exposure. Early investigators debated whether pulmonary toxicity was caused by gastrointestinal absorption of hydrocarbons with subsequent pulmonary toxicity, or caused by direct aspiration into pulmonary parenchyma.28,60,66,82,105,133,177,180,233 The rat and baboon models made it clear that hydrocarbons are absorbed in the gastrointestinal tract and can be recovered from lung and many other tissues.15,140 Based upon the amounts absorbed in these animal studies, however, the volume of ingested hydrocarbon needed to cause pulmonary toxicity is enormous. A number of other animal models (dogs, monkeys, and baboons) employing gastric instillation of hydrocarbon demonstrated lack of pulmonary toxicity when aspiration did not occur.63,105,242,248 It is currently held that aspiration is the main route of injury from ingested hydrocarbons. The mechanism of pulmonary injury, however, is not completely understood. Intratracheal instillation of small amounts (0.2 mL/kg) of kerosene causes physiologic abnormalities in lung mechanics (decreased compliance and total lung capacity) and pathologic changes such as interstitial inflammation, polymorphonuclear exudates, intra-alveolar edema and hemorrhage, hyperemia, bronchial and bronchiolar necrosis, and vascular thrombosis.82,83,92,100,184,185 These changes most likely reflect both direct toxicity to pulmonary tissue and disruption of the lipid surfactant layer.86,193,240 Several factors are associated with pulmonary toxicity after hydrocarbon ingestion. These include specific physical properties of the hydrocarbon ingested (Table 86–2) and historical information involving the volume ingested and the occurrence of vomiting. The properties of viscosity, surface tension, and volatility of a particular hydrocarbon are the main determinants of its aspiration potential (Table 86–2).84,105 Viscosity is the measurement of a fluid’s resistance to flow. Kinematic viscosity is the absolute viscosity divided by the fluid’s density, usually expressed in stokes or in centistokes (mm2/sec).

One method of quantifying viscosity is by the agent’s rate of flow through a calibrated orifice. This is measured in Saybolt seconds universal (SSU). At a given temperature, viscosity values can be converted from SI units of kinematic viscosity (eg, the stoke or the centistoke) to SSU. Substances with low viscosities (SSU 5% body surface area burn, electrocardiographic monitoring and large-bore intra-

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venous access should be established, and laboratory studies sent for calcium, magnesium, serum electrolytes, type, cross-match, and coagulation profiles. Topical calcium gel should be applied to the affected area. This is prepared by mixing 3.5 g of calcium gluconate powder in 5 ounces of sterile water-soluble lubricant, or 25 mL of 10% calcium gluconate in 75 mL of sterile water-soluble lubricant.5,23,84 If calcium gluconate is unavailable, calcium chloride or calcium carbonate can be used in a similar formulation.29 If none of these are available, a sterile magnesium solution (3.48 g of magnesium gluconate in 5 ounces of lubricating jelly) has also demonstrated some efficacy in the treatment of HF burns.23 Topical therapy for both severe and non-life-threatening exposures may scavenge the fluoride ions prior to dermal penetration. An animal study examining the efficacy and mechanism of topical calcium gel therapy found the fluoride ion concentration of the gel significantly higher than in the non-calcium-containing gel controls. Although a limited study, these animals also had a decrease in urinary fluoride ion concentration as compared to controls, suggesting less overall absorption of the HF into the tissues.92 Quaternary ammonium compounds, such as topical benzalkonium chloride, have also been advocated in the treatment of HF burns and can be used when available112; however, calcium-containing gels appear to be more efficacious. Intradermal injection of calcium and magnesium salts and intravenous infusions of magnesium may also be therapeutic. Hand exposures are by far the most common presentation of hydrofluoric acid exposure. Several therapy options have been studied and described in animal models for treatment of topical HF burns. Unfortunately, many study designs use histologic or subjective wound inspection as outcome parameters,23,146 some with unblinded inspection.20,47,91,92 These animal models do not address the parameters of pain reduction, cosmesis, and functionality that are important clinically. There are four types of therapies that have had variable success in human exposures. These include the application of calcium via topical, intradermal, intravenous, and intra-arterial routes. After irrigation, a gel solution of calcium carbonate or gluconate can be mixed directly into a sterile surgical glove and then placed onto the patient’s hand for 30 minutes. Two case series report limited success with this therapy.5,29 Some patients describe prompt and dramatic relief of pain within minutes. Magnesium hydroxide and magnesium gluconate gel used in rabbit models also show some histologic evidence of efficacy,23 but their use has not been reported in humans. Alternatively or simultaneously, analgesics can be administered orally or intravenously as needed, but preferably not to the point of sedation, because local pain response will guide therapy. Digital blocks with subcutaneous lidocaine or bupivacaine can be used for patients presenting 12–24 hours after the injury from a low concentration of HF and no systemic signs of toxicity.46 All patients with digital exposures should be observed over 4–6 hours, as the pain is likely to recur and reapplication of the gel or alternative therapy may be necessary. In addition, wound margins may become apparent and require débridement, and even if successful pain control is achieved, the patient will require specialized followup or wound care. If topical gel therapy fails within the first few minutes of application, consideration should be given to intradermal therapy with calcium gluconate, because the benefit in pain control often occurs immediately. This treatment may have limited utility, however, in small spaces, such as fingertips. Histologic studies in animal mod-

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els demonstrate that 10% calcium chloride solution can be damaging to the tissues and should be avoided.46,67 The preferable method is to approach the wound from a distal point of injury and inject intradermally no more than 0.5 mL/cm2 of 5% calcium gluconate. One author recommends a palmar fasciotomy whenever this method of treatment is used.5 This seems extreme, and is not currently recommended unless a compartment syndrome is present, as the potential for iatrogenic injury is increased. The limits of intradermal injection include potential to increase soft-tissue damage without adequate relief, infection, and inadequate space to safely inject without causing a compartment syndrome. This is especially problematic under the nail. Some authors have recommended removal of the nail. This has some advantages in accessing the affected area; however, it is a painful procedure that is often cosmetically undesirable and the outcome is not always significantly improved. If the wound is large or in a section of the fingerpad or an area that is not amenable to intradermal injections, then consideration should be given to the use of intra-arterial calcium gluconate. This procedure delivers calcium directly to the affected tissue from a proximal artery. Placement should be ipsilateral and proximal to the affected area, usually in the radial or brachial artery. The method of obtaining access is somewhat debated. Because of the potential to sclerose and damage the endothelial lining of the artery, and because extravasation can have potentially devastating consequences, the placement of an intra-arterial infusion line was originally recommended with confirmation of an arteriogram or placement under direct visualization of the vessel. This is still recommended in cases in which cannulation of the artery is expected to be difficult because of prior surgery or deformity. If the arterial line is carefully placed in a single attempt, and a good confirmatory arterial tracing is obtained, the infusate can be started. The recommended drip consists of 10 mL of 10% calcium gluconate in either 40 mL of D5W or normal saline to run over 4 hours.5,90,148,173,190,191 This gives a 2% calcium gluconate solution for arterial infusion. An animal model examined the effect of undiluted 10% calcium gluconate intra-aortically in rats. Although the model did not include HF, there was significant tissue injury in the vessel wall as compared to 2% calcium gluconate.46 Calcium chloride has also been used successfully, although the potential for vessel injury may increase and complications of calcium chloride extravasation can lead to significant tissue necrosis itself.189,206 The overall complications of intra-arterial calcium infusion in several case series were relatively benign, including radial artery spasm, hematoma, and inflammation at the puncture site, and, in some cases, a fall in serum magnesium.173,190 After the drip is initiated, patients typically experience significant pain relief. Patients requiring an arterial line for treatment should be admitted to the hospital, as the majority will require more than one treatment, and some patients may require as many as five separate infusions of calcium gluconate. In addition, wounds may require débridement,5 and one author suggests that after the drip, tissue can be salvaged that initially would not have been considered viable.191 There have been no reported cases of clinically significant hypercalcemia with this therapy, although serum calcium levels were not recorded in every series. Other reported therapies have included an intravenous Bier block technique that uses 25 mL of 2.5% calcium gluconate. The effects lasted 5 hours and there were no adverse events.70 This technique is not reported as being used in a substantial number of patients, and has yet to be studied as an alternative therapy.

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A rabbit model of empiric intravenous magnesium therapy for the management of dermal HF burns suggested an efficacy for wound healing when compared to untreated controls.37 Another animal model suggested a potential benefit to wound healing with empiric therapy as well.199 Both of these models are limited, and this therapy has never been well examined in humans. An approach of both local and systemic therapy with calcium and magnesium may be required to provide adequate relief for patients with HF hand injuries.

SUMMARY Assessing the severity of injuries in patients with caustic exposures can be clinically challenging. For all ingestions, primary consideration should be given to airway assessment and stabilization. The clinician must then consider multiple bedside, laboratory and radiographic factors to decide how best to inspect the tissues of the gastrointestinal tract. Ideally, the gastroenterologists and surgeons are involved in the care of the patient early, so that any surgical intervention deemed necessary can be performed promptly. Other types of exposures to the skin and eyes require rapid decontamination with simple irrigants such as normal saline solution. Household and industrial exposures to caustic agents constitute a potentially life-threatening global health concern. Public health efforts to decrease access to high concentrations of caustic agents should be encouraged, especially in developing nations.

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92. Kono K, Yoshida Y, Watanabe M, et al: An experimental study on the treatment of hydrofluoric acid burns. Arch Environ Contam Toxicol 1992;22:414–418. 93. Kost KM, Shapiro RS: Button battery ingestion—A case report and review of the literature. J Otolaryngol 1987;16:252–254. 94. Krenzelok EP: Liquid automatic dishwashing detergents: A profile of toxicity. Ann Emerg Med 1989;18:60–63. 95. Kuhn JR, Tunell WP: The role of cineesophagoscopy in caustic esophageal injury. Am J Surg 1983;146:804–806. 96. Kulig K, Rumack C, Rumack B, Duffy J: Disk battery ingestion— Elevated urine mercury levels and enema removal of battery fragments. JAMA 1983;249:2502–2504. 97. Kwok MC, Svancarek WP, Creer M: Fatality due to hydrofluoric acid exposure. J Toxicol Clin Toxicol 1987;25:333–339. 98. Lacouture PG, Gaudreault P, Lovejoy FH: Clinitest tablet ingestion: An in vitro investigation concerned with initial emergency management. Ann Emerg Med 1986;15:143–146. 99. Lahoti D, Broor SL, Basu P, et al: Corrosive esophageal strictures: Predictors of response to endoscopic dilatation. Gastrointest Endosc 1995;41:196–200. 100. Landau GD, Saunders WH: The effect of chlorine bleach on the esophagus. Arch Otolaryngol 1964;80:174–176. 101. Leape LL, Ashcraft KW, Scarpelli DG, Holder TM: Hazard to health—Liquid lye. N Engl J Med 1971;284:578–581. 102. Lee DC, Wiley JF, Snyder JW: Treatment of inhalational exposure to hydrofluoric acid with nebulized calcium gluconate [letter]. J Occup Med 1993;35:470. 103. Leonard LG, Scheulen JJ, Munster AM: Chemical burns: Effect of prompt first aid. J Trauma 1982;22:420–423. 104. Lepke S, Paasow H: Effects of fluoride on potassium and sodium permeability of the erythrocyte membrane. J Gen Physiol 1968;51: 365S–372S. 105. Lidbeck WL, Hill IB, Beeman JA: Acute sodium fluoride poisoning. JAMA 1943;121:826–827. 106. Litovitz T, Butterfield AB, Holloway RR, Marion LI: Battery ingestion: Assessment of therapeutic modalities and battery discharge state. J Pediatr 1984;105:868–873. 107. Litovitz T, Schmitz BF: Ingestion of cylindrical and button batteries: An analysis of 2382 cases. Pediatrics 1992;89:747–757. 108. Liu A, Richardson M, Robertson WO: Effects of N-acetylcysteine on caustic burns. Vet Hum Toxicol 1985;28:316. 109. Lowe JE, Graham DY, Boisaubin EV, Lanza FL: Corrosive injury to the stomach: The natural history and role of fiberoptic endoscopy. Am J Surg 1979;137:803–806. 110. Mack RB: Decant the wine, prune back your long-term hopes. N C Med J 1987;48:593–595. 111. MacKinnon MA: Hydrofluoric acid burns. Dermatol Clin 1988;6: 67–74. 112. MacKinnon MA: Treatment of hydrofluoric acid burns [letter]. J Occup Med 1986;28:804. 113. Madden JW, Davis WM, Butler C, Peacock EE: Experimental esophageal lye burns II: Correcting established strictures with beta-aminoproprionitrile and bougienage. Ann Surg 1973;178: 277–284. 114. Mallory A, Schaefer JW: Clinitest ingestion. Br Med J 1977;2: 105–107. 115. Mandarikan BA: Ingestion of dishwasher detergent by children. Br J Clin Pract 1990;44:35–36. 116. Manoguerra AS, Neuman TS: Fatal poisoning from acute hydrofluoric acid ingestion. Am J Emerg Med 1986;4:362–363. 117. Martel W: Radiologic features of esophagogastritis secondary to extremely caustic agents. Diagn Radiol 1972;103:31–36. 118. Maull KI, Osmand AP, Maull CD: Liquid caustic ingestions: An in vitro study of the effects of buffer, neutralization, and dilution. Ann Emerg Med 1985;14:1160–1162. 119. Maull KI, Scher LA, Greenfield LJ: Surgical implications of acid ingestion. Surg Gynecol Obstet 1979;148:895–898.

120. Maves MD, Carrithers JS, Brick HG: Esophageal burns secondary to disc battery ingestion. Ann Otol Rhinol Laryngol 1984;93:364–369. 121. Mayer L, Guelich J: Hydrogen fluoride (HF) inhalation and burns. Arch Environ Health 1963;7:445–447. 122. Mayer TG, Gross PL: Fatal systemic fluorosis due to hydrofluoric acid burns. Ann Emerg Med 1985;14:149–153. 123. McClure FJ: A review of fluorine and its physiologic effects. Physiol Rev 1933;13:277–300. 124. McCulley JP, Whiting DW, Petitt MG, Lauber SE: Hydrofluoric acid burns of the eye. J Occup Med 1983;25:447–450. 125. McIvor ME: Delayed fatal hyperkalemia in a patient with acute fluoride intoxication. Ann Emerg Med 1987;16:1165–1167. 126. McIvor M, Baltazar RF, Beltran J, et al: Hyperkalemia and cardiac arrest from fluoride exposure during hemodialysis. Am J Cardiol 1983; 51:901–902. 127. McIvor ME, Cummings CE, Mower MM, et al: Sudden cardiac death from acute fluoride intoxication: The role of potassium. Ann Emerg Med 1987;16:777–781. 128. McKinney PE: Zinc chloride ingestion in a child—Exocrine pancreatic insufficiency. Ann Emerg Med 1995;25:562. 129. McKinney PE, Brent J, Kulig K: Acute zinc chloride ingestion in a child—Local and systemic effects. Ann Emerg Med 1994;23: 1383–1387. 130. McNeely MDD: Urinalysis. In: Sonnenwirth AC, Jarrett L, eds: Gradwohl’s Clinical Laboratory Methods and Diagnosis. St. Louis, Mosby, 1980, p. 483. 131. Menchel SM, Dunn WA: Hydrofluoric acid poisoning. Am J Forensic Med Pathol 1984;5:245–248. 132. Meredith W, Kon ND, Thompson JN: Management of injuries from liquid lye ingestion. J Trauma 1988;28:1173–1180. 133. Middelkamp JN, Ferguson TB, Roper CL, Hoffman FD: The management and problems of caustic burns in children. J Thorac Cardiovasc Surg 1969;57:341–347. 134. Mills LJ, Estrera AS, Platt MR: Avoidance of esophageal stricture following severe caustic burns by the use of an intraluminal stent. Ann Thorac Surg 1979;28:63–65. 135. Mitani M, Hirata K, Fukuda M, Kaneko M: Endoscopic ultrasonography in corrosive injury of the upper gastrointestinal tract by hydrochloric acid. J Clin Ultrasound 1996;24:40–42. 136. Moazam F, Talbert JL, Miller D, Mollitt DL: Caustic ingestion and its sequelae in children. South Med J 1987;80:187–190. 137. Morris JB, Smith FA: Regional deposition and absorption of inhaled hydrogen fluoride in the rat. Toxicol Appl Pharmacol 1982;62: 81–89. 138. Mozingo DW, Smith AA, McManus WF, et al: Chemical burns. J Trauma 1988;28:642–647. 139. Muhletaler CA, Gerlock AJ, de Soto L, Halter SA: Acid corrosive esophagitis: Radiographic findings. Am J Radiol 1980;134: 1137–1140. 140. Mutaf O, Avanoglu A, Ozok G: Management of tracheoesophageal fistula as a complication of esophageal dilatations in caustic esophageal burns. J Pediatr Surg 1995;30:823–826. 141. Noonan T, Carter EJ, Edelman PA, Zawacki BE: Epidermal lipids and the natural history of hydrofluoric acid (HF) injury. Burns 1994;20:202–206. 142. Norton RA: Esophageal and antral strictures due to ingestion of household ammonia—Report of two cases. N Engl J Med 1960;262: 10–12. 143. Ochi K, Ohashi T, Sato S, et al: Surgical treatment for caustic ingestion injury of the pharynx, larynx, and esophagus. Acta Otolarygol 1996;522(Suppl):116–119. 144. O’Connor HJ, Dixon MF, Grant AC, et al: Fatal accidental ingestion of Clinitest in an adult. J R Soc Med 1984;77:963–965. 145. O’Neil K: A fatal hydrogen fluoride exposure. J Emerg Nurs 1994; 20:451–453. 146. Paley A, Seifter J: Treatment of experimental hydrofluoric acid corrosion. Proc Soc Exp Biol Med 1941;46:190–192.

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147. Payten RJ: Clinitest tablet stricture of the esophagus. Br Med J 1972;4:728–729. 148. Pegg SP, Siu S, Gillett G: Intra-arterial infusions in the treatment of hydrofluoric acid burns. Burns 1985;11:440–443. 149. Penner GE: Acid ingestion—Toxicology and treatment. Ann Emerg Med 1980;9:374–379. 150. Potter JL: Acute zinc chloride ingestion in a young child. Ann Emerg Med 1981;10:267–269. 151. Previtera C, Guisti F, Guglielmi M: Predictive value of visible lesions (cheeks, lips, oropharynx) in suspected caustic ingestion: May endoscopy reasonably be omitted in completely negative pediatric patients? Pediatr Emerg Care 1990;6:176–178. 152. Ragheb MI, Ramadan AA, Khalia MA: Management of corrosive esophagitis. Surgery 1976;79:494–498. 153. Ray JF III, Myers WO, Lawton BR, et al: The natural history of liquid lye ingestion—Rationale for an aggressive surgical approach. Arch Surg 1974;109:436–439. 154. Reyes HM, Hill JL: Modification of the experimental stent technique for esophageal burns. J Surg Res 1976;20:65–70. 155. Reyes HM, Lin CY, Schlunk FF, Repogle RL: Experimental treatment of corrosive esophageal burns. J Pediatr Surg 1974;9:317–327. 156. Reynolds KE, Whitford GM, Pashley DH: Acute fluoride toxicity: The influence of acid-base status. Toxicol Appl Pharmacol 1978;45: 415–427. 157. Ribet ME: Esophagogastrectomy for acid injury. Ann Thorac Surg 1992;53:738–742. 158. Ritter FN, Newman MH, Newman DE: A clinical and experimental study of corrosive burns of the stomach. Ann Otol Rhinol Laryngol 1968;77:830–842. 159. Rivera EA, Maves MD: Effects of neutralizing agents on esophageal burns caused by disk batteries. Ann Otol Rhinol Laryngol 1987;96: 362–366. 160. Rose L: Further evaluation of hydrofluoric acid burns to the eye [letter]. J Occup Med 1984;26:483. 161. Rosenberg N, Kunderman PJ, Vroman L, Moolten SE: Prevention of experimental esophageal stricture by cortisone II. Arch Surg 1953;66:593–598. 162. Rubinfeld RS, Silbert DI, Arentsen JJ, Laibson PR: Ocular hydrofluoric acid burns. Am J Ophthalmol 1992;114:420–423. 163. Rumack BH, Burrington JD: Caustic ingestions: A rational look at diluents. Clin Toxicol 1977;11:27–34. 164. Rumack CM, Rumack BH: Battery ingestions. Pediatrics 1992;89: 771–772. 165. Sadove R, Hainsworth D, Van Meter W: Total body immersion in hydrofluoric acid. South Med J 1990;83:698–700. 166. Safarti E, Gossot D, Assens P, Celerier M: Management of caustic ingestion in adults. Br J Surg 1987;74:146–148. 167. Schild JA: Caustic ingestion in adult patients. Laryngoscope 1985; 95:1199–1201. 168. Scott JC, Jones B, Eisele DW, Ravich WJ: Caustic ingestion injuries of the upper aerodigestive tract. Laryngoscope 1992;102:1–8. 169. Shabino CL, Feinberg AN: Esophageal perforation secondary to alkaline battery ingestion. JACEP 1979;8:360–362. 170. Sheikh A: Button battery ingestions in children. Pediatr Emerg Care 1993:224–229. 171. Sheridan RL, Ryan CM, Quinby WC Jr, et al: Emergency management of major hydrofluoric acid exposures. Burns 1995;21:62–64. 172. Shirazi S, Schulze-Delrieu K, Custer-Hagen T, et al: Motility changes in opossum esophagus from experimental esophagitis. Dig Dis Sci 1989;34:1668–1676. 173. Siegel DC, Heard J: Intra-arterial calcium infusion for hydrofluoric acid burns. Aviat Space Environ Med 1992;63:206–211. 174. Sigalet D, Lees G: Tracheoesophageal injury secondary to disc battery ingestion. J Pediatr Surg 1988;23:996–998. 175. Sinar DR, Fletcher JR, Cordova CC, et al: Acute acid-induced esophagitis impairs esophageal peristalsis in baboons. Gastroenterology 1981;80:1286.

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176. Souba WW: Nutritional support. N Engl J Med 1997;336:41–48. 177. Spiller HA, Quadrani-Kushner DA, Cleveland P: A five-year evaluation of acute exposures to phenol disinfectant (26%). J Toxicol Clin Toxicol 1993;31:307–313. 178. Stremski ES, Grande GA, Ling LJ: Survival following hydrofluoric acid ingestion. Ann Emerg Med 1992;21:1396–1399. 179. Subbarao KSVK, Kakar AK, Chandrasekhar V, et al: Cicatricial gastric stenosis caused by corrosive ingestion. Aust N Z J Surg 1988;58: 143–146. 180. Sugawa C, Lucas CE: Caustic injury of the upper gastrointestinal tract in adults: A clinical and endoscopic study. Surgery 1989;106: 802–807. 181. Sugawa C, Mullins RJ, Lucas CE, Leibold WC: The value of early endoscopy following caustic ingestion. Surg Gynecol Obstet 1981; 153:553–556. 182. Tenenbein M: Whole-bowel irrigation for toxic ingestions. J Toxicol Clin Toxicol 1985;23:177–184. 183. Tepperman PB: Fatality due to acute systemic fluoride poisoning following a hydrofluoric acid skin burn. J Occup Med 1980;22: 691–692. 184. Tewfik TL, Schloss MD: Ingestion of lye and other corrosive agents— A study of 86 infant and child cases. J Otolaryngol 1980;9: 72–77. 185. Thompson JN: Corrosive esophageal injuries I: A study of nine cases of concurrent accidental caustic ingestions. Laryngoscope 1987;97: 1060–1066. 186. Thompson JN: Corrosive esophageal injuries II: An investigation of treatment methods and histochemical analysis of esophageal strictures in a new animal model. Laryngoscope 1987;97:1191–1202. 187. Trevino MA, Hermann GH, Sprout WL: Treatment of severe hydrofluoric acid exposures. J Occup Med 1983;25:861–863. 188. Upfal M, Doyle C: Medical management of hydrofluoric acid exposure. J Occup Med 1990;32:727–731. 189. Upton J, Mulliken JB, Murray JE: Major intravenous extravasation injuries. Am J Surg 1979;137:497–506. 190. Vance MV, Curry SC, Kunkel DB, et al: Digital hydrofluoric acid burns: Treatment with intraarterial calcium infusion. Ann Emerg Med 1986;15:890–896. 191. Velvart J: Arterial perfusion for hydrofluoric acid burns. Hum Toxicol 1983;2:233–238. 192. Viscomi GJ, Beekhuis GJ, Whitten CF: An evaluation of early esophagoscopy and corticosteroid therapy in the management of corrosive injury of the esophagus. J Pediatr 1961;59:356–360. 193. Votteler TP, Nash JC, Rutledge JC: The hazard of ingested alkaline disc batteries in children. JAMA 1983;249:2504–2506. 194. Warren JB, Grifin DJ, Olson RC: Urine sugar reagent tablet ingestion causing gastric and duodenal ulceration. Arch Intern Med 1984;144:161–162. 195. Webb WR, Koutras P, Ecker RR, Sugg WL: An evaluation of steroids and antibiotics in caustic burns of the esophagus. Ann Thorac Surg 1970;9:95–101. 196. White JE, McClafferty K, Orfon RB, et al: Ocular alkali burn associated with automobile air bag activation. Can Med Assoc J 1995;153: 933–934. 197. Wiesskopf A: Effects of cortisone on experimental lye burn of the esophagus. Ann Otol Rhinol Laryngol 1952;61:681–691. 198. Wijburg FA, Beukers MM, Heymans HS, et al: Nasogastric intubation as sole treatment of caustic esophageal lesions. Ann Otol Rhinol Laryngol 1985;94:337–341. 199. Williams JM, Hammad A, Cottington EC, Harchelroad FC: Intravenous magnesium in the treatment of hydrofluoric acid burns in rats. Ann Emerg Med 1994;23:464–469. 200. Wilson DAB, Wormald PJ: Battery acid—An agent of attempted suicide in black South Africans. S Afr Med J 1994;84:529–531. 201. Wilson JA, Phillips EM: Endoscopic retrieval of a miniature battery [letter]. Gut 1985;26:215. 202. Wing JS, Sanderson LM, Brender JD, et al: Acute health effects in a community after a release of hydrofluoric acid. Arch Environ Health 1991;46:155–159.

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203. Woodring JH, Heiser MJ: Detection of pneumoperitoneum on chest radiographs: Comparison of upright lateral and posteroanterior projections. Am J Radiol 1995;165:45–47. 204. Wu MH, Lai WW: Surgical management of extensive corrosive injuries of the alimentary tract. Surg Gynecol Obstet 1993;177:12–16. 205. Yolken R, Konecny P, McCarthy P: Acute fluoride poisoning. Pediatrics 1976;58:90–93. 206. Yosowitz P, Ekland DA, Shah RC, Parsons RW: Peripheral intravenous infiltration necrosis. Ann Surg 1975;182:553–556.

207. Zargar SA, Kochhar R, Mehta S, Mehta SK: The role of fiberoptic endoscopy in the management of corrosive ingestion and modified endoscopic classification of burns. Gastrointest Endosc 1991;37: 165–169. 208. Zargar SA, Kochhar R, Nagi B, et al: Ingestion of corrosive acids: Spectrum of injury to upper gastrointestinal tract and natural history. Gastroenterology 1989;97:702–707.

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ANTIDOTES IN DEPTH

Calcium 1 mg/dL

=

0.25 mmol/L = 0.5 mEq/L

Normal Range Total 8.4–10.2 mg/dL 2.10–2.55 mmol/L 4.20–5.10 mEq/L Ionized 4.48–4.92 mg/dL 1.12–1.23 mmol/L 2.24–2.46 mEq/L

Calcium Mary Ann Howland In the clinical practice of medical toxicology, there is good evidence to support the administration of calcium to overcome the effects of calcium channel blockers (CCBs), to correct the hypocalcemia induced by ethylene glycol and the fluoride from hydrofluoric acid exposures, to complex with fluoride to limit tissue destruction, to treat iatrogenic magnesium poisoning, and to counteract the cardiac effects of hyperkalemia (except when associated with cardiac glycoside toxicity). The use of calcium in the management of
-adrenergic antagonist overdoses is being investigated, and the role of calcium to counteract muscle spasms resulting from black widow spider envenomations is being questioned.

PHYSIOLOGY Calcium is essential in maintaining the normal function of the heart, vascular smooth muscle, skeletal system, and nervous system. It is vital to many enzymatic reactions, intimately involved in neurohormonal transmission, and critical for the maintenance of cellular integrity.22,37 The endocrine system keeps the serum calcium concentration within the physiologic range. Approximately half of the total serum calcium is ionized and active, and the rest is bound primarily to albumin. Excess calcium raises the threshold for nerve and muscle excitation, resulting in muscle weakness, lethargy, and coma.22 Insufficient calcium facilitates stimulation of nerves and muscles, resulting in tetany and seizures.22

CALCIUM CHANNEL BLOCKERS Calcium channel blocker overdoses result in hypotension, myocardial depression, bradycardia, sinus arrest, arteriovenous (AV) block, shock, pulmonary edema, altered mental status, nausea, vomiting, constipation, metabolic acidosis with hyperglycemia, and, rarely, seizures.42 Calcium may enter a cell in numerous

ways; of these the voltage-dependent L-types channels in cardiac and smooth muscles are inhibited by calcium channel antagonists with varying degrees of selectivity depending on the agent.2,53 Calcium channel blockers do not alter receptor-operated channels, the release of calcium from intracellular stores, or serum calcium concentrations.57 In patients who overdose with CCBs, the serum calcium concentration therefore remains normal. Intravenous administration of small doses of calcium to dogs poisoned with verapamil or diltiazem improves cardiac output secondary to an increase in inotropy.2,21 Heart rate and cardiac conduction are affected minimally, if at all, unless greater amounts of calcium are given.19,21,49 Case reports and reviews of the literature suggest similar findings in humans.1,9,18,24,33,45,46,55 Calcium should be administered to symptomatic patients with CCB overdoses and often produces a beneficial response. Unfortunately, the sickest patients usually respond inadequately, and other measures are required. Calcium administered to a patient with digoxin toxicity could prove quite harmful. In the event of concurrent overdose with both digoxin and a calcium channel blocker, early use of digoxin-specific antibody fragments should make the subsequent use of calcium less dangerous. The amount of calcium needed to treat overdoses with CCBs is unknown. In animal experiments, there appears to be a doserelated improvement.9,21 The customary approach is to administer an initial intravenous dose of 1 g of calcium chloride or 3 g of calcium gluconate, both about 4 mg/kg in a 70-kg adult, and to repeat this dose every 10–20 minutes for 3–4 additional doses, as needed.42 Therapy in children is based on the current recommended pediatric dose of calcium for hypocalcemia, which is 5–7 mg/kg of elemental calcium infused slowly at a rate ≤100 mg/min and repeated once in 10 minutes. Calcium chloride 10% contains 27.2 mg/mL of elemental calcium, and calcium gluconate 10% contains 9 mg/mL of elemental calcium. Therefore, a starting dose in children should be about 0.6 mL/kg of calcium gluconate 10%. To avoid hypercalcemia, serum calcium concentration should be monitored when more than 2 doses are administered. However, calcium administration may not be as consequential as feared. One author successfully used 6 g of calcium gluconate intravenously over 20 minutes, followed by 6 g over the second hour and then 2 g/h for a total of 30 g of calcium gluconate without adverse effects

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in a CCB overdose.9 Another author administered 18 g of calcium gluconate over 3 hours to a patient who overdosed on sustainedrelease verapamil. The serum calcium rose to 3.04 mmol/L without obvious toxicity and the patient survived.32

ETHYLENE GLYCOL Ethylene glycol poisoning results in the generation of toxic metabolites that frequently produce central nervous system, cardiovascular, renal, and metabolic abnormalities. The generation of oxalic acid, which complexes with calcium and subsequently precipitates in the kidneys, brain, and elsewhere, is believed to account for the hypocalcemia that occurs with this poisoning.1,25,41,53,56 After exposure to ethylene glycol, serum calcium should always be monitored. Signs of hypocalcemia include widening of the QT interval of the electrocardiogram (ECG), the presence of Chvostek and Trousseau signs, and tetany. Intravenous calcium should be administered in the customary doses (see above) to patients with these findings, accompanied by frequent monitoring of serum calcium.

HYDROFLUORIC ACID Any body contact with hydrofluoric acid can result in severe burns and death, depending on the concentration of hydrofluoric acid and duration of exposure. The pathophysiologic derangements result from (a) release of free hydrogen ions; (b) complexation of fluoride with calcium and magnesium to form insoluble salts, which cause cellular necrosis; (c) liberation of potassium ions; and (d) cellular dehydration.5,6,10,17,34,36,38,58 Following hydrofluoric acid exposure, the gluconate salt of calcium is used topically and subcutaneously to manage minor to moderate cutaneous burns, intravenously to treat systemic hypocalcemia and intra-arterially to manage significant burns.1,5,7,10–12,15,17,20,34,36,38,43,48,50,52,58–60,62 The chloride salt is acceptable for topical therapy. Experimental studies demonstrate that when concentrated hydrofluoric acid burns are immediately flushed with water and then covered with 2.5% calcium gluconate gel or topical dimethyl sulfoxide (DMSO)/10% calcium gluconate plus subcutaneous 10% calcium gluconate, there is a significant reduction in burn size.7,58 Unfortunately, neither DMSO nor a commercial calcium gluconate gel is readily available. A topical calcium gel can be prepared from calcium carbonate tablets or calcium gluconate powder or solution, and a water-soluble jelly such as K-Y Jelly (mix 3.5 g calcium gluconate powder or 25 mL of calcium gluconate 10% solution or 10 g of calcium carbonate tablets with 5 ounces of K-Y Jelly). Calcium chloride should not be injected subcutaneously or allowed to extravasate as it may lead to tissue necrosis. Deaths from hypocalcemia secondary to skin, gastrointestinal, and inhalational hydrofluoric acid toxicity are documented in the literature.11,20 In severe hydrofluoric acid exposures, aggressive administration of intravenous or intra-arterial calcium may be required, along with frequent serum calcium determinations in addition to other therapies as indicated, such as antidysrhythmic therapy (Chap. 87). To facilitate the availability of maximum amounts of calcium, simultaneous administration of oral and nebulized 2.5% calcium gluconate should also be given if there are no contraindications. To prepare nebulized calcium gluconate, mix 1.5 mL of 10% calcium gluconate solution with 4.5 mL of sterile

water or saline to make a 2.5% solution. One patient who was massively exposed to hydrofluoric acid required a total of 267 mEq of calcium over 24 hours.20 An ingestion of 30 mL of 70% hydrofluoric acid theoretically generates 660 mEq of fluoride. For moderate to severe burns (generally from hydrofluoric acid concentrations greater than 10%) of the fingers and hands, an intra-arterial calcium infusion may be more effective than local (or IV) therapy, although it is more invasive43,52,59,60 and more hazardous.52 One group successfully used 10 mL of 10% calcium gluconate solution mixed in 40–50 mL of 5% dextrose infused intra-arterially over 4 hours followed by subsequent 40-mL infusions after 4 hours when pain persisted.59 Serum calcium and serum magnesium concentrations should be carefully monitored in all severely poisoned patients.52,59

HYPERMAGNESEMIA Hypermagnesemia causes both direct and indirect depression of skeletal muscle, resulting in neuromuscular blockade, loss of reflexes, and profound muscular paralysis.22 Excess magnesium also causes widening of the PR interval and QRS complex on the ECG and slows the sinoatrial (S-A) node, ultimately resulting in cardiac arrest. Intravenous calcium serves as a physiologic antagonist to the effects of magnesium.

HYPERKALEMIA Hyperkalemia causes significant myocardial depression. On ECG, the height of the T wave increases, and the PR interval and QRS complex widen; impulse generation and conduction are depressed, and cardiac arrest occurs.22 Calcium may make the membrane threshold potential less negative so that a greater stimulus is required to depolarize the cell. This amounts to a stabilization effect, which may antagonize the hyperexcitability caused by modest hyperkalemia. When hyperkalemia is severe, voltage-gated sodium channels are inactivated and cannot be depolarized, regardless of the strength of the impulse. Calcium may transform the voltage sensor of the sodium channel from inactive to closed, thus allowing the sodium channel to be opened with depolarization.23 However, if hyperkalemia is secondary to the toxic effects of digoxin on the Na+-K+-ATPase pump, then intravenous calcium would potentially exacerbate an already excessive intracellular calcium concentration and is therefore contraindicated.

BETA-ADRENERGIC ANTAGONISTS In vitro studies suggest that the negative inotropic action of propranolol and analogues is related to interference with both the forward and reverse transport of calcium in the sarcoplasmic reticulum and to inhibition of microsomal and mitochondrial calcium uptake.16,30,36 In a canine model of propranolol poisoning, the administration of a bolus of calcium chloride followed by a continuous infusion improved mean arterial pressure, maximal left ventricular pressure change over time, and peripheral vascular resistance, but had no effect on bradycardia or QRS prolongation.31 Several case reports attest to the beneficial effects of calcium in
-adrenergic antagonist overdose.8,26,44,51 As long as no contraindications exist, a trial of intravenous calcium seems reasonable.

CHAPTER 87

BLACK WIDOW SPIDER ENVENOMATION Envenomation by a black widow spider (Latrodectus spp.) leads to local and systemic symptoms. Severe abdominal or back pain that begins within several hours of envenomation is the most common finding among symptomatic exposures.13 How the venom exerts its effects is unclear, but the release of synaptic transmitters, including norepinephrine and acetylcholine, is believed to be involved.47 Intravenous calcium, along with analgesics, benzodiazepines, and muscle relaxants, is used to successfully relieve the pain and muscle spasms.13,27 Rarely, antivenom may be indicated. Animal studies suggest that the venom induces changes in the permeability of calcium that may be overcome by increasing the extracellular concentration of calcium.28,40 One prospective study noted improvement in 6 of 13 patients treated with calcium gluconate.27 However, a large retrospective study of 163 patients casts doubt on the effectiveness of calcium.13 Very few patients in the study had received adequate pain relief from calcium, and all but one patient had also required opioids.13 More research is necessary to clarify the role of calcium, if any, in the management of black widow spider envenomation.

SAFETY ISSUES AND CALCIUM PREPARATIONS Severe hypercalcemia is defined by a serum calcium concentration greater than 3.5 mmol/L in a patient with a normal albumin concentration. The adverse effects of hypercalcemia (independent of the rate of administration) include nausea, vomiting, constipation, hypertension if intravascular volume is maintained, shortened QT interval on ECG, polyuria, polydipsia, cognitive difficulties, hyporeflexia, coma, and enhanced sensitivity to digitalis.3 Significant hypercalcemia may lead to myocardial depression. The symptoms exhibited depend on the patient’s age, rate of increase in the serum calcium, and duration of the hypercalcemia.3 A variety of calcium salts are available for parenteral administration. The two most commonly used are calcium chloride and calcium gluconate (Table 87–2). Calcium chloride is an acidifying

TABLE 87–2.

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salt and is extremely irritating to tissue. It should never be given intramuscularly, subcutaneously, or perivascularly.22,37 Calcium gluconate is less irritating, but care should also be taken to avoid extravasation. The best reason for choosing calcium gluconate in almost all clinical situations is that the tissue risk is far less. Equal doses of calcium chloride and calcium gluconate produce similar serum ionized calcium measurements, with peaks occurring within 30 seconds and accompanied by similar measured hemodynamic values.35 These measurements support the idea that simple dissociation of calcium from gluconate is responsible for releasing calcium, rather than hepatic metabolism. Earlier evidence suggesting that infusions of intravenous calcium chloride produce slightly larger increases in ionic calcium than do infusions of calcium gluconate has been challenged.35,61 Intravenous calcium must be administered slowly, at a rate not exceeding 0.7–1.8 mEq/min or one 10-mL vial of calcium chloride over 10 minute in adults. In cases of extreme life-threatening hypocalcemia or for a patient in extremis, faster rates may be required. More rapid administration may lead to vasodilation, hypotension, bradycardia, dysrhythmias, syncope, and cardiac arrest.4,14,29,37,54

SUMMARY In summary, intravenous calcium is an effective remedy for the hypocalcemia induced by ethylene glycol and hydrofluoric acid. It serves as a physiologic antagonist to the cardiac and/or neurologic effects of hypermagnesemia and hyperkalemia (except when associated with cardiac glycosides) and counteracts the effects of calcium channel antagonist overdoses. It may have some benefit in the treatment of
-adrenergic receptor antagonist overdoses. The efficacy of calcium in the management of patients with black widow spider envenomation has yet to be clarified. Great care must be taken to avoid extravasation. Calcium chloride, in particular, can be quite toxic to tissue. Equal doses of calcium gluconate and calcium chloride deliver equal amounts of ionic or active calcium. Electrocardiographic monitoring and frequent serum calcium determinations are required to prevent iatrogenic toxicity. Although most clinical experience involves intravenous use, advances in intra-arterial topical and inhalational calcium therapy offer unique potential advantages in certain circumstances.

The Two Most Commonly Used Calcium Salts

10% solution

Adult dose

Pediatric dose*

*Not to exceed adult dose.

1343

Calcium Chloride

Calcium Gluconate

10 mL = 1 g of calcium chloride = 1.36 mEq/mL elemental calcium = 27.2 mg/mL elemental calcium 10 mL of 10 % solution Repeat dose q10–20 min for 3–4 doses as needed Infuse ≤0.7–1.8 mEq/min or 10 mL of 10% CaCl2 over 10 min Monitor serum calcium 5–7 mg/kg elemental calcium 0.2–0.25 mL/kg of 10% solution Infuse slowly over several min; repeat dose in 10 min if needed Monitor serum calcium

10 mL = 1 g of calcium gluconate = 0.45 mEq/mL elemental calcium = 9 mg/mL elemental calcium 30 mL of 10% solution over 10 min Repeat dose q10–20 min for 3–4 doses as needed Infuse ≤0.7–1.8 mEq/min or 30 mL of 10% Ca gluconate over 10 min Monitor serum calcium 5–7 mg/kg elemental calcium 0.6–0.8 mL/kg of 10% solution Infuse slowly over several min; repeat dose in 10 min if needed Monitor serum calcium

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REFERENCES 1. Anderson WJ, Anderson JR: Hydrofluoric acid burns of the hand: Mechanism of injury and treatment. Am J Hand Surg 1988;13:52–57. 2. Bean BP: Classes of calcium channels in vertebrate cells. Annu Rev Physiol 1989;51:367–384. 3. Belezekian JP: Management of acute hypercalcemia. N Engl J Med 1992;326:1196–1215. 4. Berliner K: The effect of calcium injections on the human heart. Am J Med Sci 1936;191:117–121. 5. Bertolini JC: Hydrofluoric acid: A review of toxicity. J Emerg Med 1992;10:163–168. 6. Boink ABTJ, Wemer J, Meulenbelt J, et al: The mechanism of fluoride-induced hypocalcemia. Hum Exp Toxicol 1994;13:149–155. 7. Bracken WM, Cuppage F, McLaury RL, et al: Comparative effectiveness of topical treatments for hydrofluoric acid burns. J Occup Med 1985;27:733–739. 8. Briacombe JR, Scully M, Swainston R: Propranolol overdose. A dramatic response to calcium chloride. Med J Aust 1991;155:267–268. 9. Buckley N, Dawson AH, Howarth D, Whyte IM: Slow-release verapamil poisoning. Med J Aust 1993;158:202–204. 10. Caravati EM: Acute hydrofluoric acid exposure. Am J Emerg Med 1988;6:143–150. 11. Chan KM, Svancarek WP, Creer M: Fatality due to acute hydrofluoric acid exposure. J Toxicol Clin Toxicol 1987;25:333–339. 12. Chick LR, Borah G: Calcium carbonate gel therapy of hydrofluoric acid burns of the hand. Plast Reconstr Surg 1990;86:935–940. 13. Clark RF, Wathern-Kestner S, Vance M, Gerkin R: Clinical presentation and treatment of black widow spider envenomation: A review of 163 cases. Ann Emerg Med 1992;21:782–787. 14. Clarke NE: The action of calcium on the human electrocardiogram. Am Heart J 1941;22:367–373. 15. Conway EE, Sockolow R: Hydrofluoric acid burn in a child. Pediatr Emerg Care 1991;7:345–347. 16. Dhalla NS, Lee SL: Comparison of the actions of acebutolol, practolol, and propranolol on calcium transport by heart microsomes and mitochondria. Br J Pharmacol 1976;57:215–221. 17. Edinburg M, Swift R: Hydrofluoric acid burns of the hands: A case report and suggested management. Aust N Z J Surg 1989;59:88–91. 18. Erickson F, Ling L, Grande G, et al: Diltiazem overdose? Case report and review. J Emerg Med 1991;9:357–366. 19. Gay R, Algeo S, Lee R, et al: Treatment of verapamil toxicity in intact dogs. J Clin Invest 1986;77:1805–1811. 20. Greco RJ, Hartford CE, Haith LR, Patton ML: Hydrofluoric acidinduced hypocalcemia. J Trauma 1988;28:1593–1596. 21. Hariman RJ, Mangiardi LM, McAllister RG, et al: Reversal of the cardiovascular effects of verapamil by calcium and sodium: Differences between electrophysiologic and hemodynamic responses. Circulation 1979;59:797–804. 22. Hayes RC: Agents affecting calcification: Calcium, parathyroid hormone, calcitonin, vitamin D, and other compounds. In: Gilman AG, Rall T, Nies A, Taylor P, eds: Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 8th ed. New York, Pergamon, 1990, pp. 1496–1501. 23. Hille B: Ionic Channels of Excitable Membranes. Sunderland MA,Sinauer Associates, 1984. 24. Hofer CA, Smith JK, Tenholder MF: Verapamil intoxication: A literature review of overdoses and discussion of therapeutic options. Am J Med 1993;95:431–438. 25. Introna F Jr, Smialek JE: Antifreeze (ethylene glycol) intoxications in Baltimore: Report of six cases. Acta Morphol Hung 1989;37: 245–263. 26. Jones JL: Metoprolol overdose. Ann Emerg Med 1982;11:114–115. 27. Key GF: A comparison of calcium gluconate and methocarbamol (Robaxin) in the treatment of latrodectism (black widow spider envenomations). Am J Trop Med Hyg 1981;30:273–277.

28. Kobernick M: Black widow spider bites. Am Fam Physician 1984; 29:241–245. 29. Kuhn M: Severe bradyarrhythmias following calcium pretreatment. Am Heart J 1991;121:1812–1813. 30. Langemeijer J, de Wildt D, de Groot G, Sangster B: Calcium interferes with the cardiodepressive effects of beta-blocker overdose in isolated rat hearts. J Toxicol Clin Toxicol 1986;24:111–133. 31. Love J, Hanfling D, Howell J: Hemodynamic effects of calcium chloride in a canine model of acute propranolol intoxication. Ann Emerg Med 1996;28:1–6. 32. Luscher TF, Noll G, Sturmer T, Muser B, et al: Calcium gluconate in severe verapamil intoxication [letter]. N Engl J Med 1994;330: 718–719. 33. MacDonald D, Alguire P: Case reports: Fatal overdose with sustained release verapamil. Am J Med Sci 1992;303:115–117. 34. MacKinnon MA: Hydrofluoric acid burns. Dermatol Clin 1988;6: 67–74. 35. Martin T, Kang Y, Robertson K, et al: Ionization and hemodynamic effects of calcium chloride and calcium gluconate in the absence of hepatic function. Anesthesiolgy 1990;73:62–65. 36. McCulley JP: Ocular hydrofluoric acid burns: Animal model, mechanism of injury and therapy. Am Ophthalmol Soc 1990;88:649–683. 37. McEvoy G, ed: AHFS Drug Information, 1997. Baltimore, American Society of Hospital Pharmacists, 1997. 38. Mistry DG, Wainwright DJ: Hydrofluoric acid burns. Am Fam Physician 1992;45:1748–1754. 39. Noack E, Kurzmack M, Verjovski-Almeida Sand Inesi G: The effect of propranolol and its analogs on Ca__ transport by sarcoplasmic reticulum vesicles. J Pharmacol Exp Ther 1978;206:281–288. 40. Pardel JF: Influence of calcium on 3H-noradrenaline release by Lactrodectus venom gland extract on arterial tissue of the rat. Toxicon 1979;17:455–465. 41. Parry MF, Wallach R: Ethylene glycol poisoning. Am J Med 1974;57: 143–150. 42. Pearigen PD, Benowitz NS: Poisoning due to calcium antagonists: Experience with verapamil, diltiazem and nifedipine. Drug Saf 1991; 6:408–430. 43. Pegg SP, Siu S, Gillet G: Intra-arterial infusions in the treatment of hydrofluoric acid burns. Burns 1985;11:440–443. 44. Pertoldi F, D’Orlando L, Mercanto W: Electromechanical dissociation 48 hours after atenolol overdose. Usefulness of calcium chloride. Ann Emerg Med 1998;31:777–781. 45. Proano L, Chiang WK, Wang RY: Calcium channel blocker overdose. Am J Emerg Med 1995;13:444–450. 46. Ramoska EA, Spiller HA, Winter M, Borys D: A one-year evaluation of calcium channel blocker overdoses: Toxicity and treatment. Ann Emerg Med 1993;22:196–200. 47. Rauber A: Black widow spider bites. J Toxicol Clin Toxicol 1983– 1984;21:473–485. 48. Roberts JR, Merigian KS: Acute hydrofluoric acid exposure. Am J Emerg Med 1989;7:125–126. 49. Sabatier J, Pouyet T, Shelvey G, Cavero I: Antagonistic effects of epinephrine, glucagon and methylatropine but not calcium chloride against atrio-ventricular conduction disturbances produced by high doses of diltiazem in conscious dogs. Fundam Clin Pharmacol 1991;5: 93–106. 50. Sadove R, Hainsworth D, Van Meter W: Total body immersion in hydrofluoric acid. South Med J 1990;83:698–700. 51. Sangster B, de Wildt D, van Dijk A: A case of acebutolol intoxication. J Toxicol Clin Toxicol 1983;20:69–77. 52. Siegel DC, Heard JM: Intra-arterial calcium infusion for hydrofluoric acid burns. Aviat Space Environ Med 1992;63:206–211. 53. Simpson E: Some aspects of calcium metabolism in a fatal case of ethylene glycol poisoning. Ann Clin Biochem 1985;22:90–93. 54. Smallwood RA: Some effects of the intravenous administration of calcium in man. Aust Acad Med 1967;16:126–131.

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55. Spiller HA, Meyers A, Ziemba T, Riley M: Delayed onset of cardiac arrhythmias from sustained release verapamil. Ann Emerg Med 1991; 20:201–203. 56. Tarr BD, Winters LJ, Moore MP, et al: Low dose ethanol in the treatment of ethylene glycol poisoning. J Vet Pharmacol Ther 1985;8: 254–262. 57. Triggle DJ: Calcium-channel antagonists: Mechanisms of action, vascular selectivities, and clinical relevance. Cleve Clin J Med 1992;59: 617–626. 58. Upfal M, Doyle C: Medical management of hydrofluoric acid exposure. J Occup Med 1990;32:726–731.

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59. Vance MV, Curry SC, Kunkel DB, et al: Digital hydrofluoric acid burns: Treatment with intraarterial calcium infusion. Ann Emerg Med 1986;15:890–896. 60. Velvart J: Arterial perfusion for hydrofluoric acid burns. Hum Toxicol 1983;2:233–238. 61. White RD, Goldsmith RS, Rodriquez R, et al: Plasma ionic calcium levels following injection of chloride, gluconate, and gluceptate salts of calcium. J Thorac Cardiovasc Surg 1976;71:609–613. 62. Zachary LS, Reus W, Gottlieb J, et al: Treatment of experimental hydrofluoric acid burns. J Burn Care 1986;7:35–39.

I. PESTICIDES

CHAPTER

88

INSECTICIDES: ORGANIC PHOSPHORUS COMPOUNDS AND CARBAMATES Richard F. Clark

A 40-year-old suicidal male was brought by relatives into the Emergency Department (ED) after drinking two sips of 50% malathion about 3 hours earlier. The patient was awake but confused and extremely diaphoretic. He had the odor of hydrocarbons, although there was no evidence that the liquid had spilled onto his clothes. His initial vital signs in the ED were: blood pressure, 210/120 mm Hg; pulse, 100 beats/min; respiratory rate, 22 breaths/min; temperature, 98.6°F (37°C); and oxygen saturation, 95% on room air. Physical examination demonstrated midsized pupils, coarse crackles in all lung fields, and copious vomiting and diarrhea. The patient was drooling between episodes of vomiting. The patient was completely undressed and his clothing placed in bags for hazardous materials. His skin was thoroughly washed with soap and water. Oxygen was administered by facemask, an intravenous line was inserted, and normal saline was infused. Even with supplemental oxygen applied, the victim’s oxygenation began to fall several minutes after arrival in the ED. His heart rate also rapidly increased to 120 beats/min, and an electrocardiogram (ECG) demonstrated a prolonged QTc duration (560 msec). A portable chest radiograph showed bilateral pulmonary edema with normal heart size. The Poison Control Center (PCC) was contacted immediately and recommended administration of atropine and pralidoxime. After administration of atropine 3 mg and pralidoxime 1 g intravenously, his breath sounds improved. But, despite therapy, his oxygenation continued to fall to 87%, and he began coughing up pink-tinged, frothy sputum and continued having large amounts of vomiting and diarrhea. A pralidoxime infusion at 200 mg/h was initiated, with recommendations to increase the rate to 300–500 mg/h if rapid improvement was not noted. The PCC advised giving additional 2-mg atropine doses every 5–15 minutes as needed to control his secretions. Although the quantity of emesis, diarrhea, and bronchorrhea improved after a total of 20 mg of atropine, the clinicians elected to intubate the patient for airway protection. He was sedated with midazolam and paralyzed with vecuronium. His oxygen saturation following intubation was 98% on 100% FIO2 at an intermittent mechanical ventilation (IMV) rate of 16, and his vital signs were blood pressure, 175/90 mm Hg; and pulse, 125 beats/min. A nasogastric tube was inserted and lavage of stomach contents performed followed by administration of 75 g of activated charcoal. He was transferred to the intensive care unit (ICU). In the ICU, the pralidoxime infusion was increased to 500 mg/h, and atropine was administered intermittently throughout the first

24 hours of admission for a total dose of 30 mg. Hematologic studies were normal except for a white blood cell count (WBC) of 19,000/mm3. His other laboratory studies were remarkable for a glucose of 195 mg/dL, potassium of 3.2 mEq/L, and serum bicarbonate of 20 mEq/L. The chest radiograph dramatically improved over the first 24 hours, and by the second day was only remarkable for a right-upper-lobe infiltrate. The patient was kept sedated with midazolam and intubated for another 24 hours to better monitor pulmonary status. His ECG gradually improved by the second day, with a heart rate of 105, and normalization of his QTc interval. On hospital day 2, because oxygenation was normal on room air, his sedation was terminated and he was extubated. His nausea and vomiting had largely improved, and no further frothy sputum was observed. Diaphoresis and diarrhea had resolved, but he continued to smell of solvents. Cholinesterase measurements sent initially showed virtually no detectable red blood cell (RBC) or butyrylcholinesterase (plasma) activity. All other laboratory results had normalized by the second day. He was transferred to a stepdown unit for observation, and did not require any further atropine that day. The pralidoxime infusion was maintained at 500 mg/h, and penicillin was begun for presumed aspiration pneumonia. With continued hydrocarbon odor present, it was advised to continue to wash the victim’s skin and hair at least on a daily basis. On hospital day 3, the patient reported feeling much better. His pralidoxime infusion was stopped and he was evaluated by the psychiatric service. That afternoon, he reported two episodes of diarrhea and some nausea, and was again administered atropine 2 mg IV and restarted on pralidoxime with resolution of symptoms once again. He required no further atropine during his hospitalization. Pralidoxime infusion was stopped successfully on hospital day 5, and he was discharged to a psychiatric facility on hospital day 7.

EPIDEMIOLOGY

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Organic phosphorus compounds and carbamates are the two groups of cholinesterase-inhibiting pesticides that produce human toxicity. Poisoning from these agents results in a rise in the concentration of acetylcholine (ACh) at muscarinic and nicotinic cholinergic receptors, which, in turn, leads to the syndrome of cholinergic excess. Although the term organophosphate has traditionally been used in clinical practice and in the literature to refer

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to all phosphorus-containing pesticides that inhibit cholinesterase, not all of these chemicals contain ester side chains off the phosphorus molecule. Some of these chemicals, such as parathion, contain thioesters, whereas others are vinyl esters. The more correct term, and the one that is used in this chapter, is organic phosphorus compound. During the past 5-year period of 1995–2000, the American Association of Poison Control Centers recorded more than 75,000 exposures to organic phosphorus compounds and more than 25,000 exposures to carbamates, with 44 fatalities, ranking these agents as the most lethal insecticides in use in the United States, and among the most lethal poisonings (Chap. 116). In Taiwan, where insecticides are often more accessible than medications in rural areas, fatality rates with exposures to these compounds are as high as 23%.134 The World Health Organization estimates that at least 1 million unintentional poisonings and 2 million suicide attempts occur annually from these agents.13 However, these figures may neglect numerous unreported and possibly unrecognized illnesses resulting from environmental exposure to these chemicals. Patients may present following unintentional or suicidal ingestion of anticholinesterase insecticides or after working in areas recently treated with these compounds.55 Children and adults can develop toxicity while playing in or inhabiting a residence recently sprayed or fogged with organic phosphorus agents by a pesticide applicator.158 Direct dermal contact with these insecticides may be rapidly poisonous. Outbreaks of mass poisoning have occurred from contamination of crops or food.13,28,36,105,129,130 Organic phosphorus agents have also been used for homicide.105,106

HISTORY The first potent synthetic organic phosphorus anticholinesterase was tetraethyl pyrophosphate (TEPP), which was synthesized by Clermont in 1854. Clermont’s report described the taste of the compound, which is remarkable, because a few drops should be rapidly fatal.57 In 1932, Lange and Krueger published an account of choking and blurred vision following inhalation of dimethyl and diethyl phosphorofluoridates.65 This report inspired Schrader to begin investigating these agents, initially as pesticides, and later for use in warfare (Chap. 100). During this research, Schrader’s group synthesized hundreds of compounds, including the popular pesticide parathion and the chemical warfare agents sarin, soman, and tabun. Allied scientists were also motivated during the same period by the work of Lange and Krueger, and independently discovered other extremely toxic compounds such as diisopropyl phosphofluoridate (DFP).144 Since that time, it is estimated that more than 50,000 organic phosphorus compounds have been synthesized and screened for pesticidal activity, with dozens being produced commercially.12 The history of carbamates was first recognized by Westerners in the 19th century when the Calabar bean (Physostigma venenosum Balfour) was used in tribal cultural practice in West Africa.143 These beans were imported to Great Britain in 1840, where, by 1864, Jobst and Hesse isolated an active alkaloid component that they named “physostigmine.”143 Physostigmine was first medicinally used to treat glaucoma in 1877.58,66 In the 1930s, the synthesis of aliphatic esters of carbamic acid led to the development and introduction of carbamate pesticides, marketed initially as fungicides.145 The Union Carbide Corporation developed and first mar-

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keted carbaryl in 1953, which was the agent prepared at Bhopal, India (Chap. 1).90

PHARMACOLOGY Organic Phosphorus Compounds Figure 88–1 shows the basic formula for cholinesterase-inhibiting organic phosphorus compounds. The “X” or “leaving group” determines many of the characteristics of the compound and provides a means of classifying organic phosphorus agents into four main groups (Table 88–1). Group 1 substances contain a quaternary nitrogen at the X position, and are collectively termed phosphorylcholines. In addition to being powerful cholinesterase inhibitors, these chemicals can also directly stimulate cholinergic receptors. Phosphorylcholines are among the most potent anticholinesterases, originally developed as war gases.43 Group 2 compounds are called fluorophosphates because they possess a fluorine molecule as the leaving group. Like group 1 agents, these compounds are volatile and highly toxic, making them well-suited for chemical warfare. The leaving group of group 3 compounds is a cyanide molecule or a halogen other than fluorine. The most well-known agents in this group are cyanophosphates such as tabun. The fourth group is the broadest and comprises various subgroups based on the configuration of the R1 and R2 groups, with the majority falling into the category of either a dimethoxy or diethoxy compound. Most of the insecticides in use today fall into this last class.43 “Direct”-acting organic phosphorus agents can inhibit acetylcholinesterase (AChE) without being structurally altered by the body. Many of the more popular pesticides, such as parathion and malathion, are “indirect” inhibitors requiring partial metabolism (to paraoxon and malaoxon, respectively) within the body to become active. Most of the indirect inhibitors undergo oxygenation in the intestinal mucosa and liver following absorption to form the more active “oxone” metabolites.74 The active form is able to combine with cholinesterase. The covalent bond is completed as the leaving group of the organic phosphorus compound is split off by AChE, resulting in a stable but reversible bond between the remaining substituted phosphate of the organic phosphorus agent and AChE, effectively inactivating the enzyme (Fig. 88–2). Although the splitting of the choline-enzyme bond in normal ACh metabolism is completed within microseconds, the severing of the organic phosphorus compound–enzyme bond can require as much as 1000 hours.43,137 In organic phosphorus compound poisoning,

Figure 88–1. General structure of organic phosphorus insecticides. X represents the leaving group. R1 and R2 may be aromatic or aliphatic groups that can be identical.

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PART D

TABLE 88–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

The Classification of Organic Phosphorus Agents by Groups.43 Leaving Groups and Examples of Each Group Are Included.

Group 1–phosphorylcholines Leaving group: substituted quarternary nitrogen Echothiophate iodide

Group 2–fluorophosphates Leaving group: fluoride Dimefox, sarin, mipafox

Group 3–cyanophosphates, other halophosphates Leaving group: CN, SCN, OCN, halogen other than fluoride Tabun Group 4–multiple constituents Leaving group: Dimethoxy Azinphos-menthyl, bromophos, chlorothion, crotoxyphos, dicapthon, dichlorvos, dicrotophos, dimethoate, fenthion, malathion, mevinphos, parathion-methyl, phosphamidon, temephos, trichlorfon Diethoxy Carbophenothion, chlorfenvinphos, chlorpyriphos, coumaphos, demeton, diazinon, dioxathion, disulfoton, ethion, methosfolan, parathion, phorate, phosfolan, TEPP Other dialkoxy Isopropyl paraoxon, isopropyl parathion Diamino Schradan Chlorinated and other substituted dialkoxy Haloxon Trithioalkyl Merphos Triphenyl and substituted triphenyl Triorthocresyl phosphate (TOCP) Mixed substituent Crufomate, cyanofenphos

the complex becomes irreversibly bound during the next 24–72 hours when one of the R groups leaves the phosphate molecule. This step is termed “aging.”127 De novo synthesis of AChE is required to replenish its supply once aging has occurred.120,143,152

Carbamates Carbamate insecticides are N-methyl carbamates derived from carbamic acid (Fig. 88–3). Medicinal carbamate compounds include

physostigmine, pyridostigmine, and neostigmine. Medications such as meprobamate and various urethanes are carbamate derivatives, but do not cause cholinesterase inhibition.143 Thiocarbamate fungicides and herbicides (eg, Maneb, Zineb, Nabam, Mancozeb) also do not inhibit AChE and do not produce cholinergic poisoning. When exposed to carbamate compounds, AChE undergoes carbamylation in a manner similar to phosphorylation by organic phosphorus agents, allowing ACh to accumulate in synapses.153

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Figure 88–2. Mechanism of inhibition of acetylcholinesterase by an organic phosphorous compound. The HX is the leaving group. A serine residue at the active site of the enzyme gives up a hydrogen atom to combine with the leaving group, while the active site undergoes phosphorylation and inhibition. This initial inhibition is reversible with pralidoxime. However, as the inhibited phosphorylated enzyme “ages,” one of the R groups is lost. The aged phosphorylated enzyme is unable to be rejuvenated by pralidoxime.

However, because aging cannot occur, the carbamate-AChE bond hydrolyzes spontaneously, resulting in reactivation of the enzyme. As such, the duration of toxic symptoms in carbamate poisoning is generally less than 24 hours.

PHARMACOKINETICS Organic Phosphorus Compounds Organic phosphorus agents are extremely well absorbed from the lungs, gastrointestinal tract, skin, mucous membranes, and con-

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junctiva following inhalation, ingestion, or topical contact.43,69,87 Intravenous and subcutaneous injections99,118,155 and percutaneous exposure may cause severe toxicity.15,69,116 The presence of broken skin and dermatitis and higher environmental temperatures enhances cutaneous absorption.43 Cholinesterase-inhibitor poisonings can be chronic or acute, although the differentiation has little clinical relevance. The difficulty in removing these compounds from the skin and clothing may explain some chronic poisonings.15 Inadequate skin and respiratory protection during pesticide application may be responsible for many of these cases. Most organic phosphorus agents are lipophilic.143 Radiolabeled parathion injected into mice distributes most rapidly into the cervical brown fat and salivary glands, with high levels also measured in the liver, kidneys, and ordinary adipose tissue.39 Adipose tissue gradually accumulates the highest levels. Cholinergic crisis may recur in patients when fat stores of unmetabolized organic phosphorus agents are mobilized.42,43 The more lipophilic compounds such as fenthion and chlorfenthion are particularly susceptible to this phenomenon.149 Peak levels of organic phosphorus agents are measured 6 hours after oral ingestion in man.112 Although serum half-lives of these compounds range from minutes to hours,65 prolonged absorption or redistribution from fat stores may allow for measurement of circulating insecticide concentrations for up to 48 days.18,44,65,124 Organic phosphorus agents are thought to be metabolized by various mixed function oxidases in the liver and intestinal mucosa, but the exact pathways are not yet well understood.43,74,139 The phosphorylating ability of these substances is lost when any of the side chains are hydrolyzed. Certain indirect-acting agents are activated to a more toxic compound by this initial metabolism. Particularly, lipophilic organic phosphorus compounds may be protected from metabolism by fat storage, markedly prolonging their elimination half-life.18,43,94 Inactive metabolites of these agents are excreted in the urine.43

Carbamates Carbamate insecticides are well absorbed across skin and mucous membranes, as well as by inhalation and ingestion. Peak serum levels of some compounds are measured 30–40 minutes following ingestion.10 Most carbamates undergo hydrolysis, hydroxylation, and conjugation in the liver and intestinal wall, with 90% excreted in the urine within 3 days.113 There are two main pharmacokinetic characteristics that distinguish carbamates from organic phosphorus compounds. First, carbamate insecticides do not easily cross into the central nervous system (CNS).43 CNS effects of carbamates are thus limited, although CNS dysfunction may still occur in massive poisonings or may result from hypoxia secondary to pulmonary toxicity and paralysis. Second, the carbamatecholinesterase bond does not “age” as in organic phosphorus compound poisoning; thus it is reversible, with spontaneous hydrolysis occurring within several hours.

PATHOPHYSIOLOGY

Figure 88–3.

General structure of carbamate insecticides.

Acetylcholine is a neurotransmitter found at both parasympathetic and sympathetic ganglia, skeletal neuromuscular junctions, terminal junctions of all postganglionic parasympathetic nerves, postganglionic sympathetic fibers to most sweat glands, and at some

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nerve endings within the central nervous system (Fig. 88–4).43 As the axon terminal is depolarized, vesicles containing ACh rupture, releasing ACh into the synapse or neuromuscular junction. Acetylcholine then binds postsynaptic receptors leading to activation (G proteins for muscarinic receptors and ligand-linked ion channels for the nicotinic receptors). Activation alters the flow of K+, Na+, and Ca2+ ionic currents, and alters membrane potential of the postsynaptic membrane, resulting in propagation of the action potential.9 Acetylcholinesterase is an enzyme that hydrolyzes ACh into two inert fragments: acetic acid and choline. Under normal circumstances, virtually all ACh released by the axon is hydrolyzed almost immediately, with choline being reuptaken into the presynaptic terminal and used to resynthesize ACh.43,114,143 Organic phosphorus agents and carbamates are powerful inhibitors of carboxylic ester hydrolases within the body, including chymotrypsin, AChE, plasma or butyrylcholinesterase (pseudocholinesterase), plasma and hepatic carboxylesterases (aliesterases), paraoxonases (A-esterases), and other nonspecific proteases. Acetylcholinesterase is found in human nervous tissue and skeletal muscle, and on erythrocyte (RBC) cell membranes. RBC cholinesterase activity levels correlate with functioning nervous system AChE. Butyrylcholinesterase is a hepatic-derived protein that is found in human plasma, liver, heart, pancreas, and brain. Although the function of this enzyme is not well understood, its activity can be

Figure 88–4.

easily measured and has important clinical implications in anesthesia (Chap. 54).

CLINICAL MANIFESTATIONS Organic Phosphorus Compounds Clinical findings in organic phosphorus pesticide poisoning are typical of those caused by excessive stimulation of muscarinic and nicotinic cholinergic receptors by ACh in the central and autonomic nervous systems, as well as at skeletal neuromuscular junctions (Fig. 88–4). Although the classically described patient with organic phosphorus insecticide poisoning is unresponsive with pinpoint pupils, muscle fasciculations, diaphoresis, emesis, diarrhea, salivation, lacrimation, urinary incontinence, and an odor of garlic, most presentations are not so typical. The onset of symptoms varies according to the agent, the route, and the degree of exposure. Patients suffering massive ingestions have become symptomatic as quickly as 5 minutes following ingestion, and deaths have occurred within 15 minutes of ingestion.43,82 Most victims of acute poisonings become symptomatic within 8 hours of exposure, and nearly all are symptomatic within 24 hours.105 The longest delays may occur with agents requiring metabolic activation, such as malathion, or very lipid-soluble agents such as fenthion. Symptoms may last for variable lengths of time, again based

Pathophysiology of cholinergic syndrome as it affects the autonomic and somatic nervous systems.

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on the agent and the circumstances of the exposure. For example, the more lipophilic compounds, such as dichlofenthion, can cause cholinergic effects for several days following oral ingestion.18 A variety of CNS findings are reported after organic phosphorus compound exposure. Many patients present awake and alert, complaining of anxiety, restlessness, insomnia, headache, dizziness, blurred vision, depression, tremors, or other nonspecific symptoms.105 The victims’ level of consciousness may deteriorate rapidly to confusion, lethargy, and coma, and they may display inappropriate behavior or convulsions.105 The effects of excessive ACh on the autonomic nervous system may be variable because cholinergic receptors are found in both the sympathetic and parasympathetic nervous systems (Fig. 88–4). Excessive muscarinic activity can be characterized by various mnemonics, including “SLUD” (salivation, lacrimation, urination, defecation) and “DUMBBELS” (defecation, urination, miosis, bronchospasm or bronchorrhea, emesis, lacrimation, salivation). Of these, miosis may be the most consistently encountered sign. Bronchorrhea can be so profuse that it mimics pulmonary edema.105 Although muscarinic findings are emphasized in these mnemonics, muscarinic signs usually do not overwhelmingly or initially predominate, except in very severe poisonings. In many cases, excessive autonomic activity from stimulation of nicotinic adrenal receptors (resulting in catecholamine release) and postganglionic sympathetic fibers offsets parasympathetic findings.143 Mydriasis is reported in as many as 13% of cases, presumably from nicotinic stimulation of sympathetic receptors.36 Bronchodilation and urinary retention can occur as a result of sympathetic activity on smooth muscle.143 Excessive adrenergic influences on metabolism result in glycogenolysis with hyperglycemia and ketosis that is occasionally mistaken for diabetic ketoacidosis.33,93 Hypoglycemia can also be seen, although the mechanism is unclear.60 Increased sympathetic activity usually precipitates demargination, resulting in leukocytosis.105 Hyperamylasemia is occasionally reported in cases of severe organic phosphorus pesticide poisoning, and although pancreatitis may result from spasm of the sphincter of Oddi,31,89 this finding is most often the result of salivary gland stimulation and not the result of pancreatic dysfunction.79 Elevations in hepatic enzymes can also occur following organic phosphorus pesticide exposures.43,86,117 The cardiovascular manifestations of organic phosphorus compound toxicity also reflect mixed effects on the autonomic nervous system.85 Increased sympathetic tone is usually initially present, and most patients manifest a sinus tachycardia,85,105 and sometimes hypertension. As toxicity becomes more severe, bradycardia with a prolonged PR interval and atrioventricular blocks of various degrees occur because of excessive parasympathetic tone, and possibly because of reduced coronary blood flow.26,73,85,105,107 Unequal sympathetic stimulation of myocardial cells is likely responsible for the occasional prolonged QT interval.85,102,126 This prolongation in QT interval can be associated with polymorphous ventricular tachycardia (torsades de pointes).8,70,85,147 Liquid preparations of organic phosphorus compounds are usually dissolved in a hydrocarbon. Pulmonary aspiration following ingestion is common in severe poisoning, and hydrocarbon pneumonitis may complicate the clinical course. Acetylcholine stimulation of nicotinic receptors also governs skeletal muscle activity. Excessive cholinergic stimulation at these sites behaves like a depolarizing neuromuscular blocking agent (similar to succinylcholine) and initially results in fasciculations

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or weakness. This effect is considered by some to be the most reliable signs of organic phosphorus pesticide toxicity.106 As the severity of poisoning progresses, paralysis ensues. Paralysis of the respiratory muscles in combination with bronchorrhea, bronchoconstriction, and CNS depression lead to hypoxemia and respiratory arrest, the most common cause of death in poisoning with organic phosphorus chemicals.105,142 Rarely, patients may present only with paralysis from nicotinic effects without other signs and symptoms suggestive of organic phosphorus agent toxicity.38,46 Respiratory depression is in part centrally mediated.105 Extrapyramidal effects such as rigidity and choreoathetosis occur uncommonly after severe anticholinesterase poisoning but can persist for several days after cholinergic features have resolved.63

Carbamates Poisoning from carbamate insecticides appears identical to that of organic phosphorus compounds except for the two main factors listed above regarding the lack of CNS penetration and rapid hydrolyzation of the carbamate-AChE bond. However, CNS abnormalities may occur in victims of severe carbamate poisonings, some of which may result from hypoxia caused by respiratory insufficiency or severe bronchorrhea.

DIAGNOSTIC TESTING Organic Phosphorus Compounds When confronted with a patient in cholinergic crisis who presents with a history of acute excessive exposure to an anticholinesterase insecticide, the diagnosis is at times straightforward. However, when the history is unreliable or does not suggest cholinesterase inhibitor poisoning, the physician must turn to other means to confirm the diagnosis of organic phosphorus or carbamate insecticide poisoning. The most reliable and appropriate laboratory test for confirming cholinesterase inhibition by insecticides measures specific insecticides and active metabolites in biologic tissues. Unfortunately, such tests or results are rarely obtainable within a few minutes or hours, and normal ranges or toxic levels are not established for most agents. If available, another useful test is the measurement of AChE activity in neuronal tissue, but this requires CNS or neuronal tissue biopsies and, even then, is not very useful unless the baseline activity is known. Thus, the diagnostic study of necessity for verifying anticholinesterase poisoning is the measurement of cholinesterase activity in readily accessible tissue, such as the plasma and erythrocytes.43,105 Butyrylcholinesterase is able to metabolize various exogenous compounds, including succinylcholine and cocaine. Erythrocytes contain a form of “true AChE,” similar to the enzyme found in neuronal tissue, that is specific for ACh.14 It should be remembered that inhibition of the red blood cell and butyrylcholinesterase serves as a marker for anticholinesterase poisoning, and inhibition of these enzymes does not directly contribute to signs and symptoms of insecticide poisoning. After a significant exposure to an organic phosphorus or carbamate insecticide, butyrylcholinesterase activity usually falls first, followed rapidly by a decrease in red blood cell cholinesterase activity. The sequence may be highly variable, but by the time patients present with acute symptoms, both cholinesterase activities

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have usually fallen well below baseline values, and often have fallen below detectable limits.105 Butyrylcholinesterase activity usually recovers before that of the red blood cell, often returning to normal within a few days if there is no repeat exposure to the inciting agent.16 However, butyrylcholinesterase activity is less specific for exposure to these insecticides than is red cell cholinesterase activity.43 Low butyrylcholinesterase activity is frequently found in patients with a number of disorders, including hereditary deficiency of the enzyme, malnutrition, hepatic parenchymal disease, chronic debilitating illnesses, and iron deficiency anemia.43 Drugs such as cocaine, succinylcholine, morphine, and codeine may cause butyrylcholinesterase activity to fluctuate, presumably by their effect on acetylcholine release from nerve terminals, but the mechanism is still unclear.110 High butyrylcholinesterase activity occurs in some individuals with nephrotic syndrome because an inverse correlation exists between enzyme activity and the concentration of serum albumin.43 Additionally, day-to-day variation in enzyme activity in healthy individuals may be as high as 20%.43 Red blood cell cholinesterase activity is thought to more accurately reflect nervous tissue AChE activity than butyrylcholinesterase because of the presence of true AChE in red blood cells. Some authors suggest that clinical organic phosphorus pesticide poisoning occurs when red blood cell cholinesterase activity falls 50% below baseline values.98,105 While these statements are generally true, there are several potential pitfalls in interpreting cholinesterase laboratory values. First, it is AChE inhibition in nervous tissue that causes toxicity, and red blood cell and butyrylcholinesterase activity may not always reflect neuronal enzyme activity. Organic phosphorus insecticides vary in their ability to inhibit butyrylcholinesterase or red blood cell cholinesterase. This variation may lead to some patients presenting highly symptomatic after minimal reductions in red blood cell cholinesterase, while others can be asymptomatic after losing 50% activity.16,55,97 The wide normal range of red blood cell and butyrylcholinesterase activity also allows for patients with high normal values to suffer significant falls in cholinesterase activity, yet still register “normal” levels of cholinesterase activity on laboratory assay.16,55,97 Red blood cell cholinesterase regenerates more slowly than AChE found in neurons.105 To completely replenish the supply, red blood cells in circulation must be replaced, or pralidoxime administered. It is estimated that an average of 66 days may be necessary for red blood cell cholinesterase to stop declining following severe inhibition16 (assuming no treatment with pralidoxime), and activity may take up to 120 days to return to normal. The patient may have completely recovered neuronal activity of AChE and resolved all cholinergic symptoms, yet still have low red blood cell cholinesterase laboratory values. For this reason, in subacute poisoning with organic phosphorus agents, it is difficult to accurately predict the time of onset or length of exposure from red blood cell cholinesterase activity alone. In fact, the ability of red blood cell cholinesterase activity to serve as a historical marker for excessive exposure to organic phosphorus insecticides provides the basis for monitoring red blood cell cholinesterase activity in pesticide workers.17,27,77 Depressed red blood cell cholinesterase activity can be noted for reasons other than insecticide poisoning, such as in antimalarial therapy and pernicious anemia. Genetic and circadian variations are also common, with daily fluctuations within the same individual as high as 10%.156 In addition, levels are normally slightly lower in children younger than 4 months of age, probably

increasing as hepatic function matures.68 Oral contraceptives raise red blood cell cholinesterase activity. The most important aspect to consider when interpreting cholinesterase activity as reported by a laboratory is how it compares with baseline values in the individual (Table 88–2). Because baseline values are usually unavailable in most cases of acute and chronic cholinesterase inhibitor poisoning, laboratories report out a “reference range” of activity. This range is based on the central 95% of values of cholinesterase activity for the general population. Our laboratory uses standard reference range intervals of 18–29 U/g Hgb for red blood cell cholinesterase, and 5200–12,800 U/L for butyrylcholinesterase, but these ranges may vary significantly with different assays. Blood samples for cholinesterase activity should be obtained in the appropriate blood tubes. Gray-top or other tubes containing fluoride will permanently inactivate the enzyme, yielding falsely low activity levels, and should not be used. Specimens for red blood cell cholinesterase are usually drawn into tubes containing a chelating anticoagulant such as ethylenediaminetetraacetic acid (EDTA) to prevent clot formation. Butyrylcholinesterase does not require an anticoagulant and can be drawn into a tube without chelators or anticoagulants. Because laboratory color coding systems for blood tubes vary, laboratory personnel should be contacted to determine the appropriate venipuncture container. If either test will not be immediately performed, tubes should be spun and frozen.

Carbamates Carbamates inhibit neuronal and red blood cell AChE, as well as butyrylcholinesterase. The relative ease with which spontaneous decarbamylation of cholinesterase takes place may result in the measurement of relatively normal red cell cholinesterase activity despite severe cholinergic symptoms if the assay is not performed

TABLE 88–2.

Advantage Site

Regeneration (untreated) Normalization (untreated) Use

False depression

Interpreting Cholinesterase Values Red Blood Cell Cholinesterase

Butyrylcholinesterase

Better reflection of synaptic inhibition RBC (reflects CNS gray matter, motor end plate) 1%/day

Easier to assay, declines faster CNS white matter, plasma, liver, pancreas, heart 25–30% in first 7–10 days

35–49 days

28–42 days

Unsuspected prior exposure with elevated plasma cholinesterase Pernicious anemia, hemoglobinopathies, antimalarial treatment, oxalate blood tubes

Acute exposure

Liver dysfunction (cirrhosis), malnutrition, hypersensitivity reactions, drugs (succinylcholine, codeine, morphine), pregnancy, genetic deficiency

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within several hours of sampling.34 Just as in organic phosphorus pesticide poisoning, the wide “normal” range of cholinesterase values may make interpretation of cholinesterase activity difficult at times without knowing the patient’s baseline values. Unlike organic phosphorus agents, carbamates generally do not produce persistent depressed red blood cell and butyrylcholinesterase activities.

Atropine Challenge An atropine sulfate challenge may be helpful in diagnosing cholinergic poisoning in a patient who presents with findings suggestive of this disorder, but in whom no history is available to suggest excessive exposure to an organic phosphorus or carbamate insecticide. A test dose of 1–5 mg of atropine in adolescents or adults, or 0.05 mg/kg in children up to an adult dose, should produce classic antimuscarinic findings such as mydriasis, tachycardia, and dry mucous membranes. The persistence of cholinergic signs and symptoms after an atropine challenge strongly suggests the presence of organic phosphorus compound or carbamate poisoning.72,105 However, some patients suffering from mild to moderate anticholinesterase poisoning may respond to these doses of atropine. Therefore, the reversal of cholinergic findings does not exclude poisoning by one of these agents.

Electromyogram (EMG) Studies Although measuring cholinesterase levels is most often used to estimate tissue and neuronal AChE activity, studies support the use of repetitive nerve stimulation testing as an accurate method of quantifying AChE inhibition at the neuromuscular junction.5,6,19 Spontaneous repetitive potentials or fasciculations following single-nerve stimulation resulting from persistent ACh at nerve terminals can be a sensitive indicator of AChE inhibition at the motor endplate, and may be useful in the early diagnosis of anticholinesterase poisoning.6 This type of evaluation may also be of benefit in early detection of rebound cholinergic crisis caused by continued insecticide absorption or redistribution from adipose, or onset of an intermediate syndrome (see below).5,19

Differential Diagnosis The differential diagnosis for cholinergic poisoning is divided into three main categories (Table 88–3). The first group comprises other noninsecticidal anticholinesterase agents. In addition to organic phosphorus and carbamate insecticides, this includes the medicinal anticholinesterases neostigmine, pyridostigmine, physostigmine, and echothiophate iodide. The most common population to suffer cholinergic poisoning syndrome from medicinal anticholinesterases is patients with myasthenia gravis who are administered excessive pyridostigmine. This group of medicinals and toxins should all produce low butyrylcholinesterase or red blood cell AChE activity. Some of these agents, like neostigmine, will not cross the blood-brain barrier and would only cause peripheral symptoms in overdose. Newer agents used to treat Alzheimer disease, such as tacrine, are also organic phosphorous compounds, but symptomatic overdose of these agents has not yet been reported. The next category of compounds producing a cholinergic poisoning syndrome contains agents with cholinomimetic activity. These compounds directly stimulate muscarinic or nicotinic cholinergic receptors, but do not inhibit AChE. In this case, bu-

TABLE 88–3.

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Categories of Cholinergic Poisoning

Anticholinesterase agents Organic phosphorus insecticides Organic phosphorus ophthlamic preparations Carbamate insecticides Carbamate medicinal preparations Cholinomimetics Pilocarpine Carbachol Aceclidine Methacholine Bethanechol Muscarine-containing mushrooms Nicotine alkaloids Coniine Lobeline Nicotine

tyrylcholinesterase and red blood cell cholinesterase activity should be normal. Cholinomimetic medicinal agents include preparations of carbachol, aceclidine, methacholine, pilocarpine, and bethanechol. Muscarine-containing mushrooms can be cholinomimetic, and some patients ingesting them can present with salivation, diaphoresis, and vomiting (Chap. 76). Finally, poisonings from nicotine alkaloids (eg, nicotine, lobeline, and coniine) cause CNS, autonomic, and skeletal muscle symptoms similar to those occurring in organic phosphorus and carbamate toxicity (Chap. 73).

MANAGEMENT Organic Phosphorus Compounds The earliest cause of death from organic phosphorus or carbamate poisoning is from respiratory failure and hypoxemia as a consequence of coma and convulsions, nicotinic effects on skeletal muscles, such as weakness and paralysis, and excessive muscarinic effects on the cardiovascular and pulmonary system causing bronchospasm, bronchorrhea, aspiration, bradydysrhythmias, and hypotension. Initial treatment is directed at ensuring an adequate airway and ventilation, and at reversing excessive muscarinic effects. Convulsions not secondary to hypoxemia are treated with standard anticonvulsants (benzodiazepines, barbiturates). Maintenance of the patient’s airway is best assured by early endotracheal intubation and positive pressure ventilation in comatose victims, in those patients with significant weakness, or in those patients unable to handle copious secretions that may accompany the poisoning. Only a nondepolarizing neuromuscular blocking agent should be used to induce pharmacologic paralysis. The metabolism of the depolarizing agent succinylcholine will be extended in the presence of low butyrylcholinesterase activity, resulting in paralysis that can be prolonged up to 24 hours or more.128 The second priority in management is to control excessive muscarinic activity. Atropine sulfate competitively antagonizes ACh at muscarinic receptors to reverse excessive secretions, miosis, bronchospasm, vomiting, diarrhea, diaphoresis, and urinary incontinence.65,105 Intravenous doses should begin at 1–5 mg in adolescents and adults, and at 0.05 mg/kg in children up to adult

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doses, and should be repeated every 2–3 minutes until atropinization occurs.43,105,158 Atropinization is present when the patient exhibits dry skin and mucous membranes, decreased or absent bowel sounds, tachycardia, reduced secretions, no bronchospasm (in absence of other causes such as aspiration), and, usually, mydriasis. An improvement in pulmonary secretions should be the target in atropine therapy and can be guided by following lung sounds and oxygenation. Tachycardia is not a contraindication to atropine therapy. Although the pupils are often helpful in gauging the need for atropine, the miosis encountered in severe ingestions and by direct ocular exposure to organic phosphorus agents may respond only to topical ophthalmic atropine.123 Isolated pulmonary manifestations may respond to administration of nebulized atropine or ipratropium, and this treatment can accompany parenteral administration of these agents. Large doses of atropine may be needed to reverse the bronchospasm, bronchorrhea, bradycardia, and heart block associated with severe organic phosphorus pesticide toxicity.43,50,87,106 Some patients with mild symptoms need only 1 or 2 mg of atropine for reversal of cholinergic toxicity, but the moderately poisoned adolescent or adult commonly requires doses as large as 40 mg.32,63 Severe poisonings may necessitate even higher doses. In severely ill adults, 5-mg boluses of atropine repeated every 2–3 minutes for stabilization may be used. Adults have received over 1000 mg of atropine in 24 hours (with pralidoxime) without producing antimuscarinic effects,32,148 and total doses as large as 11,000 mg during the course of treatment have been reported.59 Children have been managed with continuous infusions of atropine starting at 0.025 mg/kg/h,7,78 and continuous infusions have been used for as long as 32 days in severely poisoned patients.44 Adult infusions of atropine can begin at 0.5–1 mg/h and should be titrated as needed. Atropine is not effective for reversing excessive nicotinic effects. Therefore, the patient who improves after receiving atropine must still be closely monitored in an intensive care setting for impending respiratory failure. When antimuscarinic CNS toxicity becomes evident, yet peripheral cholinergic findings necessitate the administration of more atropine (eg, bradycardia, bronchorrhea, vomiting), glycopyrrolate bromide can be substituted for atropine because its quaternary ammonium structure limits CNS penetration. The intravenous dose of glycopyrrolate is 1–2 mg, repeated as needed in adolescents and adults, or 0.025 mg/kg in children up to adult doses. Although scopolamine has also been used in place of atropine, it may cause more pronounced CNS effects. A urinary catheter should be inserted in all atropinized patients to prevent urinary retention.

Pralidoxime Although phosphorylated AChE undergoes hydrolytic regeneration at a very slow rate, this process can be markedly enhanced by using an oxime such as pralidoxime chloride (2-PAM) (Fig. 88–5).151 In addition to rejuvenating AChE, pralidoxime may also reverse organic phosphorus compound toxicity by directly inactivating free organic phosphorus molecules and by exhibiting an apparent antimuscarinic effect on nervous tissue.43,71 Regeneration of AChE lowers ACh concentrations to normal levels, reversing both muscarinic and nicotinic effects. An immediate rise in red blood cell cholinesterase activity, presumably paralleling a rise in neuronal AChE activity, is often noted after the administration of pralidoxime. Unfortunately, pralidoxime is unable to rejuvenate

Figure 88–5. Mechanism of rejuvenation of acetylcholinesterase by pralidoxime. The positively charged aromatic nitrogen of pralidoxime is “attracted” to the anionic site of acetylcholinesterase, allowing the reactive oxime portion of the molecule to position itself over the phosphorylated active site of the enzyme. Pralidoxime then becomes phosphorylated, rejuvenating acetylcholinesterase.

active enzyme from the organic phosphorus compound–AChE complex that has undergone aging.32,54 Therefore, pralidoxime therapy is most effective if started early in the course of toxicity.30,127 It is presumed that most phosphorylated AChE will be aged within 24–48 hours of exposure.43,143 The actual rate of aging, however, varies significantly among organic phosphorus agents. In addition, circulating organic phosphorus pesticide concentrations have been measured for as long as 48 days after exposure,18,44 either because of prolonged absorption from the GI tract or, more likely, because of redistribution from fat stores.7,32,43,44,105 Therefore, some AChE may still be undergoing new inhibition for days or weeks after ingestion in symptomatic patients, and such inhibition may be reversible by pralidoxime.149 Case reports support this by noting dramatic effects in reversing paralysis, weakness, and cholinergic symptoms after late administration of pralidoxime.19–21,23,94,105,109 The initial dose of pralidoxime in adolescents and adults is 1–2 g intravenously over 10–15 minutes (30–50 mg/kg IV over 10–15 minutes in children up to adult doses).65 Minimal plasma concentrations of 4 µg/mL are estimated to be necessary for maintenance of enzyme reactivation.140 Bolus dosing of pralidoxime every 4–8 hours is ineffective in maintaining these levels,92 and a constant

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infusion appears to be more appropriate. Present recommendations in adults are to begin the infusion at 250–500 mg/h, titrating to symptoms.65 Alternative dosing by weight in other studies suggests 4–5 mg/kg as a loading dose over 15–30 minutes, followed by a continuous infusion of 2–4 mg/kg/h to maintain serum concentrations.92,150 Pharmacokinetics of pralidoxime in children are extremely variable and different from adults.125 Reports suggest that loading doses in children should be 25–50 mg/kg of pralidoxime intravenously over 15–30 minutes (not to exceed adult doses, unless clinically indicated), followed by a continuous infusion of 10–20 mg/kg/h. This regimen is efficacious in treating symptoms associated with organic phosphorus pesticide poisoning and does not result in pralidoxime-associated toxicity.37,125 Side effects of pralidoxime are usually minimal at normal doses.47,108 Severely poisoned patients have received 0.5 g/h for weeks without adverse effects.44,105 Rapid infusion can cause mild cholinergic effects because of transient blockade of AChE105 and has resulted in neuromuscular blockade and central respiratory depression.65,143 Some effects of pralidoxime are not well understood. Unlike atropine, the quaternary ammonium compound structure of pralidoxime should prevent it from crossing the blood-brain barrier.105 But case reports of organic phosphorus compound toxicity describe pralidoxime-induced reversal of convulsions and improvements in mental status and electroencephalograms not attributable to improved ventilation or perfusion.35,41,52,53,67,83,84,110 Pralidoxime is not equally effective in reversing cholinergic symptoms in all types of organic phosphorus compound poisonings.65,105 It is particularly efficacious in reversing toxicity from parathion, diazinon, methyl parathion, EPN, TEPP, dimethoate, and dichlorvos.43 Dimethoxy compounds, such as malathion and methyl demeton, can be more resistant to reversal.43 Diazepam may improve survival in victims of severe organic phosphorus pesticide poisoning. Animal studies demonstrate that administering diazepam with oximes in the treatment of organic phosphorus nerve gases (sarin, soman, tabun, VX) can increase survival and decrease the incidence of seizures and neuropathy.71,72,76,84,103,122 Diazepam can also decrease cerebral morphologic damage resulting from organic phosphorus compound– related convulsions.91,136

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coal may adsorb some organic phosphorus insecticides, there are no studies evaluating whether repeat administration of activated charcoal changes the outcome or clinical course of patients with organic phosphorus pesticide poisoning. Thus, it is recommended that patients with anticholinesterase poisoning receive a single dose of 1 g/kg activated charcoal because ileus may develop during atropine therapy.

Disposition Even after atropinization, patients with anticholinesterase poisoning should be continuously observed for evidence of deteriorating neurologic function and the potential for paralysis. It is common for patients to develop confusion and agitation following large doses of atropine as a consequence of the central antimuscarinic effects. Red blood cell and butyrylcholinesterase activities should be measured intermittently after the institution of pralidoxime therapy.64,76,135,149,154 Butyrylcholinesterase may not normalize with pralidoxime therapy because this enzyme does not contain an anionic site to attract the compound. Red blood cell cholinesterase activity may be markedly depressed long after neuronal AChE levels have returned to normal. Therefore, it is not unusual to send a patient home with subnormal cholinesterase activity as long as the individual remains asymptomatic. A significant fall in cholinesterase activity may reflect redistribution of insecticide from fat stores or prolonged absorption and may be accompanied by the redevelopment of cholinergic symptoms 3 or 4 days after initial resolution of symptoms.32,43,94 Further deterioration of cholinesterase activity should be treated by reinstituting a pralidoxime infusion, even though the patient may still be asymptomatic. After another 24 hours of pralidoxime, assuming the patient is still asymptomatic, pralidoxime can be halted again, and red blood cell and butyrylcholinesterase activities monitored. When available, electromyographic studies detecting signs of motor endplate dysfunction and early AChE inhibition may be a more sensitive method for identifying recurrent cholinergic toxicity.6 When a patient becomes asymptomatic and has not needed pralidoxime and atropine for 1–2 days, and the cholinesterase activity is documented to be stable (independent of AChE activity), the patient may be discharged. It is important that the patient not wear clothing home that was worn when the poisoning occurred.

Decontamination Rapid cutaneous absorption of organic phosphorus pesticides and carbamates necessitates removal of all clothing. Medical personnel should avoid self-contamination by wearing neoprene or nitrile gloves. Double-gloving with standard vinyl gloves may be protective for short intervals. Skin should be triple-washed with water, soap, and water, and rinsed again with water. Although alcoholbased soaps are sometimes recommended to dissolve hydrocarbons,40 these products can be difficult to find, and expeditious skin cleansing should be the primary goal. Cutaneous absorption can also occur as a result of contact with vomitus and diarrhea if the initial exposure was through ingestion. Oily insecticides may be difficult to remove from thick or long hair, even with repeated shampooing, and shaving scalp hair may be necessary. In acute ingestions, if emesis has not occurred, evacuation of stomach contents is recommended. Because the onset of coma, seizures, and paralysis can be rapid, lavage is the only option if gastric emptying is desired, and induced emesis should be avoided. Although there are data suggesting that activated char-

Carbamates The treatment of patients with carbamate poisoning is identical to that of organic phosphorus compound poisoning with two exceptions. First, it has been suggested to avoid pralidoxime in monomethylcarbamate exposure because animal data imply that pralidoxime may increase AChE inactivation in carbaryl poisoning.43,75,81 However, other studies and subsequent anecdotal experience have found that pralidoxime is useful in treating intoxications with the less common dimethylcarbamates such as isolan,43 and may not adversely impact monomethylcarbamate poisoning in humans. Comparative human data investigating the use of pralidoxime in carbamate poisonings are lacking. Fortunately, because of the rapid hydrolysis of the carbamate-AChE complex, symptoms, including weakness and paralysis, usually resolve within 24–48 hours without pralidoxime therapy. Administering pralidoxime to a poisoned patient in a cholinergic crisis is appropriate if it is unknown whether the patient is suffering from organic phosphorus or carbamate pesticide poisoning. If the poi-

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soning is from a carbamate pesticide, pralidoxime therapy may not be necessary, but should not prove detrimental. Second, significant inhibition of red blood cell and butyrylcholinesterase by carbamates generally does not last for more than 1–2 days, assuming absorption is complete. Patients usually have normal red blood cell and butyrylcholinesterase values by the time of discharge. There are no reported cases of recurrent or delayed poisonings following carbamate insecticide intoxication. Therefore, repeating cholinesterase tests after patients are asymptomatic is usually unnecessary.

Chronic Toxicity Illness may also result from chronic exposure to excessive amounts of organic phosphorus insecticides. Chronic organic phosphorus compound poisoning is most common in workers regularly coming in contact with these substances, but it may also occur in individuals who have repeated exposures to excessive amounts of organic phosphorus insecticides in their living environments. Cholinergic ophthalmic preparations can lead to toxicity in this manner.88 Although tolerance to all systemic effects (including death in rats) of these compounds may be observed with long-term exposures,43 persons undergoing such contact may become symptomatic after variable lengths of time. Symptoms can range from vague neurologic complaints, such as weakness and blurred vision, to miosis, nausea, vomiting, diarrhea, diaphoresis, and other cholinergic effects.88,96,119 Red blood cell cholinesterase activity is the most sensitive measure of chronic poisoning.43,56

Delayed Syndromes Intermediate Syndrome. Delayed muscle weakness without fasciculations or cholinergic features can be noted in patients 24–96 hours after acute organic phosphorus compound poisoning.51,65,111,115,121,131 This phenomenon was first described in 1987, and is termed the “intermediate syndrome” (IMS).131 The majority of reported cases of IMS presented initially with cholinergic signs and symptoms that improved with atropine and oxime therapy over the first day or two after the exposure. Relapse with peripheral neurologic impairment caused by IMS is usually recorded around 48 hours after presentation. IMS is seen most often in patients poisoned with parathion, methylparathion, diazinon, malathion, fenthion, monocrotophos, dimethoate, and methamidophos.51,131 A redistribution of the lipophilic pesticide from adipose tissue is suggested as an etiology,19,21–25,42,80,133 but there are no data suggesting that the syndrome is caused by anticholinesterase activity. There is growing speculation that IMS may result from inadequate oxime therapy,19–21 although recent case reports question this theory.138 The most frequently encountered clinical findings of IMS include weakness, cranial nerve palsies, and areflexia. Fasciculations are seen in some cases. Level of consciousness is rarely affected. The muscle weakness in these patients can progress to respiratory distress and paralysis.51,115,121,131 The most commonly affected muscles are the facial, extraocular, palatal, respiratory, and those of the proximal limbs.51,121,131 Clinical examination remains the most reliable means of predicting the occurrence of IMS.21 Electromyograms will often show tetanic fade in these patients, and suggest both pre- and postsynaptic involvement.65 However, repetitive nerve stimulation may not always accurately predict the occurrence or severity of IMS.21

The treatment of IMS is largely supportive with airway protection and ventilatory assistance. There are no substantial data demonstrating that pralidoxime or atropine is effective in the treatment of this disorder, although patients may be on these medications for control of cholinergic symptoms. The weakness and paralysis commonly resolve in 5–18 days.51,65,131 Encephalopathy and Peripheral Neuropathies. Peripheral neuropathies can occur after chronic organic phosphorus pesticide exposures and several days or weeks after acute exposures. This disorder appears to result from inhibition of an enzyme within nervous tissue named neurotoxic esterase or neuropathy target esterase (NTE).61,65,111 Symptoms appear to be initiated by the phosphorylation of this enzyme, or perhaps of some related compound, followed by aging of the complex.157 Such neuropathies may even result from exposure to organic phosphorus compounds that do not inhibit red blood cell cholinesterase or produce clinical cholinergic toxicity.11 Some of the more commonly implicated chemicals include triaryl phosphates, such as triorthocresyl phosphate (TOCP), and dialkyl phosphates, such as merphos, mipafox, and chlorpyrifos.62,105 Pathologic findings in anticholinesterase neuropathy demonstrate effects primarily on large distal neurons, with axonal degeneration preceding demyelination.104 Contaminated foods and beverages can be responsible for epidemics of organic phosphorus compound–induced delayed polyneuropathies and encephalopathy. In the 1930s, thousands of individuals in the United States became weak or paralyzed after drinking rum containing triorthocresyl phosphate, an outbreak nicknamed “Jamaican ginger paralysis.”3,95,100,101 Contaminated cooking and mineral oils were connected with outbreaks of delayed polyneuropathies in Vietnam and Sri Lanka.28,129,130 Vague distal muscle weakness and pain are often the presenting symptoms, but weakness may progress to paralysis.38,49 The onset and clinical course of these symptoms do not seem to be altered by the administration of atropine or pralidoxime.38,105,146 Pyramidal tract signs may appear weeks to months after exposure.65,146 Electromyograms and nerve conduction studies may be helpful in diagnosing this disorder and differentiating it from similar presentations such as Guillain-Barré syndrome.1,133 Recovery in these patients is variable over months to years, with residual deficits common.4,101,132 Delayed neuropathies are not usually associated with carbamate insecticides. One reason for this difference is presumed to be that aging of the complex is a requirement for neuron degeneration. Ironically, studies suggest that subgroups of carbamates may actually bind NTE and exert a protective effect against more toxic organic phosphorus compounds.2 However, several cases of possible delayed neuropathy associated with carbamates have been reported.29,145,157 These cases involve ingestions of carbaryl, m-tolyl methylcarbamate, and carbofuran, include both sensory and motor tracts, and tend to resolve over 3–9 months. EMG findings in these subjects are variable.

Behavioral Toxicity Behavioral changes may also occur after acute and chronic exposure to organic phosphorus compounds.65 Symptoms include confusion, psychosis, anxiety, drowsiness, depression, fatigue, and irritability.43,94,128,141 Changes may be noted on the electroencephalogram of these patients and can last for weeks.43,48,56 Single photon emission computed tomography (SPECT) scanning re-

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vealed morphologic changes in the basal ganglia of one child following anticholinesterase poisoning.7 Even though no specific treatment is effective, most psychological abnormalities resolve within a year.45 Behavioral toxicity following carbamate exposure is extremely rare.

SUMMARY Anticholinesterase compounds are increasingly popular as pesticides. As the use of these agents expands, instances of both acute and chronic exposure are likely to become more common. The clinical presentation of toxicity from these compounds relates to their ability to stimulate the parasympathetic, and, to a lesser extent, the sympathetic branches of the autonomic nervous system. The early clinical findings in anticholinesterase poisoning may be mixed, with signs and symptoms that can include weakness, fasciculations, tachycardia, hypertension, vomiting, diaphoresis, diarrhea, salivation, small (or less often large) pupils, and either micturition or urinary retention. As acetylcholine concentrations continue to rise, the clinical course usually changes to mainly reflect muscarinic, skeletal muscle, and CNS abnormalities, with bradycardia, heart block, hypotension, bronchorrhea, bronchospasm, salivation, diaphoresis, lacrimation, vomiting, diarrhea, urinary incontinence, miosis, fasciculations and paralysis, hyperglycemia, and ketosis. Secretions may become copious from every orifice and hinder resuscitation efforts. With supportive care, some patients with anticholinesterase poisoning improve rapidly with signs and symptoms resolving within 2 or 3 days. In other cases, redistribution and absorption of these chemicals may continue for days, leading to prolonged or recurrent cholinergic symptoms and lengthy hospitalizations. Although measuring cholinesterase activity can be helpful when the diagnosis of anticholinesterase poisoning is not clear, most laboratories are unable to rapidly produce results of these tests. Expeditious recognition of cholinergic syndrome and appropriate therapy with atropine to control muscarinic activity and an oxime to regenerate acetylcholinesterase (in the case of organic phosphorus pesticides) can be coupled with supportive care to improve clinical outcome.

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145. Umehara F, Izumo S, Arimura K, Osame M: Polyneuropathy induced by m-tolyl methyl carbamate intoxication. J Neurol 1991;238: 47–48. 146. Vasilescu C, Alexianu M, Dan A: Delayed neuropathy after organophosphorus insecticide (Dipterex) poisoning: A clinical, electrophysiological and nerve biopsy study. J Neurol Neurosurg Psychiatry 1984;47:543–548. 147. Wang MH, Tseng CD, Bair SY: Q-T interval prolongation and pleomorphic ventricular tachycardia (“torsade de pointes”) in organophosphate poisoning: Report of a case. Hum Exp Toxicol 1998; 17:587–590. 148. Warriner RA, Nies AS, Hayes WJ: Severe organophosphate poisoning complicated by alcohol and turpentine ingestion. Arch Environ Health 1977;32:203–205. 149. Willems JL, De Bisschop HC, Verstraete AG, et al: Cholinesterase reactivation in organophosphorus poisoned patients depends on the plasma concentrations of the oxime pralidoxime methylsulphate and of the organophosphate. Arch Toxicol 1993;67:79–84. 150. Willems JL, Langenberg JP, Verstaete AG, et al: Plasma concentrations of pralidoxime methylsulphate in organophosphorus poisoned patients. Arch Toxicol 1992;66:260–266. 151. Wilson IB: Molecular complementarity and antidotes for alkylphosphate poisoning. Fed Proc 1959;18:752–758. 152. Wilson IB, Hatch MA, Ginsburg S: Carbamylation of acetylcholinesterase. J Biol Chem 1960;235:2312–2315. 153. Winteringham FW, Fowler KS: Substrate and dilutional effects on the inhibition of acetylcholinesterase by carbamates. Biochem J 1966;101:127–134. 154. Woodard CL, Calamaio CA, Kaminskis A, et al: Erythrocyte and plasma cholinesterase activity in male and female rhesus monkeys before and after exposure to sarin. Fundam Appl Toxicol 1994;23: 342–347. 155. Wulfsohn NL, Smith JC, Foldes FF: Acute phospholine intoxication after intracutaneous injection. Clin Pharmacol Ther 1966;7:44–47. 156. Yager J, McLean H, Hudes M, Spear RC: Components of variability in blood cholinesterase assay results. J Occup Med 1976;18: 242–244. 157. Yang PY, Tsao TCY, Lin JL, Lyu RK, Chiang PC: Carbofuraninduced delayed neuropathy. J Toxicol Clin Toxicol 2000;38:43–46. 158. Zwiener RJ, Ginsburg CM: Organophosphate and carbamate poisoning in infants and children. Pediatrics 1988;81:121–126.

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Pralidoxime Mary Ann Howland

tal muscle) and pseudocholinesterase or butyrlcholinesterase (found in plasma, liver, heart, pancreas, and brain).36 The organic phosphorus compound binds firmly to the serine-containing esteratic site on the enzyme, inactivating it by phosphorylation.22,36,51 This reaction results in the accumulation of acetylcholine at muscarinic, nicotinic, and central nervous system (CNS) synapses, leading to the manifestations of organic phosphorus poisoning. After the organic phosphorus pesticide binds to cholinesterase, the enzyme is inactivated and can undergo one of three processes: endogenous hydrolysis of the phosphorylated enzyme; reactivation by a strong nucleophile, such as 2-PAM; and biochemical changes that render the phosphorylated molecule inactive (“aged”). Endogenous hydrolysis of organic phosphorus compounds can be extremely slow and, for the most part, is considered insignificant. The positively charged quaternary nitrogen of pralidoxime is attracted to the negatively charged anionic site on the phosphorylated enzyme, bringing it in close proximity to the phosphorous moiety. Pralidoxime exerts a nucleophilic attack on the phosphate moiety, successfully competing for it and releasing it from the acetylcholinesterase enzyme.35 This action liberates the enzyme and permits enzymatic function.

EFFICACY RELATED TO TIME OF ADMINISTRATION AFTER POISONING Pralidoxime (2-hydroxyiminomethyl-1-methyl pyridinium chloride; 2-PAM) is the only currently available cholinesterase-reactivating agent in the United States.24 It is employed with atropine in the management of patients poisoned with organic phosphorus pesticides and, at times, in the management of patients poisoned with carbamate pesticides. Administration should be initiated as soon as possible after pesticide exposure, but pralidoxime may remain effective for days, and should be administered to all symptomatic patients independent of delay. Continuous infusion is preferable to intermittent administration for patients with serious toxicity and a prolonged therapeutic course may be required.

CHEMISTRY Pralidoxime is a quaternary ammonium oxime with a molecular weight of 173 daltons. The chloride salt exhibits excellent water solubility and physiologic compatibility.

REACTIVATION OF CHOLINESTERASES FOLLOWING ORGANIC PHOSPHORUS COMPOUND POISONING Organic phosphorus pesticides are powerful inhibitors of carboxylic esterase enzymes, including acetylcholinesterase (true cholinesterase, found in red blood cells, nervous tissue, and skele-

Early in vitro evidence suggested that to be successful, cholinesterase reactivators must be administered within 24–48 hours of exposure to the organic phosphorus compounds; otherwise the acetylcholinesterases would be irreversibly inactivated. It is no longer believed that there is a true time limitation on reactivator function. The 48-hour limit was derived from in vitro experiments using a small number of tightly bound compounds and reactivators such as nicotinehydroxamic acid methiodide (NHA), monoisonitrosoacetone (MINA), and oximes (obidoxime and pralidoxime methiodide). These studies used data from plasma pseudocholinesterase enzyme activity, which is now recognized to be relatively unaffected by oxime nucleophilic attack. The early data were accepted without adequate consideration of numerous factors such as relevance to human systems, the use of newer and less tightly bound compounds, temperature and pH variation, blood flow, fat solubility, and species specificity. Fat-soluble organic phosphorus compounds redistribute from fat stores over time, acting similarly to sustained-release products. They have not aged and they continue to reinhibit acetylcholinesterase for days. An in vitro experiment assessed the effect of aging on the ability of pralidoxime to regenerate rat erythrocyte and brain cholinesterases using three different organic phosphorus compounds.55 The rate of reactivation of erythrocyte and brain cholinesterases by pralidoxime was significantly decreased over time for fenitrothion and methylparathion, with no reactivation occurring at 48 hours. In contrast, a very high reactivation rate for ethylparathion was still apparent at 48 hours. This demonstrates that the structure of the organic phosphorus compound plays a significant role in the rate of aging and reactivation with pralidoxime. Fenitrothion and

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methylparathion are both O′O dimethylorganic phosphorus compounds, whereas ethylparathion is an O′O diethylorganic phosphorus compound.55 Other studies also suggest that 2-PAM and obidoxime are effective long after the previously suggested 48hour window of therapy.2,4,7,10,11,13,18,19,31,33

CARBAMATES Acetylcholinesterase inactivated by carbamates spontaneously reactivates with plasma elimination half-lives of 1–2 hours, with clinical recovery in several hours, and rarely in more than 24 hours.25 Although pralidoxime is rarely indicated for carbamate poisoning, it was previously suggested that pralidoxime was contraindicated following exposure to a carbamate. This approach was based solely on data derived from the study of a single carbamate—carbaryl (Sevin)—and inappropriately generalized to all carbamates. In vitro experiments demonstrated that pralidoxime had no effect on the reactivation of erythrocyte acetylcholinesterase carbamylated by aldicarb, methoxyl, and carbaryl.27 Pralidoxime decreased the rate of carbamylation by 16 insecticidal carbamates and only modestly increased the rates for 3, 1 of which was carbaryl.12 Animal studies demonstrated the beneficial effects of pralidoxime and obidoxime in doubling the lethal dose for a number of carbamate insecticides.37,48 However, with carbaryl (Sevin), obidoxime and pralidoxime mesylate worsened intoxication, possibly because the carbamate-oxime complex may be a more potent cholinesterase inhibitor than carbaryl alone.17,37,44,48 Even in the presence of carbaryl, atropine and the oxime resulted in survival data comparable to that of atropine alone.17 This evidence suggests that although pralidoxime is not usually a necessary adjunct to atropine in a pure carbamate overdose, it may occasionally improve morbidity and mortality.8 Pralidoxime should always be used in conjunction with atropine and should not be the sole therapy. Pralidoxime should not be withheld in a seriously poisoned patient because of the possibility that the agent may be a carbamate.

PHARMACOLOGY Pralidoxime’s action is most striking at nicotinic sites, often improving muscle strength within 10–40 minutes after administration.36,51 Pralidoxime is effective at muscarinic sites and may demonstrate synergism with atropine at these sites.14 The primary effect of atropine is to block the muscarinic and CNS symptoms of organic phosphorus compound poisoning. Because pralidoxime and atropine work synergistically, 2-PAM should rarely be used alone.14 Some organic phosphorus compounds respond much better to 2-PAM than do other compounds; it depends on the affinity of pralidoxime for the particular type of phosphorylated enzyme and its reactivating ability.59 The CNS effects of 2-PAM, a quaternary nitrogen compound,36 are controversial, as the molecule is not expected to cross the blood-brain barrier.30,36 Animal studies offer conflicting results, possibly because of the use of brain homogenate models rather than cortical slices.32 Rat studies using radiolabeled pralidoxime demonstrated a lack of any radioactivity in the CNS after IV administration.54 Following exposure to IV fenitrothion, intravenous administration of pralidoxime in rats failed to improve survival or to reactivate brain cholinesterase, whereas intramedullary prali-

doxime partially restored brain cholinesterase and eliminated fatalities.54 Clinical observations have certainly suggested a CNS action, with a return of consciousness in some cases.35,36,40,57 A 3-year-old child who was comatose from parathion intoxication was given 500 mg of 2-PAM IV over 15 minutes with continuous electroencephalographic (EEG) monitoring. Within 2 minutes there was a dramatic response on the EEG, followed by normalization of consciousness.28 Early work with cats led to a proposal that 4 µg/mL was a desired therapeutic concentration for pralidoxime.50 Recent in vitro work with human erythrocytes and a mouse hemidiaphragm model suggests that much higher serum concentrations are actually needed.59 Twenty percent reactivation was achieved with serum concentrations of 10 µg/mL, and 70% reactivation was achieved with concentrations of 17 µg/mL using paraoxon as the inhibitor.59 The understanding of the pathophysiology of the intermediate syndrome is inadequate to determine whether pralidoxime can prevent the development of the syndrome.49 Certain organic phosphorus pesticides may lead to the development of delayed onset neurotoxicity that cannot be prevented by pralidoxime treatment.

OTHER REVERSAL AGENTS To improve the central effect of pralidoxime, the dihydropyridine derivative of pralidoxime (2-PAM) was synthesized.5 This derivative, known as pro-2-PAM, acts as a “prodrug,” or drug carrier, which allows passage through membranes such as the blood-brain barrier. Once across the membranes, in vivo oxidation converts pro-2-PAM to the active species, demonstrating a 13-fold higher level of 2-PAM in the brain than PAM administered under similar conditions. Further experiments supported the significantly increased central effects of pro-2-PAM.43 The use of sugar oximes (the molecular combination of glucose with 2-PAM derivatives) to promote CNS penetration appears promising.41 Obidoxime (Toxogenin) is an oxime used outside the United States that contains two active sites per molecule and is considered by some to be more effective than 2-PAM.14,59 An in vitro study utilizing human erythrocyte acetylcholinesterase supported the superiority of obidoxime to pralidoxime in reactivating acetylcholinesterase inhibited by the dimethylphosphoryl and diethylphosphoryl organic phosphorus compounds paraoxon, mevinphos, and malaoxon. Obidoxime is approximately 4 times more active in reactivating acetylcholinesterase than is pralidoxime.59 The H series of oximes (named after Hagedorn) were developed to act against the chemical warfare nerve agents. These agents have superior effectiveness against certain chemical warfare agents (ie, sarin, VX) but they are less efficacious in organic phosphorus insecticide poisoning, and their toxicity profile is inadequately defined.9,23,26,29,42,59 In addition to reactivating acetylcholinesterases, these agents have direct central and peripheral anticholinergic effects.42

DURATION OF TREATMENT The signs and symptoms of organic phosphorus compound poisoning are usually manifest within 12–24 hours.36 Delayed manifestations occur with the fat-soluble organic phosphorus compounds, such as fenthion or chlorfenthion, and other compounds requiring metabolic conversion to active agents, such as

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parathion, which undergoes hepatic conversion to paraoxon. The route of exposure may also influence the onset of systemic symptoms; for example, there may be a delay following dermal contact, which does not occur following ingestion or inhalation. When symptoms are delayed or prolonged, or when treatment is delayed, prolonged therapy with 2-PAM may be indicated.1,7,33 In one case of poisoning with the fat-soluble organic phosphorus compound fenthion, there was a 5-day delay before cholinergic symptoms appeared, and some symptoms persisted for 30 days.33 Pralidoxime and atropine were administered continuously in varying doses for most of that period.

PHARMACOKINETICS AND PHARMACODYNAMICS Pralidoxime pharmacokinetics are characterized by a two-compartment model. Pharmacokinetics vary depending on whether calculations are determined in healthy volunteers or poisoned patients. In volunteers, the steady-state volume of distribution is about 0.8 L/kg and the half-life is 75 minutes.20,47 Pralidoxime is renally excreted, and within 12 hours, 80% of the dose has been recovered unchanged in the urine.47 Thiamine administered intravenously at 100 mg/h for 2.5 hours prolonged the half-life, increased the volume of distribution and peak plasma concentrations, and decreased the plasma, intercompartmental, and renal clearances when pralidoxime (5 mg/kg) was given intravenously.21 Thiamine and pralidoxime are both strong bases, and thiamine might decrease renal clearance through competition for renal secretion.21 The benefit of using thiamine in poisoned patients to prolong the plasma half-life of pralidoxime has never been tested. A dose of 10 mg/kg of 2-PAM IM or IV to volunteers results in peak plasma concentrations of 6 µg/mL (reached 5–15 minutes after IM injection) and a plasma half-life of approximately 75 minutes.47 Animal data suggest that a plasma level greater than 4 µg/mL is effective against nicotinic symptoms, but recent studies suggest that even higher levels may be necessary.6,50,59 Following a standard IV 30-minute infusion dose of 1 g of 2-PAM in a 70-kg man, the plasma level was less than 4 µg/mL at 1.5 hours. In a simulated model, a continuous infusion of 500 mg/h of 2-PAM leads to a level greater than 4 µg/mL after 15 minutes, which can be maintained throughout the infusion.52 In a human volunteer study, an intravenous loading dose of 4 mg/kg over 15 minutes followed by 3.2 mg/kg/h for a total of 4 hours maintained pralidoxime serum concentrations greater than 4 µg/mL for 257 minutes. The same total dose, 16 mg/kg, administered over 30 minutes only maintained those concentrations for 118 minutes.31 In poisoned patients, and in those patients receiving continuous infusions of pralidoxime as opposed to intermittent infusions, the volume of distribution and the half-life are increased. A volume of distribution of 2.77 L/kg, an elimination half-life of 3.44 hours, and a clearance of 0.57 L/kg/h have been reported in poisoned adults administered a mean loading dose of 4.4 mg/kg followed by an infusion of 2.14 mg/kg/h.57 In poisoned children and adolescents, the volume of distribution varied with severity of poisoning from 8.8 L/kg in the severely poisoned patients compared with 2.8 L/kg in those moderately poisoned.45 After a mean loading dose of 29 mg/kg followed by a continuous infusion of about 14 mg/kg/h, a steady-state serum concentration of 22 µg/mL, a halflife of 3.6 hours, and a clearance of 0.88 L/kg/h were calculated.45

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Oral administration of salts of 2-PAM (not used clinically because of anticholinesterase poisoning–induced vomiting) demonstrated peak concentrations at 2–3 hours, a biologic half-life of 1.7 hours, and an average urine recovery of 27% of unchanged 2-PAM.25

ADVERSE EFFECTS Adverse effects of therapeutic doses of 2-PAM in humans are minimal and may not be evident unless plasma levels are exceptionally high at >400 µg/mL.15,16,34–36,40,52 Transient dizziness, blurred vision, and elevations in diastolic blood pressure may be related to the rate of administration.20,21,31 Rapid IV administration has produced sudden cardiac and respiratory arrest.38,46,58

DOSING AND ADMINISTRATION The optimal dosage regimen for pralidoxime is unknown. Traditionally the recommended initial adult dose is 1–2 g in 100 mL of 0.9% sodium chloride solution given intravenously over 15–30 minutes.39 Rapid administration (bolus or >200 mg/min in adults) can lead to respiratory and cardiac arrest. The pediatric dose is 20–40 mg/kg as a loading dose given intravenously over 30 minutes. These initial doses can be repeated in 1 hour if muscle weakness and fasciculations are not relieved. Thereafter, additional doses may be needed every 3–8 hours as long as signs of poisoning recur.39 Alternatively, a loading dose followed by a continuous maintenance infusion has been reported to be safe and effective in a limited number of adults and children.45,53,56,57 Serious intoxication may require continuous infusion of 500 mg/h in adults and 10–20 mg/kg/h in children. One author suggests a loading dose of 25–50 mg/kg in children, depending on the severity of the poisoning, to be followed by a continuous infusion of 10–20 mg/kg/h.45 Continuous infusion may be more effective than multiple single injections.34,36 In the case of pulmonary edema, the dose can be given as a 5% solution (concentrations above 35% w/v produce muscle necrosis in animals).47 Long-term dosing may be necessary, depending on the patient’s clinical condition.

AVAILABILITY Pralidoxime chloride (Protopam) is supplied in 20-mL vials containing 1 g of powder, ready for reconstitution with sterile water for injection.24

SUMMARY Pralidoxime is an effective reactivator of acetylcholinesterase in many organic phosphorus compound poisonings. It primarily reverses neuromuscular manifestations, but has some CNS effects. New oximes may improve CNS penetration and efficacy. Pralidoxime and atropine are synergistic and should be used together in the management of organic phosphorus poisonings. If a patient requires multiple doses of atropine for muscarinic symptoms, then the use of 2-PAM is indicated. In symptomatic patients, acetylcholinesterase is partially inactivated and will remain so until new enzyme is synthesized or inactivated enzyme is reactivated. The

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resolution of all signs or symptoms with atropine alone indicates only that inactivation is less than 50% and that endogenous hydrolysis of phosphorylated enzyme is sufficient to eliminate symptoms. This clinical response does not mean, however, that the enzyme systems are fully active; patients may still benefit from enzyme regeneration with the safe and effective antidote pralidoxime. Finally, because newer fat-soluble organic phosphorus pesticides are currently available, it may be necessary to administer atropine and 2-PAM for more prolonged periods of time than previously suggested.50

18. 19.

20.

21. 22.

ACKNOWLEDGMENT

23.

Cynthia K. Aaron contributed to this discussion in a previous edition.

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41. Rachaman E, Ashani Y, Leader H, et al: Sugaroximes, new potential antidotes against organophosphorus poisoning. Arzneimittelforschung 1979;29:875–876. 42. Rousseaux CG, Du AK: Pharmacology of HI-6, an H-series oxime. Can J Physiol Pharmacol 1989;67:1183–1189. 43. Rump S, Faff J, Borkowska G, et al: Central therapeutic effects of dihydro-derivative of pralidoxime (pro-2-PAM) in organophosphate intoxication. Arch Int Pharmacodyn Ther 1978;232:321–331. 44. Sanderson DM: Treatment of poisoning by anticholinesterase insecticides in the rat. J Pharm Pharmacol 1961;13:435–442. 45. Schexnayder S, James L, Kearns G, Farrar H: The pharmacokinetics of continuous infusion pralidoxime in children with organophosphate poisoning. J Toxicol Clin Toxicol 1998;36:549–555. 46. Scott RJ: Repeated asystole following PAM in organophosphate selfpoisoning. Anesth Intensive Care 1986;4:458–460. 47. Sedell FR, Groff WA: Intramuscular and intravenous administration of small doses of 2-pyridinium aldoxime methylchloride to man. J Pharm Sci 1971;60:1224–1228. 48. Sterri S, Rognerud B, Fiskum S, Lyngaas S: Effect of toxogenin and P2S on the toxicity of carbamates and organophosphorus compounds. Acta Pharmacol Toxicol 1979;45:9–15. 49. Sudakin D, Mullins M, Horowitz Z, et al: Intermediate syndrome after malathion ingestion despite continuous infusion of pralidoxime. J Toxicol Clin Toxicol 2000;38:47–50. 50. Sundwall A: Minimum concentrations of n-methyl pyridinium-2aldoxime methane sulphonate (PS2) which reverse neuromuscular block. Biochem Pharmacol 1961;8:413–417. 51. Taylor P: Anticholinesterase agents. In: Hardman JG, Limbind LE, Molinoff PB, Ruddoev RW, eds: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, Macmillan, 1996, pp. 100–119.

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52. Thompson DF, Thompson GD, Greenwood RB, Trammel HL: Therapeutic dosing of pralidoxime chloride. Drug Intell Clin Pharm 1987; 21:1590–1593. 53. Tush G, Anstead M: Pralidoxime continuous infusion ion the treatment of organophosphate poisoning. Ann Pharmacother 1997;31: 441–444. 54. Uehara S, Hiromori T, Isobe N, et al: Studies on the therapeutic effect of 2-pyridine aldoxime methiodide (2-PAM) in mammals following organophosphorous compound (op)-poisoning (report III): Distribution and antidotal effect of 2-PAM in rats. J Toxicol 1993;18: 265–275. 55. Uehara S, Hiromori T, Suzuki T, et al: Studies on the therapeutic effect of 2-pyridine aldoxime methiodide (2-PAM) in mammals following organophosphorous compound (op)-poisoning (report II): Aging of op-inhibited mammalian cholinesterase. J Toxicol 1993;18: 179–183. 56. Willems JL, BeBisschop HC, Verstraete AG, et al: Cholinesterase reactivation in organophosphorus poisoned patients depends on the plasma concentrations of the oxime pralidoxime methylsulfate and of the organophosphate. Arch Toxicol 1993;97:79–84. 57. Willems JL, Langenberg JP, Verstraete AC, et al: Plasma concentrations of pralidoxime methyl sulfate in organophosphorus poisoned patients. Arch Toxicol 1992;66:260–266. 58. Wislicki L: Differences in the effect of oximes on striated muscle and respiratory centre. Arch Int Pharmacodyn Ther 1960;120:1–19. 59. Worek F, Backer M, Thiermann H, et al: Reappraisal of indications and limitations of oxime therapy in organophosphate poisoning. Hum Exp Toxicol 1997;16:466–472.

CHAPTER

89

INSECTICIDES: ORGANOCHLORINES, PYRETHRINS, AND DEET Michael G. Holland

A 2-year-old boy (weight, 15 kg) was brought to the Emergency Department (ED) after vomiting and having a witnessed seizure at home. The only history available was that the child had a cold and a “skin condition.” By pursuing the connection between seizures and a skin condition, the poison information specialist obtained further history that implicated lindane. The child’s grandmother was unable to read the instructions on the bottle, and had given him 1 teaspoon (5 mL, or 50 mg) of 1% lindane orally 3 times a day, rather than applying topically. The child probably received a total of 6 doses (300 mg over 2 days, or 20 mg/kg), the last dose being approximately 3 hours prior to admission. On examination, the child was alert, asymptomatic, with normal vital signs. He was given 1 g/kg (15 g) of activated charcoal aqueous slurry to adsorb any lindane remaining in the gastrointestinal tract. The child was observed in an intensive care setting for 12 hours. He remained asymptomatic, had no recurrence of seizures, and was discharged home in good condition.

ORGANOCHLORINES Organochlorine pesticides are complex, cyclic chlorinated hydrocarbons having molecular weights generally in the range of 300–550 Da. They are solids at room temperature (ie, nonvolatile). Most organochlorines have a negative temperature coefficient, making them more insecticidal at lower temperatures, and less toxic to warm-blooded organisms.102 Most act as central nervous system (CNS) stimulants. In contrast, chlorinated hydrocarbon solvents and fumigants are low molecular weight, alkyl compounds that are volatile liquids or gases, and that generally have CNS depressant effects (Chap. 86).19 The organochlorine pesticides are grouped into four categories based on their chemical structures and similar toxicities: (a) hexachlorocyclohexane (lindane, the γ isomer; with the commonly used misnomer γ-benzene hexachloride), the primary organochlorine pesticide still in common clinical and agricultural use in the United States. Isomerism is important, because the
and  isomers are CNS depressants and have no insecticidal properties.1,16,67 (b) Dichlorodiphenyltrichloroethane (DDT) and related analogues; (c) cyclodienes (the related isomers aldrin, dieldrin, and endrin; as well as heptachlor, endosulfan), and related compounds (toxaphene, dienochlor); and (d) mirex and chlordecone (Table 89–1; Fig. 89–1). These compounds differ substantially, both between and within groups, with respect to toxic doses, skin absorption, fat storage, metabolism, and elimination.18 The signs and symptoms of toxicity in humans, however, are remarkably similar within each group.

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Historical Perspectives Until the 1940s, commonly available pesticides included highly toxic arsenicals, mercurials, lead, sulfur, and nicotine.81 When Nobel Prize-winning chemist Paul Müller demonstrated the insecticidal properties of DDT in the early 1940s, a whole new class of pesticides was introduced.25 The organochlorine insecticides were inexpensive to produce, nonvolatile, environmentally stable, and had relatively low acute toxicity when compared to previous insecticides (see Table 89–1). Widespread use of these compounds occurred from the 1940s until the mid-1970s. They were highly effective and revolutionized modern agriculture, allowing unprecedented output from each acre of arable land. Because of their stability, organochlorines were used extensively in structural protection and soil treatments. Medical and public health applications of DDT and its analogues were also found in the control of typhus and eradication of malaria.18 By 1953, DDT alone was credited for saving an estimated 50 million lives, and with averting 1 billion cases of human disease.26 It has been suggested that because of this unprecedented impact on human health, DDT is the single most important factor in the population explosion that occurred between 1950 and 1970.26 However, the properties that made these chemicals such effective insecticides also made them environmental hazards: they are slowly metabolized, lipid soluble, chemically stable, and environmentally persistent. In her 1962 book Silent Spring, Rachel Carson, a biologist with the US Fish and Wildlife Service, demonstrated that organochlorines are bioconcentrated and biomagnified up the food chain.10 The organochlorine residues in predatory birds, most notably grebes, peregrine falcons, bald eagles, and pelicans, caused eggshell thinning and decreased reproductive success.32 These facts, and the finding of DDT residues in humans, led to the severe restriction or total ban of many organochlorines in North America and Europe.18 However, because they are still highly effective and very inexpensive, the organochlorines are widely used in developing countries, and will be for the foreseeable future.

Toxicokinetics of the Organochlorine Insecticides Absorption. All of the organochlorine pesticides are well absorbed orally and by inhalation; transdermal absorption is variable, depending on the particular compound. Absorption by any route may be affected by the vehicle, as well as the physical state (solid or liquid) of the pesticide. None of the organochlorines are water-soluble, and are usually either dissolved in organic solvents or manufactured as powders for dusting.

CHAPTER 89

TABLE 89–1.

INSECTICIDES: ORGANOCHLORINES, PYRETHRINS, AND DEET

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Classification of Organochlorine Pesticides Current U.S. EPA Registration

Acute Oral Toxicity

Dermal Absorption

Lipid Storage

Classes

CAS1 Registry #

Brand Name(s)

Hexachlorocyclohexanes

Lindane ( isomer) 58-89-9

Kwell

Topical scabicide; seed treatment: RED2 2001

Moderate

High

Low

Topical scabicide: seizures, CNS excitation; musty odor

DDT and analogues

DDTDichlorodiphenyltrichloroethane 50-29-3 Methoxychlor 72-43-5 Dicofol 115-32-2

Neocid, Ixodex, Anofex, others

Canceled 1972

Low to moderate

Low

Highest

Tremors, CNS excitation; odorless

Marlate

Suspended 1/14/2000

Low

Low

Less toxic DDT substitute

Kelthane

Residential use banned 1998; cotton, citrus, apple Citrus miticide

Low

Low

Moderate Low

Low

Low

Low

Much less environmental persistence than DDT

Cyclodienes and related compounds, toxaphene

Chlorbenzilate 510-15-6

Benzilan, BenzoChlor

Aldrin 309-00-2

Aldrex, Octalene, Toxadrin

Canceled 1974

High

High

High

Rapidly metabolized to dieldrin; mild “chemical” odor

Dieldrin 60-57-1

Dieldrite, Octalox, Quintox Hexadrin

Canceled 1974

High

High

High

Canceled 1974

Highest

High

None

Canceled 1988

Moderate

High

High

Stereoisomer of endrin; early and late seizures; odorless Most toxic organochlorine; rapid onset seizures; status epilepticus Early and late seizures occur

RED 2000

High

High

Low

Strong sulfur odor

Moderate

High

High

Toxic metabolite heptachlor epoxide; odor of camphor

Telodrin

Restricted: fire ant control; soil treatment Never registered in US

High

Moderate

High

Pentac

Canceled

NA

Low

Low

Alltox, Chemphene, Toxakil, others

Canceled 1982

Moderatehigh

Low

Low

Also inhibits Mg++- ATPase; mild “chemical” odor Toxic metabolite binds to GSH Seizures; terpene odor, often mixed with parathion

Chlordecone 143-50-0

Kepone

Canceled 1977

Moderate

High

High

Mirex 2385-85-5

Dechlorane

Canceled 1976

Low

High

High

Endrin 72-20-8 Chlordane 57-74-9 Endosulfan 115-29-7 Heptachlor 76-44-8 Isobenzan 297-78-9 Dienochlor 2227-17-0 Toxaphene (Polychlorinated Camphene) 800-35-2 Chlordecone and Mirex

Specific Characteristics

Octachlor, Toxichlor, others Thiodan, Cyclodan, others Drinox

“Kepone shakes”; seizures not seen; structurally similar to mirex (?) Converted to chlordecone; toxicity identical

1. Cas: Chemical Abstracts Service # provided here to facilitate Toxline, Medline database searches 2. RED: Registration Eligibility Decision

Dichlorodiphenyltrichloroethane (DDT) and its analogues methoxychlor, dicofol, and chlorbenzylate are very poorly absorbed transdermally, unless the pesticide is dissolved in a suitable hydrocarbon solvent.72 DDT has limited volatility, so that air concentrations are usually low, and toxicity by the respiratory route is unlikely.

All of the cyclodienes have significant transdermal absorption rates. In fact, cutaneous absorption of dieldrin is so high that toxicity by the dermal route is approximately 50% that of the oral route.18 Oral absorption of the cyclodienes is high, and significant poisonings have occurred when foodstuffs were contaminated with these pesticides;4 in addition, consuming pesticide residues

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Lindane (γ hexachlorocyclohexane)

Toxaphene

DDT Aldrin (metabolized to dieldrin)

Methoxychlor Dieldrin (metabolite of aldrin)

Endrin (stereoisomer of dieldrin)

Figure 89–1.

Chlordecone

Structures of various organochlorine Pesticides.

on feed sources has killed livestock and wild animals.86 Toxaphene is poorly absorbed through the skin in both acute and chronic exposures.80 Lindane is well absorbed after skin application, and has a documented forearm skin absorption rate in adults of 9.3% of a topically applied dose over 24 hours.28 Anatomic sites vary in their absorptive capacities: axillary rates are 3.6 times greater, while scrotal absorption is 42 times greater than that of forearm rates.9,31,43,87 Animal studies and case reports suggest that the young, the malnourished, and those who receive repeated topical doses may have increased accumulation and increased risk for seizures.68 Hot baths, the vehicle for the lindane, and a disturbed cutaneous integrity all enhance dermal penetration.88 Additionally, occlusive clothing or bandages substantially increases absorption, as does application to abraded or irritated skin,87 or to skin affected by dermatoses. The state of hydration of the skin also affects the amounts absorbed, so that bathing just prior to application can enhance absorption and increase the likelihood of toxicity.56,87 Lindane is a stable compound, and volatilizes easily when heated. It was used extensively in the past in home vaporizers, and toxicity was common via inhalation, as well as when these tablets were unintentionally ingested by children.18 Review of data when lindane was ingested therapeutically as an anthelmintic

demonstrates that 40 mg/d for 3–14 days often produced no symptoms.18 An epidemic of lindane poisoning related to the unintentional substitution of lindane powder for sugar in coffee demonstrated a delay of 20 minutes to 3 hours before the onset of nausea, vomiting, dizziness, facial pallor, severe cyanosis of the face and extremities, collapse, convulsions, and hyperthermia. Affected patients ingested an average of 86 mg/kg of lindane in a single dose.18 Mirex and chlordecone are efficiently absorbed via skin, by inhalation, and orally.27 Distribution. All organochlorines are lipophilic, a property that allows penetration to their sites of action in the nerves of both target and nontarget species.13 The fat-to-serum ratios at equilibrium are high, in the range of 660:1 for chlordane;35 220:1 for lindane;81 and 150:1 for dieldrin.19 Central nervous system redistribution of the organochlorines to the blood and then to fat may account for the apparent rapid CNS recovery in spite of the persistent substantial total body burden. In the rat model, there is a relationship between the concentration of DDT or dieldrin in the brain and the clinical signs produced after a single dose of the insecticide.18,22 Serum lindane levels peak at 6 hours, and have a half-life of 18 hours after topical application.29

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Metabolism. The high lipid solubility and very slow metabolic disposition of DDT, DDE (metabolite of DDT), dieldrin, heptachlor, chlordane, mirex, and chlordecone causes significant adipose tissue storage and increasing body burdens in chronically exposed populations.27,72 Organochlorines that are rapidly metabolized and eliminated, such as endrin (an isomer of dieldrin), endosulfan, lindane, methoxychlor, dienochlor, chlorbenzilate, dicofol, and toxaphene tend to have less persistence in body tissues, despite being highly lipid soluble.72 Most organochlorines are metabolized by the hepatic microsomal enzyme systems. They are dechlorinated, oxidized, and then conjugated. However, metabolism may result in the production of a more toxic metabolite, such as heptachlor to heptachlor epoxide, chlordane to oxychlordane, and aldrin to dieldrin. Animal studies show that most organochlorine pesticides are capable of inducing the hepatic microsomal enzyme systems.17,81,104 Enzyme induction has led to changes in biodegradation of the pesticide in rodents,93 and in certain animal models the acute toxicity of organic phosphorus compounds and carbamates may be reduced by the administration of organochlorines. This protective effect is presumably induced by the hepatic microsomal metabolism of the organic phosphorus compound because administering piperonyl butoxide, an inhibitor of the liver microsomal enzyme system, can block it.18,104 However, induction of hepatic enzymes has not been described in man, except in rare cases of massive exposure that had concomitant neurologic findings.27,35 Elimination. The elimination half-life of lindane is 21 hours in adults. Because of its rapid metabolism, it does not seem to bioaccumulate in tissues.57 The half-lives of fat-stored compounds such as DDT and chlordecone are measured in months or years. The primary route of excretion of the organochlorines is in the bile, but most also have detectable urinary metabolites. However, as with other compounds excreted in bile, most of the organochlorines have significant enterohepatic recirculation. There are also significant enterohepatic and enteroenteric recirculations of mirex and chlordecone.8,15,27 All of these lipophilic toxins are excreted in maternal milk.73

Mechanisms of Toxicity The same neurotoxic properties that make the organochlorines lethal to the target insects make them potentially toxic to higher animals. The organochlorines exert their effects in various areas of the nervous system, most importantly in the CNS.26 Electrophysiologic studies demonstrate that the organochlorine insecticides affect the neuronal membrane by either interfering with repolarization, by prolonging depolarization, or by impairing the maintenance of the polarized state of the neuron. The end result is hyperexcitability of the nervous system and repetitive neuronal discharges. DDT primarily affects the axon, by causing the voltage-dependent Na+ channels to remain open after depolarization, allowing repetitive action potentials to travel down the axon.60,89 Low-level stimuli cause exaggerated responses, seen clinically as prominent tremors and abnormal startle reflexes in test animals.41,98 Evidence of this mechanism of action is the amelioration of DDT-induced tremor by pretreatment with phenytoin, a sodium channel blocker, which reduces the ability of voltage-dependent Na+ channels to recover from inactivation.42,97

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The cyclodienes and lindane are γ-aminobutyric acid (GABA) antagonists. They inhibit the GABAA-dependent chloride channels at the GABA-receptor-chloride ionophore complex in the CNS by interacting at the picrotoxinin binding site.1,5,16,30,34,37,61,67 In fact, the degree of binding at this site correlates well with the amount of Cl influx inhibited and the relative neurotoxicity of each insecticide6,34 (see graphic of GABAA receptor [Figs. 10–9, 10–10, and 89–2]). Indeed, development of cyclodiene resistance seems to be related to alterations of the GABAA receptor in these affected insects.7,59 This also explains the efficacy of GABA agonists, such as benzodiazepines and phenobarbital, in treating the seizures and neurotoxicity of the cyclodienes38 and lindane.105 Similarly, toxaphene seems to exert its principal toxicity by inhibiting the GABAA receptor-chloride ionophore complex.80 The mechanisms of action of mirex and chlordecone are not as well understood. They appear to inhibit the Na+,K+-ATPase, as well as the Ca+2-ATPase “pumps.” However, lindane, DDT, and the cyclodienes also inhibit these enzymes yet have very different symptoms of toxicity. Phenytoin and serotonin agonists exacerbate the prominent tremor seen with chlordecone intoxication, but conversely attenuate the tremors in DDT poisoning.27 Mirex and chlordecone are poor inhibitors of the GABA-dependent chloride

GABAA chloride channel complex

Cl−

Cl−

Cl−

X G

Resting/Normal

Enhanced Chloride Channel Opening

Chloride Channel Closed

Benzodiazepine binding site Barbiturate binding site Volatile anesthetics binding site Picrotoxin binding site GABA binding site Picrotoxin, also lindane, cyclodienes GABA Figure 89–2. Chloride channel. Under resting conditions, a tonic influx of chloride maintains the nerve cell in a polarized state. Binding of GABA or an indirect acting GABA agonist (benzodiazepine, barbiturate, volatile anesthetic) opens the chloride channel. The subsequent chloride influx hyperpolarizes the cell membrane, making the neuron less likely to propagate an action potential in response to a stimulus. GABA antagonists, such as picrotoxin, close the chloride channel reducing chloride influx. The resulting decreased membrane polarity causes the neuron to become hyperexcitable to even to those stimuli that are normally subthreshold in nature. For a further discussion of the chloride channel see Chap. 10.

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

channel, suggesting that their mechanism of action is not at this site.6 Seizures have not been described with mirex or chlordecone. Organochlorines cause sensitization of the myocardium to endogenous catecholamines and predispose test animals to dysrhythmias, presumably in a fashion similar to the chlorinated hydrocarbon solvents (Chap. 86).72

Drug Interactions There are theoretical consequences of liver enzyme induction, such as enhanced metabolism of therapeutic drugs and/or reduced efficacy. Dysfunctional uterine bleeding was attributed to enhanced oral contraceptive metabolism induced by chlordane, but this was in a single patient with weeks of excessive exposure to chlordane.35 A large group of workers poisoned by chlordecone over many months had some increased hepatic microsomal activity, but no evidence of drug interactions or adverse clinical effects.27 Thus, induction of the hepatic microsomal enzyme system by organochlorines probably occurs only with extended, heavy exposure.72 There are no definitive reports of enhanced metabolism of therapeutic drugs or adverse reactions because of microsomal enzyme induction in man.

Laboratory Testing Blood levels document exposure, but may have no other clinical value, and are not readily available. Most humans studied have measurable levels of DDT in adipose tissue. In a study of a community with a very large exposure to DDT, serum DDT levels continued to increase with age. These increasing levels were not associated with any apparent adverse health effects, but were associated with increasing levels of the liver enzyme GGT.50 In a group of factory workers with a prolonged exposure to chlordecone, clinical signs and symptoms of toxicity seemed to correlate with blood levels.15 Again serum lindane levels document exposure, and most laboratories report toxic ranges. Lindane-exposed workers with chronic neurologic symptoms showed a blood lindane level of 0.02 mg/L.3,39 A limited series of acute oral ingestions suggests that a serum level of 0.12 mg/L correlates with sedation, and that 0.20 mg/L is associated with seizures and coma.3 However, after cutaneous application, lindane levels in the CNS–the site of its major toxic effect–are 3–12 times higher than serum levels.24,87

Clinical Manifestations Acute Exposure. In sufficient doses, organochlorine pesticides lower the seizure threshold and produce CNS stimulation, with resultant seizures, respiratory failure, and death.4,11,14,25,37,38,46,47,74,76 In the case of DDT, tremor may be the only initial manifestation. Nausea, vomiting, hyperesthesia of the mouth and face, paresthesias of face, tongue, and extremities, headache, dizziness, myoclonus, leg weakness, agitation, and confusion may subsequently occur. Seizures only occur after high doses.25,38,47 However, with lindane, the cyclodienes, and toxaphene, there often are no prodromal signs or symptoms, and more often than not, the first manifestation of toxicity is a generalized seizure.4,11,25,26,38,47,74,91 If seizures develop, they often occur within 1–2 hours of ingestion when the stomach is empty, but may be delayed as much as 5–6 hours when the ingestion follows a substantial meal.38 Seizures related to dermal application of 1% lindane for treatment of ectoparasitic diseases may occur following a single inap-

propriate application,52,68,95 or, more commonly, after repetitive prolonged exposures.48,70 The time from application to seizure onset can vary from hours to days. The seizures are often self-limited, but may recur and result in status epilepticus. The cyclodienes are notable for their propensity to cause seizures for several days following an acute exposure. If the seizures are brief and hypoxia has not occurred, recovery is usually complete. Electroencephalographic (EEG) abnormalities have been recorded before, during, and sometimes following seizures.47 Fever secondary to central mechanisms, increased muscle activity, and/or aspiration pneumonitis is common.26 The ingestion of combinations of agents may result in significantly increased toxicity because of synergy. This has been demonstrated for DDT and lindane.39 Single, acute, oral doses of 10 mg/kg or more of DDT are usually necessary to produce symptoms.38 Risks of Toxicity from Therapeutic Use of Lindane. Patients are at risk for developing central nervous system toxicity caused by 1% lindane from improper topical therapeutic use such as exceeding recommended application times or amounts, repeated applications, application following hot baths, and use of occlusive dressings or clothing after application. Toxicity also occurs after unintentional oral ingestion, as the illustrative case in this chapter demonstrates. Rarely, toxicity occurs after proper therapeutic use.3,20,29,48,52,63,68,70,88,94,95 An evaluation of published English-language case reports and those submitted to the Food and Drug Administration divided toxicity into those associated with concentrations of lindane greater than or less than 1%.48 Only 6 of 26 cases could be considered probably related to 1% lindane; 4 of these 6 cases were secondary to ingestion or inappropriate skin application. Young children appear at greatest risk, possibly because of greater skin permeability, increased ratio of body surface area to mass, immature liver enzymes, and oral absorption from licking the skin. Impaired hepatic metabolism may be contributory.39 The elderly may also be at risk. Three of 19 elderly patients treated topically with 1% lindane developed a single seizure of 5–10 minutes duration within 4–5 days of application.95 Although it was not recommended, all of the patients received a hot bath prior to lindane application, and they may have been given up to twice the recommended dose. This combined with atrophic skin, a generalized dermatitis in one patient, and perhaps an age-related increased sensitivity, may have predisposed these patients to seizures. Patients with preexisting conditions making them more prone to seizures may be at risk of developing toxicity from therapeutic use. This includes chlorpromazine treatment, CNS disease, skin absorption changes, bathing just prior to and dressing immediately after application.87 Chronic Exposure. Chlordecone, unlike the other organochlorines, produces an insidious picture of chronic toxicity related to its extremely long persistence in the body. Because of poor industrial hygiene practices in a makeshift chlordecone factory in Hopewell, VA, 133 workers were heavily exposed for 17 months in 1974–1975. They developed toxicity, which became known as the “Hopewell epidemic,” and consisted of a constellation of symptoms, most notably a prominent tremor of the hands, but also a fine tremor of the head and trembling of the entire body, known

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INSECTICIDES: ORGANOCHLORINES, PYRETHRINS, AND DEET

as the “Kepone Shakes.” Other symptoms included weakness, opsoclonus (rapid, irregular, dysrrhythmic ocular movements), ataxia, mental status changes, rash, weight loss, and elevated liver enzymes.27 Pseudotumor cerebri, oligospermia, and decreased sperm motility were also found in these factory workers.15 Severely affected workers even exhibited an exaggerated startle response, remarkably similar to that seen in animal studies.27 The exposures were so intense that some workers went home covered with chlordecone, and several workers’ wives developed neurologic symptoms, presumably from exposures while laundering their husbands’ work clothes. Organochlorines and Breast Cancer. DDT and other organochlorine insecticides were shown to have estrogenic effects in several assays.21,90 These environmental estrogenic compounds adversely affect birds because differentiation of the avian reproductive system is estrogen dependent.32 Breast cancer incidence rates in the United States have steadily climbed 1% per year since the 1940s, coinciding with the worldwide use of DDT. Because lifetime exposure to excess estrogen is a known risk factor for human breast cancer, women who have higher levels of estrogenic organochlorines may be at risk for developing breast cancer.78,79,107 Several small case-control studies of women with breast cancer showed that women with the disease had higher average body burdens of DDT, DDE, and polychlorinated biphenyls (PCBs) than their age-matched controls. These studies implicated the organochlorines as a cause of human breast cancer. However, more recently, larger studies have shown no increased risk of breast cancer due to exposure to organochlorines, and that currently accepted hereditary and lifestyle risk factors were present in the patients with cancer.44,49,77,78 In addition, other natural dietary estrogens such as flavenoids, ligans, sterols, and fungal metabolites are present in the human diet, and the organochlorine contribution is probably minimal by comparison.33 Some reports suggest an association between long-term exposure to organochlorine pesticides and aplastic anemia.71,75 Chlordane and heptachlor exposures are weakly associated with leukemias and drug-induced thrombocytopenic purpura.38 The organochlorines can induce liver tumors in mice, but have not been shown to do so in rats or hamsters.39 There is no convincing evidence that any of these agents are carcinogenic in humans. Workers heavily exposed to DDT and dieldrin do not have an increased incidence of neoplasms.39 Epidemiologic evidence suggests that the incidence of deaths from liver cancer has steadily decreased since 1930, which includes the more than 50 years since the introduction of the organochlorines.38 There is some evidence that DDT can be a facilitator of carcinogenesis induced by other agents, such as aflatoxin, and that chlordane may have the same facilitative character with regard to diethylnitrosamine.38 A recent comprehensive review found no evidence of human cancer risk from exposure to aldrin or dieldrin.92

Diagnostic Clues The history of exposure to an organochlorine pesticide is the most critical piece of information, because exposure is otherwise rare. By law, the package label of these products must list the ingredients, the concentrations, and the vehicle. The EPA-registered use of the insecticide may be helpful in determining which agent is involved (Table 89–2). The presence of an unusual odor in the mouth, in the vomitus, or on the skin may be helpful. Toxaphene,

TABLE 89–2.

1371

Common Household Pesticides

Pest

Usual Recommendation

Ants

Baygon, bendiocarb, chlorpyrifos, diazinon, permethrin, resmethrin, silica gel-pyrethrum, baits containing boric acid Permethrin Baygon, bendiocarb, chlorpyrifos, diazinon, permethrin, resmethrin, silica gel pyrethrum, tetramethrin, boric acid Baygon, bendiocarb, chlorpyrifos, d-limonene, permethrin, pyrethrins, silica gel pyrethrum, resmethrin, tetramethrin Allethrin, pyrethrum, resmethrin, tetramethrin Allethrin, pyrethrum, pyrethrins, resmethrin, tetramethrin Baygon, bendiocarb, boric acid, chlorpyrifos, diazinon, silca gel pyrethrum Baygon, bendiocarb, chlorpyrifos, diazinon, permethrin, pyrethrins, resmethrin, tetramethrin Effective pesticides restricted in use for application by certified applicators Baygon, chlorpyrifos, diazinon, malathion, tetramethrin

Bedbugs Cockroaches Fleas Flies (house) Mosquitoes Silverfish Spiders Termites Ticks

Reproduced, with permission, from Guide to Safe Pest Management Around the Home. New York State College of Agriculture and Life Sciences of Cornell University, 1997/1998, Misc Bull 74 Media Services at Cornell University.

a chlorinated pinene, has a mild turpentinelike odor, and endosulfan has a unique “rotten egg” sulfur odor (see Table 89–1). An abdominal radiograph may reveal the presence of a radiopaque chlorinated pesticide, because radiopacity may correlate with the number of chlorine atoms per molecule (Chap. 8).23 A large number of other toxins lead to seizures as the first manifestation of toxicity, and must be considered in the differential of an unknown exposure (Chaps. 10 and 19).

Laboratory Tests Gas chromatography can detect organochlorine pesticides in serum, adipose tissue, and urine.19,44 If confirmation is necessary for legal purposes, it may be necessary to measure concentrations of organochlorines. If the patient’s history and toxidrome are obvious, then laboratory evaluation is unnecessary, as this determination will not alter the course of management, and these blood tests are not available on an emergent basis. At present, there are no data correlating health effects and tissue concentrations. Routine surveillance of serum levels in the occupationally exposed is not currently performed.19

Management Organochlorine poisoning may result in hypoxia secondary to seizures, aspiration of vomitus, or respiratory failure. Hyperthermia as a consequence of seizures or from a central mechanism may occur. As with any patient who presents with an altered mental status, dextrose and thiamine should be administered. Skin decontamination is essential, especially in the case of topical lindane. Clothing should be removed and placed in a plastic bag and the skin washed with soap and water. Healthcare providers should be protected with rubber gloves and aprons. Because these pesticides are almost invariably liquids, a nasogastric tube can be used to suction and lavage gastric contents. This is most appropriate if the ingestion occurred within several hours. Activated charcoal can be used after or instead of gastric lavage, when lavage is not indicated.38,56 The ability of activated charcoal to bind various

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organochlorines has never been adequately studied. A murine model of lindane toxicity following intragastric administration showed a trend, but not a statistically significant benefit, of activated charcoal.45 The use of cholestyramine, a nonabsorbable bile acid-binding anion exchange resin, in the same murine model did show a statistically significant benefit by raising both the convulsive dose and the lethal dose.45 The doses of activated charcoal or cholestyramine were 2.25 g/kg, or about 12–28 times the lethal and convulsive doses of lindane, respectively. Oil-based cathartics should never be used, as they may facilitate absorption. Seizures should be controlled with a benzodiazepine followed by phenobarbital if further intervention is indicated. Phenytoin is probably less effective in these cases, particularly with the GABA antagonists lindane, toxaphene, and the cyclodienes.52,80,97 If these measures are inadequate, more aggressive measures should be instituted rapidly, such as a pentobarbital infusion and, if necessary, neuromuscular blockade to control the peripheral manifestations of seizures, thereby preventing metabolic acidosis and rhabdomyolysis. Hyperthermia should be managed aggressively with external cooling. Cholestyramine should be administered to all patients symptomatic from chlordecone, and possibly other organochlorines. Chlordecone undergoes both enterohepatic and enteroenteric recirculation, which can be interrupted by cholestyramine at a dosage of 16 g/d.15 Cholestyramine increased the fecal elimination of chlordecone 3–18-fold in industrial workers exposed during the Hopewell epidemic.15 The extent of toxicity appears to be related to the tissue levels of chlordecone and improves following cholestyramine therapy.

PYRETHRINS AND PYRETHROIDS The pyrethrins are the active extracts from the flower Chrysanthemum cinerariaefolium. These insecticides are important historically, having been used in China since the 1st century AD,18 and developed for commercial application by the 1800s. They are produced by organic solvent extraction from ground Chrysanthemum flowers. The resulting concentrates have greater than 90% purity. Pyrethrum, the first pyrethrin identified, consists of 6 esters derived from chrysanthemic acid and pyrethric acid. These insecticides are highly effective contact poisons, and their lipophilic nature allows them to readily penetrate insect chitin (exoskeleton), and paralyze their nervous systems through Na+ channel blockade.13,59,72,89 When applied properly, they have essentially no systemic mammalian toxicity because of their rapid hydrolysis. Pyrethrins break down rapidly in light and in water, and therefore have no environmental persistence or bioaccumulation. This fact makes them expensive to use, as they must be constantly reapplied. The pyrethroids are the synthetic derivatives of the natural pyrethrins (see Table 89–3 and Fig. 89–3). They were developed in an effort to produce more environmentally stable products. The development of the pyrethroids can be divided into “generations,” based on efficacy and dates of introduction.102 The first generation began in 1949, with the development of allethrin. The second generation began in 1965, with the introduction of tetramethrin. The major advance of the second generation was pyrethroids with potencies many times that of the pyrethrins. The third generation, introduced in the 1970s and including fenvalerate and permethrin, were the first pyrethroids with practical agricultural use. They

TABLE 89–3. Class Type I*

Synthetic Pyrethroids Generic Name, CAS # Allethrin 584-79-2 Bioallethrin 584-79-2 Dimethrin 70-38-2 Phenothrin 26002-80-2 Resmethrin 10453-86-8 Bioresmethrin 28434-01-7 Tetramethrin 7696-12-0 Permethrin 52645-53-1

Type II

Bifenthrin 82657-04-3 Prallethrin 23031-36-9 Imiprothrin 72963-72-5 Fenvalerate 51630-58-1 Acrinathrin 103833-18-7 Cyfluthrin 68359-37-5 Cyhalothrin 91465-08-6 Cypermethrin 52315-07-8

Deltamethrin 52918-63-5

Esfenvalerate 66230-04-4 Fenpropathrin 39515-41-8 Flucythrinate 70124-77-5 Fluvalinate 102851-06-9 Tefluthrin 19538-32-2 Tralomethrin 66841-25-6

Brand Names Pynamin D-trans Dimetrin Fenothrin, Forte, Sumithrin Benzofluroline, Chrysron, Crossfire, Premgard, Pynosect, Pyretherm, Synthrin,

Neo-Pynamin Ambush, Biomist, Dragnet, Ectiban, Elimite, Ipitox, Ketokill, Nix, Outflank, Perigen, Permasect, Persect, Pertox, Pounce, Pramex, etc Capture, Talstar SF, Etoc Multicide, Pralle, Raid Ant & Roach Belmark, Evercide, Extrin, Fenkill, Sanmarton, Sumicidin, Sumifly, Sumipower, Sumitox, Tribute Rufast Baythroid, Bulldock, Cyfoxylate, Eulan SP, Solfac, Tempo 2 Demand, Karate, Ninja 10WP, Scimitar, Warrior Ammo, Barricade, CCN52, Cymbush, Cymperator, Cynoff, Cypercopal; Cyperkill, Cyrux, Demon, Flectron, KafilSuper, Ripcord, Siperin, others Butoflin, Butox, Crackdown, Decis, DeltaDust, DeltaGard, Deltex, K-Othrine, Striker, Suspend Asana, Asana-XL, Sumi-alpha, Danitol, Herald, Meothrin, Rody AASTAR, Cybolt, Fluent, Payoff Evict, Fireban, Force, Mavrik, Raze, Yardex Demand, Force, Karate, Scimitar Dethmor, SAGA, Scout, Scout X-tra, Tralex

*These agents are listed in their approximate order of introduction and potency.

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pyrethroids (permethrin, allethrin, tetramethrin, fenothrin) lack a cyano group, whereas the type II agents (cypermethrin, deltamethrin, fenpropathrin, fluvalinate, fenvalerate) have a cyano group at the ester linkage, and are generally more potent and toxic than the type I pyrethroids (see Fig. 89–3).26,55,72 Permethrin (Elimite, Nix), a type I pyrethroid, is used medicinally for topical treatment of ectoparasitic conditions in humans, as well as impregnated in clothing for its insect repellant properties. There have been no seizures or other serious toxicities with permethrin. Because of its excellent safety profile, permethrin may well replace lindane (Kwell) as the drug of choice for these conditions. During the summer of 2000, the identification of West Nile virus in dead birds throughout New York State led to pesticide spraying for mosquito control in various counties. Fourteen human West Nile virus cases were diagnosed in the New York City area. The primary pesticides used for mosquito control efforts were pyrethroids, which included sumithrin (Anvil) and resmethrin (Scourge). Preliminary review of surveillance data did not reveal any indications of fatalities or widespread acute health effects from these pesticide applications. More detailed review of the data is ongoing (personal communication, Matthew P. Mauer, DO, MPH; NYS Department of Health, Bureau of Occupational Health; January 19, 2001).

Toxicokinetics

Figure 89–3.

Representative structures of Pyrethrin and Pyrethroids.

were more potent, as well as more environmentally stable, with efficacious crop residues lasting 4–7 days. The current fourth generation includes mostly type II pyrethroids, which have even greater insecticidal activity, as well as environmental stability for nearly 10 days after application.55,102 There are more than 1000 pyrethroids, of which 6–10 are in widespread use today.18,26,66 Pyrethrins and pyrethroids are found in more than 2000 commercially available products. These insecticides have a rapid paralytic effect (“knock down”) on insects. Most mammalian species are relatively resistant, because the pyrethrins can be rapidly detoxified by ester cleavage and oxidation.66 Toxicity of the pyrethrins and pyrethroids is enhanced in insects by combination with synergists such as piperonyl butoxide or N-octyl bicycloheptene dicarboximide, which inhibit microsomal enzymes and further impairs the capacity of the insect to metabolize the pyrethrins. The pyrethroids can be divided into two types based on their structures and their clinical manifestations in overdose. Type I

The oral toxicity of pyrethrins in mammals is extremely low, because they are so readily hydrolyzed into inactive compounds, and therefore have an extremely high LD50 in humans. Their dermal toxicity is even lower, owing to their slow penetration and rapid metabolism.26,66 The pyrethroids are more stable than the natural pyrethrins, and systemic absorption by the oral route resulting in toxicity has occurred.40 Absorption probably also occurs through the oral mucosa, as noted by a large study of Chinese insecticide sprayers who frequently used their mouths to clear clogged spray nozzles.12 Most exposures are from dermal absorption, the rate of which may vary depending on the solvent vehicle. Direct absorption of pyrethroids through the skin to the peripheral sensory nerves probably accounts for the facial paresthesias that occur in these cases, as symptoms were prominent in areas of direct contact.12,53 The pyrethroids are also absorbed via inhalation; however, in this same large study of sprayers, inhalation was not found to be a clinically significant route of exposure by breathing zone assays.12 The pyrethroids and pyrethrins are lipophilic and as such are rapidly distributed to the site of toxicity, the central nervous system.26 Because they are rapidly metabolized, there is no storage or bioaccumulation, and this limits chronic toxicity.25 There is no evidence of enterohepatic recirculation. The microsomal monooxygenase system efficiently detoxifies the pyrethroids in animals and man. Piperonyl butoxide, a monooxygenase inhibitor, acts as a synergist to enhance the potency of pyrethroids 10–300-fold to target insects. It is often added to ensure lethality, as the initial “knock down” effect of a pyrethroid alone is not always lethal to the insect.25 Parent compounds, as well as metabolites of the pyrethroids, are found in the urine.72 Deltamethrin disappeared from the urine of exposed workers within 12 hours, and fenvalerate disappeared within 24 hours.12

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Pathophysiology Like DDT, pyrethrins and pyrethroids prolong the inactivation of the voltage-dependent sodium channel by binding to it in the open state, causing a prolonged depolarization30,59,60 (Chap. 10). Type I pyrethroids induce repetitive discharges more readily than type II, but type II agents cause the Na+ channel to remain open longer, and allow a greater degree of depolarization.89,101 Type II agents are thus more potent, and lead to significant after-potentials, which can produce repetitive depolarizations and eventual nerve conduction block. Some studies show some interference of the type II agents with the GABA-mediated inhibitory chloride channels, but only in high concentrations.13,59 It is now generally accepted that suppression of the GABA chloride channels has no significant role in pyrethroid toxicity.59 Type I pyrethroids have a negative temperature coefficient, similar to DDT, and are more selectively toxic to nonwarm-blooded target species. Type II agents have a positive temperature coefficient, which makes them more insecticidal at higher ambient temperatures.102 However, this property partly explains the greater mammalian toxicity of type II agents as compared to type I.59

Clinical Manifestations Pyrethrum has an LD50 of well over 1 g/kg in man, extrapolated from animal data. Most cases of toxicity associated with the pyrethrins are the result of allergic reactions.66,103 At highest risk are patients who are sensitive to ragweed pollen, 50% of whom may cross-react with chrysanthemums (ragweed and chrysanthemum are in the same botanical genus). These allergic reactions actually may result from other natural components present in the extracts.72 The synthetic pyrethroids generally do not induce allergic reactions.66 In animals, type I pyrethroid poisoning most closely resembles that of DDT, with extensive tremors, twitching, increased metabolic rate, and hyperthermia. Excluding the rare possibility of skin irritation or allergy, the type I agents are unlikely to cause systemic toxicity in humans. The type II agents are generally more potent, and cause profuse salivation, ataxia, coarse tremor, choreoathetosis, and seizures in animals. In humans, type II agents cause paresthesias (secondary to sodium channel effects in sensory nerves), salivation, nausea, vomiting, dizziness, fasciculations, altered mental status, coma, seizures, and pulmonary edema.40,53 A review of more than 500 cases of acute pyrethroid poisoning from China highlights some similar manifestations between a massive acute type II pyrethroid overdose and an organic phosphorus compound overdose.40 However, serious atropine toxicity and death has resulted when poisoning from a type II pyrethroid was mistaken for an organic phosphorus compound, and treatment was directed at these seemingly cholinergic signs.40 Although the type II agents contain a cyanide moiety, cyanide poisoning does not occur and cyanide antidotal therapy is not indicated.

Treatment Initial treatment should be directed toward skin decontamination, as most poisonings occur from exposures by this route. Patients with large oral ingestions of a type II pyrethroid should be treated with a single standard dose of activated charcoal. Contact dermatitis and acute systemic allergic reactions should be treated in the usual manner, utilizing corticosteroids,
-adrenergic agonists, and epinephrine as clinically indicated.

Treatment of systemic toxicity is entirely supportive and symptomatic, because no specific antidote exists. Benzodiazepines should be used for tremor and seizures. Topical vitamin E oil (dl-tocopheryl) is especially effective in preventing and treating the cutaneous paresthesias seen in these exposures.18,66

DEET

The topical insect repellant, N,N-diethyl-3-methylbenzamide (DEET, former nomenclature N,N-diethyl-m-toluamide), was patented by the US Army in 1946, and marketed in the United States since 1956. Currently, it is used worldwide by more than 200 million persons annually. The EPA estimates that 38% of the US population uses DEET each year. It can be purchased without prescription in concentrations ranging from 5% to 100%, and in multiple formulations of solutions, creams, lotions, gels, and aerosol sprays. DEET seems to repel insects by interfering with the chemoreceptors that attract the insects to their hosts.30

Toxicokinetics DEET is extensively absorbed via the gastrointestinal tract.69 Skin absorption is significant, depending on the vehicle and the concentration. It does not bind to stratum corneum, and only 0.08% or less of a dose remains in the skin 8 hours after application.69 DEET is lipophilic, and skin absorption usually occurs within 2 hours, although it is eliminated from plasma within 4 hours. The volume of distribution is large, in the range of 2.7–6.21 L/kg in animal studies. DEET is extensively metabolized by oxidation and hydroxylation by the hepatic microsomal enzymes. DEET is excreted in the urine within 12 hours, mainly as metabolites, with 15% or less appearing as the parent compound.30,69

Pathophysiology The exact mechanism of DEET toxicity is unknown. A recent review of adverse reactions to DEET showed 26 cases had major morbidity including N, encephalopathy, ataxia, convulsions, respiratory failure, hypotension, anaphylaxis or death, particularly after ingestion or dermal exposure to large amounts.30,62,64,96,99 These primarily neurologic adverse reactions occurred mainly in children, and most involved prolonged use and excessive dosing beyond what is currently recommended. One fatal case involved a child who was known to be heterozygous for ornithine carbamoyl transferase (OCT) deficiency, and death was due to a Reyelike syndrome with hyperammonemia. This child had experienced prior episodes of hyperammonemia unrelated to DEET use, and DEET does not appear to affect OCT activity in humans.65 There is currently no evidence that enzyme polymorphism affects DEET metabolism or influences individual susceptibility to toxicity. Although single, large, acute oral doses (1–3 g/kg) in rats produced seizures and CNS damage,100 smaller acute doses (500 mg/kg and less) and chronic multigenerational dosing in another

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rat study produced no obvious toxicity.82 Teratogenicity studies in rats and rabbits fail to demonstrate toxicity except at the highest doses,83,106 and DEET was not found to be carcinogenic.84 In view of the millions of applications, the number of reports of toxicity appears exceedingly small, and suggests a remarkably wide margin of safety.30,36,69,65

Clinical Manifestations Most calls to poison control centers regarding DEET exposures involve minor or no symptoms, and symptomatic exposures occur primarily when DEET is sprayed in the eyes or inhaled.99 Except for suicidal ingestions, most serious reactions consist of seizures in children overexposed via the dermal route; in fact, some of these cannot be definitely attributed to DEET.36,65 Most symptoms resolve without treatment and the majority of the cases of serious toxicity recover fully with supportive care.

Treatment DEET poisonings are treated with supportive care aimed at the primarily neurologic symptoms. In cases of dermal exposures skin decontamination should be a priority to prevent further absorption. Oral ingestions should receive a single dose of activated charcoal if clinically indicated. Avoiding the overuse of DEET seems prudent. The American Academy of Pediatrics recommends DEET concentrations of 10% or less for use on children,85 and most commercial formulations marketed for use on children are approximately 5–7%. One application lasts 4–6 hours or more, so frequent reapplication is unnecessary. Soaking the skin is not more effective and may contribute to toxicity. DEET should be applied only to exposed skin. One should avoid abraded skin, or skin with rashes. Care should be taken to avoid exposure to eyes and sensitive skin areas. Avoid use on children’s hands, so that the child does not wipe on eyes, mouth, genitalia, and so on. Adults should apply DEET to their own hands and then wipe onto the child’s face, rather than spraying onto a child’s face. Because mosquitoes are most active for a few hours preceding and following dusk, DEET should be promptly washed off the child’s skin when protection is no longer needed (ie, after going indoors). Avoid using combination products such as sunscreen mixed with DEET, when the repellant component is not needed. Other options for protection include mechanical means, such as mosquito netting.

INSECTICIDES, DEET, AND THE GULF WAR SYNDROME During operations Desert Shield/Desert Storm, nearly 700,000 Americans served in the Persian Gulf. Some returning troops began reporting a variety of symptoms and illnesses they attributed initially to exposure to burning oil well fires in Kuwait. Approximately 10% of these veterans, or 67,000, have registered with the Persian Gulf Registry Health Examination Program. This program was initiated to study whether veterans were experiencing adverse health effects related to exposures encountered in the Persian Gulf War. The most common symptoms are largely nonspecific and multiorgan and include fatigue, rashes, headache, muscle aches, memory problems, dyspnea, insomnia, and gastrointestinal (GI) symptoms. Multiple studies and expert panels

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have been unable to identify a causative agent responsible for this “Persian Gulf syndrome.” Some investigators have suggested that combinations of DEET, permethrin, and pyridostigmine have additive neurotoxic effects and could be a cause of the symptoms.51 Although there is laboratory evidence of synergy of these agents in causing neurotoxicity in test animals,2,54 it is difficult to apply this to human experience in the Gulf War. The exposures in the veterans were primarily dermal, except for the pyridostigmine tablets, whereas the experimental animals were either gavaged or injected with the insecticides. In addition, the pyridostigmine was only taken for 2 weeks or less during cooler weather when biting insects were dormant, so concomitant use with permethrin and DEET would have been low. It appears unlikely that these compounds were used together at toxic dosages for any sustained time period. Given the diversity and multisystem nature of symptoms experienced by these veterans, it is unlikely that use of these chemicals is responsible for the illnesses. Further study is ongoing.58

LEGAL STANDARDS FOR AN INSECTICIDE LABEL The Federal Insecticide, Fungicide and Rodenticide Act of 1962 (Table 88–4) established criteria for a “signal word” on an insecticide label, which implies the degree of toxicity based on an oral LD50. Also, the label on the original container of these products is usually instructive and should always be brought to the medical facility. The label provides the following information: ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Brand name Intended product use Active and inert ingredients and their percent composition Directions for use Pests to be controlled; crops, animals, or sites to be treated Dosage, time interval, and method of application Warnings to protect users, consumers of treated foods, beneficial plants, animals, and endangered species “Keep out of reach of children” Antidotes and first-aid instructions Net content Name and address of manufacturer EPA registration number and signal word based on the LD50

Consumers asking for help in choosing the most effective and safest pesticides should be told to contact their county agricultural or cooperative extension agents. It is important to choose an effective pesticide as well as a product formulated for use in the requisite area (indoors vs outdoors), because concentrations and residues vary. Instructions must always be read carefully and followed, as failure to do so may lead to toxicity (Table 89–4).

SUMMARY The ideal insecticide is one that has low acute toxicity to humans and nontarget species (pyrethroids, DDT), is inexpensive to apply and produce (organic phosphorus compounds, DDT), but would have no environmental persistence or bioaccumulation (organic phosphorus compounds, pyrethroids). With mass production techniques, some of the newer pyrethroids may come closer to this

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TABLE 89–4. Criteria Established by the Federal Insecticide, Fungicide, and Rodenticide Act of 1962 Signal Word

Toxicity

Danger Poison Skull and crossbones figure Call physician immediately Keep out of reach of children

High

Warning No antidote Keep out of reach of children

Moderate

Caution No antidote Keep out of reach of children

Low

No Signal Word Keep out of reach of children

Relatively safe

Oral LD50 mg/kg 0–50

50–500

500–5000

> 5000

ideal than those most commonly used today. Until that goal is achieved, the neurotoxic organochlorines will continue to be used. In January 2000, the Associated Press reported that 21 people in Iran were poisoned, and 3 died, when DDT powder was inadvertently used in food preparation instead of flour. Although banned in North America and Europe, organochlorine pesticides are still widely used in other parts of the world, and will have important implications for toxicologists for some time to come.

REFERENCES 1. Abalis IM, Eldefrawi ME, Eldefrawi AT: Effects of insecticides on GABA-induced chloride influx into rat brain microsacs. J Toxicol Environ Health 1986;18:13–23. 2. Abou-Donia M, Wilmarth K, Jensen K, et al: Neurotoxicity resulting from coexposure to pyridostigmine bromide, DEET, and permethrin: Implications of Gulf War chemical exposures. J Toxicol Environ Health 1996;48:35–56. 3. Aks SE, Krantz A, Hryhorczuk DO, et al: Acute accidental lindane ingestion in toddlers. Ann Emerg Med 1995;26:647–651. 4. Anonymous: Acute convulsions with endrin poisoning: Pakistan. Morb Mortal Wkly Rep 1986;33:687–688, 693. 5 Bloomquist JR: Intrinsic lethality of chloride-channel-directed insecticides and convulsants in mammals. Toxic Lett 1992;60:289–298. 6. Bloomquist JR, Adams PM, Soderlund DM: Inhibition of gammaaminobutyric acid-stimulated chloride flux in mouse brain vesicles by polychlorocycloalkane and pyrethroid insecticides. Neurotoxicology 1986;7:11–20. 7. Bloomquist JR, French-Constant RH, Roush RT: Excitation of central neurons by dieldrin and picrotoxinin in susceptible and resistant Drosophila melanogaster. Pesticide Sci 1991;32:463–470. 8. Boylan JJ, Cohn WJ, Egle JL, et al: Excretion of chlordecone by the gastrointestinal tract: Evidence for a nonbiliary mechanism. Clin Pharmacol Ther 1979;25:579–585. 9. Brisson, P: Percutaneous absorption. Can Med Assoc J 1974;110: 1182–1185. 10. Carson R: Silent Spring. Boston, Houghton Mifflin Company, 1962. 11. Carvalho WA, Matos GB, Cruz SLB, Rodrigues DS: Human aldrin poisoning. Braz J Med Biol Res 1991;24:883–887. 12. Chen S, Zhang Z, He F, et al: An epidemiological study on occupational acute pyrethroid poisoning in cotton farmers. Br J Ind Med 1991;48:77–81.

13. Coats JR: Mechanisms of toxic action and structure-activity relationships for organochlorine and synthetic pyrethroid insecticides. Environ Health Perspect 1990;87:255–262. 14. Coble Y, Hildebrandt P, Davis J, et al: Acute endrin poisoning. JAMA 1967; 202:153–157. 15. Cohn WJ, Boylan JJ, Blanke RV, et al: Treatment of chlordecone (kepone) toxicity with cholestyramine. N Engl J Med 1978;298: 243–248. 16. Cole LM, Casida JE: Polychlorocycloalkane insecticide-induced convulsions in mice in relation to disruption of the GABA-regulated chloride ionophore. Life Sci 1986;39:1855–1862. 17. Conney AH, Welch RM, Kuntzman R, Burns JJ: Effects of pesticides on drug and steroid metabolism. Clin Pharmacol Ther 1966;8: 1–10. 18. Costa, LG: Basic Toxicology of pesticides. In: Keifer MC, ed: Occupational Medicine: State of the Art Reviews. Human Health Effects of Pesticides. Philadelphia, Hanley and Belfus, 1997, pp. 251–268. 19. Coye MJ, Lowe JA, Maddy KJ: Biological monitoring of agricultural workers exposed to pesticides: II. Monitoring of intact pesticides and their metabolites. J Occup Med 1986;28:628–636. 20. Crosby AD, D’Andrea GH, Geller RJ: Human effects of veterinary biological products. Vet Hum Toxicol 1986;28:569–571. 21. Cummings AM: Methoxychlor as a model for environmental estrogens. Crit Rev Toxicol 1997;27:367–379. 22. Dale WE, Gaines TB, Hayes WJ: Poisoning by DDT: Relationship between clinical signs and concentrations in rat brain. Science 1963; 142:1474–1476. 23. Dally S, Garnier R, Bismuth C: Diagnosis of chlorinated hydrocarbon poisoning by x-ray examination. Br J Ind Med 1987;44: 424–425. 24. Davies JE, Dedhia HV, Morgade C, Barquet A, Maibach HI: Lindane poisonings. Arch Dermatol 1983;119:142–144. 25. Ecobichon DJ: Toxic effects of pesticides. In: Klaassen CD, ed: Casarett and Doull’s Toxicology: The Basic Science of Poisons, 5th ed. New York, Macmillan, 1996, pp. 643–669. 26. Ecobichon DJ, Joy RM: Pesticides and Neurological Diseases, 2nd ed. Boca Raton, FL, CRC Press, 1994. 27. Faroon O, Kueberuwa S, Smith L, DeRosa C: ATSDR evaluation of health effects of chemicals II. Mirex and chlordecone: Health effects, toxicokinetics, human exposure, and environmental fate. Toxicol Ind Health 1995;11:1–188. 28. Feldmann RJ, Maibach HI: Percutaneous penetration of some pesticides and herbicides in man. Toxicol Appl Pharmacol 1974;28: 126–132. 29. Fischer TF: Lindane toxicity in a 24-year-old woman. Ann Emerg Med 1994;24:972–974. 30. Fradin MS: Mosquitoes and mosquito repellents: A clinician’s guide. Ann Intern Med 1998;128:931–940. 31. Franz TJ: Kinetics of cutaneous drug penetration. Int J Dermatol 1983;22:499–505. 32. Fry MD: Reproductive effects in birds exposed to pesticides and industrial chemicals. Environ Health Perspect 1995;103:165–171. 33. Gaido K, Dohme L, Wang F, et al: Comparative estrogenic activity of wine extracts and organochlorine pesticide residues in food. Environ Health Perspect 1998;106:1347–1351. 34. Gant D, Eldefrawi ME, Eldefrawi AT: Cyclodiene insecticides inhibit GABAA receptor-regulated chloride transport. Toxicol Appl Pharmacol 1987;88:313–321. 35. Garrettson LK, Guzelian PS, Blanke RV: Subacute chlordane poisoning. J Toxicol Clin Toxicol 1984–85;22:565–571. 36. Goodyer L, Behrens R: Short report: The safety and toxicity of insect repellents. Am. J Trop Med Hyg 1998;59:323–324. 37. Grutsch JF, Khasuwinah A: Signs and mechanisms of chlordane intoxication. Biomed Environ Sci 1991;4:317–326. 38. Hayes WJ: Chlorinated hydrocarbon insecticides. In: Hayes WJ, Lawes ER, eds: Pesticides Studied in Man. San Diego, Academic Press, 1991, pp. 731–868.

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39. Hayes WJ, Lawes ER, eds: Handbook of Pesticide Toxicology. San Diego, Academic Press, 1991. 40. He F, Wang S, Liu L, et al: Clinical manifestations and diagnosis of acute pyrethroid poisoning. Arch Toxicol 1989;63:54–58. 41. Herr DW, Gallus JA, Tilson HA: Pharmacological modification of tremor and enhanced acoustic startle by chlordecone and p,p9-DDT. Psychopharmacology 1987;91:320–325. 42. Hong JS, Herr DW, Hudson PM, Tilson HA: Neurochemical effects of DDT in rat brain in vivo. Arch Toxicol 1986;9:14–26. 43. Idson B: Vehicle effects in percutaneous absorption. Drug Metab Rev 1983;14:207–222. 44. Hunter DJ, Hankinson SE, Laden F, et al: Plasma organochlorine levels and the risk of breast cancer. N Engl J Med 1997;337: 1253–1258. 45. Kassner JT, Maher TJ, Hull KM, Woolf, AD: Cholestyramine as an adsorbent in acute lindane poisoning: A murine model. Ann Emerg Med 1993;22:1392–1397. 46. Kintz P, Baron L, Tracqui A, et al: A high endrin concentrate in a fatal case. Forensic Sci Int 1992;54:177–180. 47. Klaassen CD: Nonmetallic environmental toxicants. In: Hardman JG, Limbird LE, Molinoff PB, and Ruddon RW, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996, pp. 1684–1699. 48. Kramer MS: Operational criteria for adverse drug reactions in evaluating suspected toxicity of a popular scabicide. Clin Pharmacol Ther 1980;27:149–155. 49. Krieger N, Wolff MS Hiatt RA, et al: Breast cancer and serum organochlorines: A prospective study among white, black, and Asian women. J Natl Cancer Inst 1994;86:589–599. 50. Kriess K, Zack MM, Kimbrough RD, et al: Cross-sectional study of a community with exceptional exposure to DDT. JAMA 1981;245: 1926–1930. 51. Kurt TL: Epidemiological association in US veterans between Gulf War illness and exposures to anticholinesterases. Toxicol Lett 1998; 102–103, 523–526. 52. Lee B, Groth P: Scabies transcutaneous poisoning during treatment. Pediatrics 1977;59:643. 53. Le Quesne PM, Maxwell IC, Butterworth STG: Transient facial sensory symptoms following exposure to synthetic pyrethroids: A clinical and electrophysiological assessment. Neurotoxicology 1980;2: 1–11. 54. McCain WC, Lee R, Johnson MS et al: Acute oral toxicity study of pyridostigmine bromide, permethrin, and DEET in the laboratory rat. J Toxicol Environ Health 1997;50:113–124. 55. Mestres R, Mestres G: Deltamethrin: Uses and environmental safety. Rev Environ Contam Toxicol 1992;124:1–18. 56. Morgan DP, Dotson TB, Lin LI: Effectiveness of activated charcoal, mineral oil, and castor oil in limiting gastrointestinal absorption of a chlorinated hydrocarbon pesticide. Clin Toxicol 1977;11:61–70. 57. Mortensen ML: Management of acute childhood poisonings caused by selected insecticides and herbicides. Pediatr Clin North Am 1986; 33:421–445. 58. Murphy FM, ed: A Guide to Gulf War Veterans’ Health: 1998 Continuing Medical Education Program. St. Louis, MO, Department of Veterans Affairs, 1998. 59. Narahashi T: Nerve membrane Na+ channels as targets of insecticides. Trends Pharmacol Sci 1992;13:236–241. 60. Narahashi T, Frey JM, Ginsburg KS, Roy ML: Sodium and GABAactivated channels as the targets of pyrethroids and cyclodienes. Toxicol Lett 1992;64/65:429–436. 61. Obata T, Yamamura HI, Malatynska E et al: Modulation of GABAstimulated chloride influx by bicycloorthocarboxylates, bicyclophosphorus esters, polychlorocycloalkanes and other cage convulsants. J Pharmacol Exp Ther 1988;244:802–806. 62. Oransky S, Roseman B, Fish D, et al: Seizures temporally associated with use of DEET insect repellent—New York and Connecticut. Morb Mortal Wkly Rep 1989;38:678–680.

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63. Ortiz Martinez A, Martinez-Conde E: The neurotoxic effects of lindane at acute and subchronic dosages. Ecotoxicol Environ Saf 1995; 30:101–105. 64. Osimitz TG, Grothaus RH: The present safety assessment of DEET. J Am Mosq Control Assoc 1995;11:274–278. 65. Osimitz TG, Murphy JV: Neurological effects associated with use of the insect repellent N,N-diethyl-m-toluamide (DEET). Clin Toxicol 1997;35:435–441. 66. Paton DL, Walker JS: Pyrethrin poisoning from commercial strength flea and tick spray. Am J Emerg Med 1988;6:232–235. 67. Pomes A, Rodriquez-Farre E, Sunol C: Disruption of GABA-dependent chloride flux by cyclodienes and hexachlorocyclohexanes in primary cultures of cortical neurons. J Pharmacol Exp Ther 1994; 271:1616–1623. 68. Pramanik A, Hansen R: Transcutaneous gamma benzene hexachloride absorption and toxicity in infants and children. Arch Dermatol 1979;115:1224–1225. 69. Qiu H, Jun HW, McCall JW: Pharmacokinetics, formulation, and safety of insect repellent N,N-diethyl-3-methylbenzamide (DEET): A review. J Am Mosq Control Assoc 1998;14:12–27. 70. Rasmussen J: The problem of lindane. J Am Acad Dermatol 1981; 3:507–516. 71. Rauch A, Kowalsky S, Lesar T, et al: Lindane (Kwell)-induced aplastic anemia. Arch Intern Med 1990;150:2393–2395. 72. Reigart JR, Roberts JR, eds: Recognition and Management of Pesticide Poisonings, 5th ed. Washington, DC, Environmental Protection Agency, 1999. 73. Rogan WJ: Pollutants in breast milk. Arch Pediatr Adolesc Med 1996;150:981–990. 74. Rowley DL, Rab MA, Hardjutunojo W, et al: Convulsions caused by endrin poisoning in Pakistan. Pediatrics 1987;79:928–934. 75. Rugman FP, Cosstick R: Aplastic anemia associated with organochlorine pesticide: Case reports and review of evidence. J Clin Pathol 1990;43:98–101. 76. Runhaar EA, Sangster B, Greve PA, Voortman M: A case of fatal endrin poisoning. Hum Toxicol 1985;4:241–247. 77. Safe SH: Environmental and dietary estrogens and human health: Is there a problem? Environ Health Perspect 1995;103:346–351. 78. Safe SH: Xenoestrogens and breast cancer. N Engl J Med 1997; 337:1303–1304. 79. Safe SH: Is there an association between exposure to environmental estrogens and breast cancer? Environ Health Perspect 1997;105: 675–678. 80. Saleh MA: Toxaphene: Chemistry, biochemistry, toxicity and environmental fate. Rev Environ Contam Toxicol 1991;118:2–85. 81. Schenker MB, Louie S, Mehler LN, Albertson TE: Pesticides. In: Rom WN, ed: Environmental and Occupational Medicine, 3rd ed. Philadelphia, Lippincott-Raven, 1998, pp. 1157–1172. 82. Schoenig GP, Hartnagel RE, Schardein JL, Vorhees CV: Neurotoxicity evaluation of N,N-diethyl-m-toluamide in rats. Fundam Appl Toxicol 1993;22:355–365. 83. Schoenig GP, Neeper-Bradley TL, Fisher LC, Hartnagel RE: Teratologic evaluations of N,N-diethyl-m-toluamide (DEET) in rats and rabbits. Fundam Appl Toxicol 1994;23:63–69. 84. Schoenig GP, Osimitz TG, Gabriel KL, Hartnagel R, Gill MW, Goldenthal EI: Evaluation of the chronic toxicity and oncogenicity of N,N-Diethyl-m-Toluamide (DEET). Toxicol Sci 1999;47: 99–109. 85. Shelov SP, ed. Caring for Your Baby and Young Child: Birth to Age 5. New York, Bantam Books, 1994. 86. Smith RA, Lewis D: A potpourri of pesticide poisonings in Alberta in 1987. Vet Hum Toxicol 1988;30:118–120. 87. Solomon BA, Haut SR, Carr EM, Shalita AR: Neurotoxic reaction to lindane in an HIV-seropositive patient. J Fam Pract 1995;40: 291–295. 88. Solomon L, Fahrner L, West D: Gamma benzene hexachloride toxicity. Arch Dermatol 1977;113:353–357.

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89. Song J, Nagata K, Tatebayashi H, Narahashi T: Interactions of tetramethrin, fenvalerate and ddt at the sodium channel in rat dorsal root ganglion neurons. Brain Res 1996;708:29–37. 90. Soto AM, Chung KL, Sonnenschein C: The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogensensitive cells. Environ Health Perspect 1994;102:380–383. 91. Starr M, Clifford N: Acute lindane intoxication. Arch Environ Health 1972;25:374–375. 92. Stevenson DE, Walborg EF Jr, North DW, et al: Reassessment of human cancer risk of aldrin/dieldrin [monograph]. Toxicol Lett 1999;109:123–186. 93. Street JC, Chadwick RW: Ascorbic acid requirements and metabolism in relation to organochlorine pesticides. Ann N Y Acad Sci 1975;258:132–143. 94. Telch J, Jarvis DA: Acute intoxication with lindane (gamma benzene hexachloride). Can Med Assoc J 1982;126:662–663. 95. Tennebein M: Seizures after lindane therapy. J Am Geriatr Soc 1991;39:394–395. 96. Tenenbein M: Severe toxic reactions and death following the ingestion of diethyltoluamide-containing insect repellents. JAMA 1987; 258:1509–1511. 97. Tilson HA, Hong JS, Mactutus CF: Effects of 5,5 diphenylhydantoin (phenytoin) on neurobehavioral toxicity of organochlorine pesticides and permethrin. J Pharmacol Exp Ther 1985;233:285–289. 98. Tilson MA, Shaw S, McLamb RL: The effects of lindane, DDT and chlordecone on avoidance responsing and seizure activity. Toxicol Appl Pharmacol 1987; 88:57–65.

99. Veltri JC, Osimitz TG, Bradford DC, Page BC: Retrospective analysis of calls to poison control centers resulting from exposure to the insect repellent N,N-diethyl-m-toluamide (DEET) from 1985–1989. J Toxicol Clin Toxicol 1994;32:1–16. 100. Verschoyle RD, Brown AW, Nolan C, et al: A comparison of the acute toxicity, neuropathology, and electrophysiology of N,Ndiethyl-m-toluamide and N,N-dimethyl-1,2-diphenylacetamide in rats. Fundam Appl Toxicol 1992;18:79–88. 101. Vijverberg HPM, van den Bercken J: Neurotoxicological effects and the mode of action of pyrethroid insecticides. Crit Rev Toxicol 1990;21:105–126. 102. Ware GW: An Introduction to Insecticides, 3rd ed. http://www. ipmworld. umn.edu/chapters/ware.htm last modified 12/23/99; accessed 11/2001. 103. Wax PM, Hoffman RS, Goldfrank LR: Fatality associated with inhalation of a pyrethrin insecticide. J Toxicol Clin Toxicol 1994;32: 457–460. 104. Williams CH, Casterline JL: Effects on toxicity and on enzyme activity of the interactions between aldrin, chlordane, piperonyl butoxide and banol in rats. Proc Soc Exp Biol Med 1970;135:46–49. 105. Woolley DE: Differential effects of benzodiazepines, including diazepam, clonazepam, Ro 5–4864 and devazepide, on lindaneinduced toxicity. Proc West Pharmacol Soc 1994;37:131–134. 106. Wright DM, Hardin BD, Goad PW, Chrislip DW: Reproductive and developmental toxicity of N,N-diethyl-m-toluamide in rats. Fundam Appl Toxicol 1992;19:33–42. 107. Wolf MS, Toniolo PG, Lee EW, et al: Blood levels of organocholrine residues and the risk of breast cancer. J Nat Cancer Inst 1993; 85:648–652.

CHAPTER

90

RODENTICIDES Neal E. Flomenbaum

A 52-year-old HIV positive man with a CD4 count of 600/mm3 and no previous history of opportunistic infections presented to the Emergency Department (ED) with a complaint of gross hematuria. He reported ingesting 8 boxes of rodenticide 6 days prior to presentation, in an attempted suicide. He was taking fluoxetine and clonazepam for depression, and his other medications included methylphenidate and testosterone injections. On physical examination, he was well developed, well appearing, and in no apparent distress. Vital signs were: blood pressure 170/70 mm Hg, pulse 76 beats/min, respiratory rate 18 breaths/ min, and temperature 36.1°C (97°F). Examination of the head, eyes, ears, nose, and throat revealed only mild bleeding from the gingival mucosa. His chest, heart, abdomen, back, and genitalia were unremarkable. Rectal examination and testing for occult blood were negative. The skin and extremities were normal with no evidence of petechiae or ecchymoses. Initial laboratory studies showed a white blood cell (WBC) count of 11.3 × 103/mm3, hemoglobin of 15.6 g/dL, and hematocrit of 44.9%; platelets were normal. The initial prothrombin time (PT) was 79.2 seconds (international normalized ratio (INR) of 38.2), and activated partial thromboplastin time (PTT) was 101.3 seconds. Specific factor analysis demonstrated factor II 12%, factor V 17%, factor VIII less than 1%, and factor IX 6%. Urinalysis revealed greater than 100 red blood cells (RBCs)/high-power field. The patient was immediately treated with 2 units of fresh-frozen plasma, and 150 mg of oral vitamin K1 initially and every 6 hours. Serial coagulation profiles and factor II and factor VII levels were monitored. After approximately 40 hours of oral vitamin K1 therapy, factor levels were considered adequate for normal coagulation. Oral vitamin K1 was continued for 5 more days and after appropriate psychiatric evaluation and care, the patient was discharged home. The patient continued taking an oral maintenance dose of 150 mg of vitamin K1 every 6 hours as an outpatient and was monitored with periodic PT/PTT levels; all values remained within normal range and the dose of vitamin K1 was tapered over the following 40 days. Vitamin K1 was eventually discontinued completely after day 46 without a clinically significant change in either the PT or specific factor levels.12 (This case was adapted with permission from Bruno GR, Howland MA, McMeeking A, Hoffman RS: Long-acting anticoagulant overdose: Brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med 2000; 36:262–267.)

13,000 and 16,000 exposures to long-acting anticoagulants—the 4 hydroxycoumarins, brodifacoum, and difenacoum, and the indandione derivatives chlorphacinone. Although the vast majority of such exposures are asymptomatic ingestions by children, approximately 250–300 ingestions yearly result in various degrees of coagulopathy. Unlike the case presented above, rodenticide exposures are most commonly associated with young children. Between 1995 and 1999, 17,000–20,000 rodenticide exposures were reported annually to AAPCC/TESS, over 85% of which involved children younger than 6 years of age (see Chapter 116 and p. 1752). Remarkably, despite the very large number of exposures, no more than 6 deaths are reported annually. The rodenticide categories identified and tracked by AAPCC/TESS are:
-naphthyl thiourea (ANTU); anticoagulant standard and long-acting, barium carbonate; cyanide, monofluoroacetate, strychnine, Vacor, “other”, and “unknown.” Long-acting anticoagulants and strychnine account for all of the deaths caused by known rodenticides, whereas the “other and unknown” categories combined account for about 14% of exposures and almost 40% of the deaths per year. Unfortunately, exposures to cholecalciferol and bromethalin, the two newest rodenticides marketed for general use in the United States, are not tracked by TESS and therefore, it is not possible to determine at present any trends in usage or related toxicity. Also not explicit in the database are exposures to compounds not specifically used as rodenticides. An example of this is Tres Pasitos, an illegally imported agent used by certain ethnic groups in the New York City region. The active ingredient is the carbamate cholinesterase-inhibitor aldicarb, which in used legally in some parts of the US as an insecticide. However it is not registered for use as a rodenticide and is sold covertly for such use in local shops. Poisoning by this highly potent agent may produce fulminant cholinergic poisoning, a syndrome that is not expected following exposure to conventional rodenticides.58a In addition to children, suicidal persons, potential homicide victims, pest control operators, and intoxicated, psychiatric, and impaired-elderly persons are at risk of intentional or unintentional rodenticide exposures. The large number of unintentional ingestions of rodenticides placed in food containers or dishes illustrates the danger of marketing toxic substances in such dishes or transferring a toxic substance to another container.

EPIDEMIOLOGY

THE DEFINITION AND CLASSIFICATION OF RODENTICIDES

The above case is an example of the most frequently encountered serious rodenticide exposure in the United States today. Each year, the American Association of Poison Control Centers (AAPCC)/ Toxic Exposure Surveillance System (TESS) reports between

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A rodenticide is any product commercially marketed to kill rodents, mice, squirrels, gophers, and other small animals. The “perfect rodenticide,” one that effectively kills rodents but is not toxic

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to humans or nonrodent pets, has yet to be discovered or synthesized. Instead, a wide variety of less-than-perfect rodenticides are commercially available differing from one another in chemical composition, mechanism for killing rodents, and toxicity to humans.34,47,48,58,65 In addition to the commonly available warfarin and cholecalciferol rodenticides, and to the more toxic, but rarely used types discussed below, new, purportedly “effective and harmless” products are occasionally introduced, only to be subsequently withdrawn when the true human toxicities become known. Some of these products may remain in basements, on hardware store shelves, or in use by professional pest control operators long after they are officially withdrawn from sale. The most important information necessary to deal effectively with rodenticide exposures therefore, are the full name or type of rodenticide involved, and the quantity, nature (acute or repetitive ingestions, inhalation, skin contact, and so on) and time of exposure. Rodenticides are a disparate group of organic and inorganic compounds and substances bearing little or no relationship to one another apart from their usage—currently or historically—as rodenticides. Rodenticides have been classified in several ways: (a) inorganic and organic compounds; (b) animal selectivity; (c) nature and onset of symptoms; and (d) LD50 in rats.

Inorganic and Organic Compounds Inorganic compounds include the salts of arsenic, thallium (sulfate), phosphorus, barium (carbonate), and zinc (phosphide); whereas organic compounds include sodium fluoroacetate, ANTU, warfarin, red squill, strychnine, norbormide, and Vacor (or PNU).5

Animal Selectivity The cardiac glycoside and potent emetic, red squill, was promoted as a rodenticide because, unlike humans, rats do not vomit and therefore would be expected to experience the cardiotoxic effects of red squill whereas humans and other animals presumably would vomit the poison prior to experiencing any cardiotoxic effects. Norbormide, an irreversible smooth-muscle constrictor, causes widespread ischemic necrosis and death in rats but does not appear to affect other animals or humans, because it acts on a specific smooth muscle-norbormide receptor found only in rats. ANTU a relatively selective rodenticide is a derivative of phenylthiourea, without the bitter taste characteristic of the thiourea. ANTU causes pulmonary edema in rats that have not developed tolerance to it. ANTU, however, is only relatively selective: although the rats are more sensitive to it than other animals, large doses (>4 g/kg) can also be lethal to primates. All of the rodenticides classified as inorganic, as well as organic rodenticides such as strychnine and sodium fluoroacetate, are nonselective and of extreme concern when ingested by humans and domestic animals. For the most part, use of this entire group of rodenticides is restricted to commercial pest control operators and government agencies.

Nature and Onset of Symptoms Although a rodenticide classification system based purely on the nature and onset of symptoms seems very appealing, such a system may be unreliable, may create a false sense of security, and may result in inappropriate management and/or inadequate followup. Many different rodenticides cause neurologic and/or gastrointestinal signs and symptoms, whereas characteristic or

pathognomonic signs such as “risus sardonicus” from strychnine, or alopecia from thallium, may not be recognized, do not always occur consistently (especially after ingesting small amounts), or, as in the case of thallium-induced alopecia, will not occur until days after an acute ingestion. Classifying rodenticides by the time of onset of symptoms may similarly lump together within a lateonset group some of the least toxic (regular warfarin type, cholecalciferol) and most toxic, (long-acting warfarin type, thallium) rodenticides.

LD50 in Rats Probably the most clinically useful way of classifying rodenticides at present is by toxicity based on LD50 data in rats. With a few noteworthy exceptions, the relative degree of toxicity per kilogram and the characteristic adverse effects generally hold among different mammals, allowing the healthcare provider the opportunity to consider a combination of historical and characteristic physical evidence to diagnose or exclude various rodenticides and to decide on an optimal management plan. The limitations of this classification system, however, must be understood in order to use it appropriately: (a) in rare cases, the LD50 may vary unpredictably among species (eg, Vacor); and (b) repeated ingestions of less toxic rodenticides (eg, short-acting anticoagulants, cholecalciferol) may, in fact, make them highly toxic (Table 90–1).

HIGHLY TOXIC RODENTICIDES (SIGNAL WORD: “DANGER”) According to the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), highly toxic rodenticides are those substances with a single-dose LD50 of less than 50 mg/kg body weight. The label “Danger” is the strongest warning by the Consumer Product Safety Commission for a potential toxic hazard. Lower hazard levels are denoted by “Warning” and “Caution” (Table 90–1 and Table 91–1). How well do current FIFRA testing guidelines protect infants and children who may be more sensitive than adults to the effects of many rodenticides? Based on the experience with lead testing in setting human exposure levels, FIFRA levels may be below current regulatory action levels even without the additional protection provided by the more recently enacted Food Quality Protection Act (FQPA).69 The highly toxic “Danger” group includes thallium, sodium monofluoroacetate (SMFA, compound 1080), fluoroacetamide (compound 1081), strychnine, zinc phosphide, elemental phosphorus, arsenic, barium carbonate, and Vacor.

Thallium Thallium sulfate is an odorless, tasteless compound absorbed easily by inhalation, through unbroken skin, and via the gastrointestinal tract.34 It may also cause death secondarily, that is, when a thallium-poisoned animal is eaten.9 Although the use of thallium as a commercial rodenticide ended in 1965, it is still used by industry and is an ingredient in some homeopathic remedies; currently, the most common setting for cases of thallium poisoning are attempted suicides or homicides.21,22,35,40,49,57,59,64 Thallium has a volume of distribution estimated to range between 3.6 L/kg in humans to 20 L/kg in rats, is excreted by both the kidneys and liver, and has a human elimination half-life of 2–15 days.49,58 Gas-

TABLE 90–1.

Management of Specific Rodenticide Ingestions

Toxin Name

Physical Characteristics

Toxic Mechanism

Highly Toxic Signal word: DANGERa (LD50 < 50 mg/kg) Thallium White, crystalline, Combines with mito(see ch 83) odorless, tasteless chondrial sulfhydryl groups, interfering with oxidative phosphorylation Sodium monoWhite, crystalline, Fluoroacetate fluoroacetate odorless, tasteless, to fluorocitrate; (SMFA, comwater soluble interferes with pound 1080); Krebs cycle Sodium fluoroSame as SMFA Same as SMFA; acetamide fluoride toxicity (compound 1081) Strychnine Bitter taste Competitive glycine antagonism at the postsynaptic spinal cord motor neuron

Zinc phosphide

Estimated Fatal Dose

Diagnostic Presenting Signs and Symptoms

Onset

Antidote and/or Treatment*

14 mg/kg

Anorexia, abdominal pain, diarrhea, painful neuropathy, delirium, coma, seizures, alopecia (late), Mees line

GI symptoms acutely, other symptoms 12–14 h delay

Activated charcoal, ferric ferrocyanide, (Berlin or Prussian blue)

3–7 mg/kg

Seizures, coma, tachycardia, PVCs, VT, VF, ST-T wave changes

2–20 h

Experimental regimens: see text

13–14 mg/kg

Same as SMFA

Same as SMFA

Same as SMFA

10–20 min

Quiet room, IV, benzodiazepines, neuromuscular blockade

Within hours; inhalation may have delayed onset

Dilution with water, milk, or NaHCO3

1–2 h

Supportive care

Symptoms: 1 h Death: 1–24 h

Succimer, dimercaprol until urine arsenic level: 5–20 interference with mg/d clotting factors II, for VII, IX, X; death >5d from hemorrhage Anticoagulant antibiotic combination eliminates intestinal vitamin K producing organisms

Bleeding with elevated INR

12–48 h

Vitamins K1, fresh frozen plasma (FFP) as indicated

Anticoagulant

?

Bleeding with elevated INR

Delayed several days

Vitamin K1, fresh frozen plasma (FFP) as indicated

Anticoagulant

?

Chronic ingestion possibly produces cardiac and neurologic symptoms as well as bleeding with elevated INR

Delayed several days`

Vitamin K1, fresh frozen plasma (FFP) as indicated

Toxic Mechanism

Moderately Toxic Signal Word: WARNINGa (LD50, 50–500 mg/kg) Alpha-naphOdorless, slightly bitter, Acute lung injury thylthiourea fine, blue-gray powder, (ANTU) water-insoluble Cholecalciferol 0.075% pellets, 364 Hypercalcemia (vitamin D3) pellets/oz; (1 pellet = 2308 U vitamin D)

Low Toxicity Signal Word: CAUTIONa (LD50, 500–5000 mg/kg) Red squill Bitter taste Cardiac glycoside; poisoning Norbormide (dicarboximide)

Yellow cormeal bait, peanut butter, 1% concentration

Bromethalin

7.5% concentrate, green pellets, with Bitrex (denatonium benzoate)

Anticogulants: Short Acting Warfarin Yellow cornmeal, rolled oats (0.025%)

Prolin

Warfarin (0.025%) plus sulfaquinoxalin (0.025%)

Anticoagulants: Long Acting Hydroxycoumarins 4-Hydroxy0.005% grain-based coumarin bait (Brodifacoum, Difenacoum) Warfacide 0.5% for dilution to (Couma0.025% white furyl) powder, tasteless, odorless Indandiones Pindone Moldy, acrid odor, (Pival) fluffy yellow powder, concentrations 0.005–2.5% Pivalyn Diphacinone Chlorophacinone Valone

Vasoconstriction and ischemia in rats only via specific norbormide receptor in rat smooth muscle Uncouples oxidative phosphorylation; interrupts nerve impulse conduction

Estimated Fatal Dose

Diagnostic Presenting Signs and Symptoms

>4 g/kg

?

?

?

?

0.5% 0.005–2.0% 0.005–2.5% 0.005–2.5%

a

The LD50 values used in this table are derived from data on acute oral ingestions of the commercial product by rats. In some cases the commercial product contains a very small percentage of active ingredient. The signal words that appear on labels of registered products may differ from the signal word assigned to the acute oral LD50 test because the label may also reflect another study (acute dermal or inhalational LD50) requiring a more severe signal word. See Chapters 89–4 and 91–1 for the Consumer Product Safety Commission definitions and use of signal words as indicators of potential hazard of toxicity. Peacock D, Biologist, Registrations Division Office of Pesticide Programs, EPA, Washington, DC. *Gastrointestinal decontamination should be provided as appropriate (Chap. 5); only unique or controversial aspects are discussed in this table.

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trointestinal signs appear 0.5–2 days following ingestion or exposure and include nausea, vomiting, hematemesis, bloody diarrhea, abdominal pain, and, later, ileus. Neurologic sequelae typically occur 2–5 days after exposure and include headache, lethargy, muscle weakness, painful paresthesias in the extremities, tremors, ptosis, ataxia, myoclonus, seizures, delirium, and coma. Nonfatal exposures have resulted in long-term neurologic impairment such as painful neuropathies, paresis, optic nerve atrophy, ataxia, choreiform movements, and dementia. Another characteristic longterm effect is alopecia (Chap. 83).

Sodium Monofluoroacetate (SMFA, Compound 1080)

The development and commercial use of sodium monofluoroacetate (SMFA, compound 1080), another highly toxic rodenticide (LD50 2 mg/kg), was the result of efforts in this country during the 1940s to find an effective rodenticide not subjected to the shortages caused by World War II.34 Since its introduction in 1946, the use of SMFA in the United States has been limited to commercial exterminators. Originally marketed as a liquid mixed with a dye to be placed in shallow paper cups in areas inaccessible to humans, by 1949 at least 12 deaths were recorded. The deaths included 5 small children who had chewed on the poison cups, 3 juveniles who encountered the poison in a soft drink bottle, and 4 adult suicides. An additional 4 deaths in children were probably caused by SMFA.34 SMFA is derived from Palicourea spp. (South America), Acacia spp. (Australia), Dichapetalum cymosum (Africa), and a few other plants, it is a white, odorless, water-soluble salt, with an appearance similar to that of flour or baking soda. SMFA is reported to be tasteless as a powder but tasting weakly like vinegar in dilute solution.34 Unlike thallium, SMFA cannot be absorbed through unbroken skin. However, it is toxic when ingested, inhaled in dusts, or absorbed through open wounds. The toxicity of SMFA is related primarily to its interference with the Krebs cycle rather than because of its fluoride content.34,66,73 All ω-monofluoro amino acids with an odd number of carbon atoms and ω-monofluoro alkanoic acids with an even number of carbon atoms are toxic.34 The toxic effects of SMFA occur 1 to several hours after exposure and result from the conversion of the nontoxic fluoroacetate ions to fluorocitric acid which, in turn, blocks the tricarboxylic acid cycle essential to energy production in mammalian cells (Figure 13–2).66 The term “lethal synthesis” was first coined to describe these in vivo effects of fluoroacetic acid.34,66 Toxic effects of SMFA, primarily involving the CNS and the heart, include nausea and apprehension followed by cardiac dysrhythmias, seizures, and coma, with death resulting from ventricular tachycardia and ventricular fibrillation or respiratory failure secondary to pulmonary edema or bronchopneumonia.16,32,73 Animals dying of SMFA poisoning rapidly develop a characteristic extensor rigor mortis and are subsequently found with extremities in hyperextension. Investigators from Taiwan retrospectively analyzed 38 consecutive cases of SMFA poisoning, including 7 deaths, that occurred

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between 1988 and 1993. Of the 38 patients, 74% had nausea or vomiting—the most common finding; 65% had hypokalemia; and 42% had hypocalcemia. The most common ECG pattern was a nonspecific, ST-T and T-wave abnormality. Hypotension, elevated serum creatinine, and acidemia were the most accurate prognostic indicators of subsequent death.18 The hypotension or shock after SMFA poisoning may be a result of diminished systemic vascular resistance and increased cardiac output.19 There is no known antidote for SMFA. Orogastric lavage followed by the use of activated charcoal and a sorbitol cathartic are recommended, although adsorption by activated charcoal is probably not significant. Glycerol monoacetate as a substrate in the blocked Krebs cycle has been used experimentally in monkeys at doses of 0.1–0.5 mL/kg body weight IV, or 0.55 g/kg IM every half hour for several hours.17 In an attempt to inhibit the conversion of fluoroacetate to fluorocitrate, 500 mL of 10% acetamide in 5% dextrose over 30 minutes every 4 hours, or a 10% solution of ethyl alcohol, have been used experimentally with limited success.16,17 An ethanol-loading regimen is described in Antidotes in Depth: Ethanol. A combination of calcium gluconate (to correct hypocalcemia) and sodium succinate (to supplement the blocked trichloroacetic acid cycle) has reduced mortality from sodium fluoroacetate in mice, but only when the calcium gluconate and sodium succinate were administered simultaneously.62

Fluoroacetamide

Fluoroacetamide (compound 1081) is a fluoroacetate derivative similar to sodium monofluoroacetate but with a slightly higher LD50 (13–14 mg/kg)34 and a somewhat slower onset of symptoms. In 2 cases of fluoroacetamide poisoning, both the life-threatening dysrhythmias and the prolonged QT intervals that preceded them responded to calcium chloride therapy, suggesting that fluoride content plays a role in fluoroacetamide toxicity.87 An acute inhalation toxicity experiment exposing rats to aerosolized 2-fluoroacetamide resulted in desquamation and necrosis of the respiratory epithelium, marked hypertrophy of hepatocytes, and renal damage.85 Because of the extreme toxicities of both fluoroacetamide and sodium monofluoroacetate, they are rarely used, even by licensed pest control operators.

Strychnine

Strychnine is a naturally occurring alkaloid from the seeds of the tree Strychnos nux vomica, which is a small poisonous tree with ovate leaves and yellowish-white tubular flowers indigenous to India, Indochina, northern Australia and Hawaii. The yellow-or-

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ange hard shelled fruit is 1.5 inches in diameter and contains greyish seeds 0.5 inches in diameter, which in turn contain 1.1 to 1.4% strychnine.41a,65a Strychnine, a highly toxic substance that had been used as a rodenticide since the 16th century, is generally encountered as an odorless, colorless crystal or bitter white powder that can be absorbed through the gastrointestinal tract or nasal mucosa.12 Strychnine is a CNS stimulant that causes muscle twitching, extensor spasm, opisthotonos, trismus or a characteristic facial grimacing known as “risus sardonicus”, painful “seizures” during which the patient is conscious, and medullary paralysis resulting in death.60,61,86,89 Ironically, considering its extreme danger to humans, strychnine is not even an effective rodenticide because rats appear to quickly learn to avoid the bitter taste it imparts to the bait. For both of these reasons, strychnine is virtually never used today as a rodenticide. However, it may still be encountered as a component of homeopathic tonics and cathartic pills,63 and as recently as 1979, had been proposed as a treatment for nonketotic hyperglycinemia in infants.37 A traditional Cambodian remedy for gastrointestinal disorders known as “slang nut” or “poisonous nut”, which is the fruit of the Strychos nux vomica, has been implicated in one recent case of strychnine poisoning41a and a different Cambodian herbal preparation was implicated in another.46a Crimidene, another rodenticide that is a synthetic chlorinated pyrimidine compound related to strychnine, produces similar CNS signs and symptoms.74 The adult lethal dose of strychnine is reportedly between 50 and 100 mg, or 1–2 mg/kg of body weight,63,65a,74 and signs and symptoms of strychnine poisoning often begin within 15–20 minutes of ingestion. There is very little protein binding, the half-life is 10–16 hours, and detoxification and elimination are primarily by hepatic metabolism.37,62a,74,80 Although initial studies involving small doses of strychnine suggested that up to 20% was excreted unchanged in the urine,58,93 more recent pharmacokinetic studies indicate that less than 1% is excreted in the urine after larger ingestions.37,62a,80 Only three published studies of strychnine exposures include multiple blood levels: In one (nonfatal) case study, 19 determinations were made including a peak level of 1.6 mg/L about 4 hours postingestion. In this instance, a t ⁄ of 10 hours was calculated by first-order kinetics.28 Results from a fatal case with 4 determinations and a peak level of 3.8 mg/L suggested both a large volume of distribution (13 L/kg) for strychnine and nonlinear, Michaelis-Menten elimination.37 More recently, another fatal case with 18 strychnine determinations between 20 minutes to 52 hours post ingestion indicated a t ⁄ of 10–16 hours by first order kinetics similar to the findings in the nonfatal case.62a Strychnine causes competitive antagonism of the inhibitory neurotransmitter glycine at the postsynaptic spinal cord motor neuron.37,44 Victims of strychnine poisoning may remain awake with relaxed muscles between episodes of opisthotonos and muscle contractions that are triggered by minimal sensory stimuli.37 Complications of strychnine-induced muscle spasm include hypoxia, hyperthermia, cardiac arrest, rhabdomyolysis, acute renal failure, and hyperthermia.37 Postmortem findings in the case with the 3.8 mg/L peak level included extensive necrosis of the cerebral cortex and brainstem, and bilateral lower lobe bronchopneumonia.37 The differential diagnosis of confusion accompanied by episodic muscle rigidity includes phencyclidine toxicity, the neuroleptic malignant syndrome, viral encephalitis, epilepsy, tetanus46a and isoniazid toxicity. Tetanus, in particular, has much

in common with strychnine poisoning such as the facial muscle grimacing known as “risus sardonicus”, sudden painful tonic muscle contractions and decorticate posturing during which time the patient remains conscious. However, strychnine poisoning typically results in more prominent alterations in mental status.46a Early useful interventions advocated for strychnine poisoning include activated charcoal3,4 and orogastric lavage with aggressive airway management.37 However, once symptoms appear, any manipulation or excitement may precipitate opisthotonos or tonicclonic “seizures,” and for this reason, a quiet environment and benzodiazepines have been advocated.34 The extensor spasm, opisthotonos, and seizures associated with strychnine poisoning may be controlled initially by a benzodiazepine such as diazepam (0.1–0.5 mg/kg, IV slowly)—which acts as an indirect GABA agonist—followed by a barbiturate such as pentobarbital (another GABA agonist). If these measures prove ineffective, immediate induction of general anesthesia and/or neuromuscular blockade with a nondepolarizing neuromuscular blocking agent should be considered.37,86 The latter is recommended because strychnine seizures are thought to originate at the level of the spinal cord and not at the cerebral cortex.37 Intubation and mechanical ventilation will permit safer gastric evacuation by orogastric lavage, and maintenance of adequate urine output with fluid and diuretic therapy may reduce the risk of acute renal failure from rhabdomyolysis.37 Acidification of the urine theoretically may enhance excretion of strychnine after ingestion of minimal amounts, but after significant exposures, renal excretion appears to be insignificant, and any benefit of acidification will almost certainly be outweighed by the risk of exacerbating the profound lactic acidosis and myoglobinuria secondary to rhabdomyolysis that have been documented in these cases.13 Chapter 69 discusses urinary acidification and rhabdomyolysis. Orogastric lavage (or even worse, emesis) in the unintubated victim of strychnine poisoning may be extremely dangerous because of the potential for generalized muscle contractions. Therefore, activated charcoal alone, administered by a nasogastric tube, may be the safest and most effective initial measure.

1

2

Zinc and Aluminum Phosphide

1

2

Both zinc and aluminum phosphide are still used as rodenticides in developing nations because they are both cheap and effective. Zinc phosphide’s dark gray color, “rotten fish odor,” and bad taste reportedly make it unattractive to animals other than rats. Typically mixed with tartar emetic, zinc phosphide is highly toxic because it releases phosphine and zinc on contact with water and acid. Phosphine inhibits cytochrome oxidase and the electron transport system,20 and causes widespread cellular toxicity, injury and necrosis to the gastrointestinal tract, liver and kidneys.27 Patients poisoned by zinc phosphide manifest, in 4 days to 2 weeks, nausea and vomiting, excitement, chills, chest tightness, cough, hypotension, dyspnea, pulmonary edema, circulatory collapse, cardiac dysrhythmias, convulsions and coma, renal damage, anuria, tetany (hypocalcemia), leukopenia, and death.2,20 Inhala-

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tion of zinc phosphide dust may induce pulmonary edema. Longterm occupational exposure results in a constellation of neuropsychiatric, cardiac, pulmonary, renal, and hepatic findings.2 Treatment advocated for zinc phosphide poisoning includes dilution with sodium bicarbonate, milk, or water, orogastric lavage, and administration of activated charcoal, a cathartic, and possibly a proton pump inhibitor type of antacid (such as omeprazole).

Yellow Phosphorus

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Arsenic Another highly toxic element still in rare use as a rodenticide is arsenic. Arsenic trioxide is a white, crystalline powder that causes dysphagia, muscle cramps, convulsions, vomiting, and bloody diarrhea following ingestion. Death from arsenic poisoning is a result of cardiovascular collapse. Immediate treatment recommendations for arsenic poisoning include orogastric lavage followed by activated charcoal and a cathartic. Succimer (Dimercaptosuccinic acid, DMSA)43,81 or dimercaprol may be used to chelate this heavy metal after it is absorbed. Between 1956 and 1974, arsenicals were identified as the single most common cause of unintentional rodenticide-related deaths. However, because of its extreme toxicity, pest control operators have avoided using arsenic for many years (Chap. 79).

Barium Carbonate

Yellow (or “white”) phosphorus, the form of elemental phosphorus still used as a rodenticide in some parts of the world, is highly poisonous—a human ingestion of 50 mg or 1 mg/kg may be fatal.23,77,84 The other commonly available form of elemental phosphorus, red phosphorus, is the only form of phosphorus still used in matches today and, in contrast to yellow phosphorus, is relatively harmless. When used as a rodenticide, yellow phosphorus is usually mixed with molasses or peanut butter and spread on bread as bait for rodents or roaches. For obvious reasons, rodenticides deployed in this manner may be unintentionally ingested by children or compromised adults. Contact with yellow phosphorus causes second- and thirddegree skin burns within minutes to hours. Yellow phosphorus is most immediately toxic to the gastrointestinal tract and liver and ingestions are usually followed by a peculiar type of vomiting, described as “smoking,” luminescent, and with a garlicky odor. Resultant stools may also be luminescent and “smoking.”84 Delirium, coma, and death from cardiovascular collapse may ensue.68,88 Yellow phosphorus has a direct toxic effect on the myocardium and peripheral vessels. Experimentally, acute phosphorus poisoning depresses rat myocardial protein synthesis.88 Patients who survive the acute effects of yellow phosphorus poisoning may then have a relatively symptom-free period lasting for a few weeks, only to experience a third stage of systemic toxicity involving the gastrointestinal tract, liver, heart, kidney, and central nervous system. Treatment for yellow phosphorus poisoning in the past has included orogastric lavage with potassium permanganate 0.1% solution, or 3% hydrogen peroxide diluted to a 2% solution to oxidize the phosphorus to harmless phosphates, followed by the use of activated charcoal and possibly a cathartic. These approaches have not been adequately investigated. Neither corticosteroids, which had been previously recommended, nor exchange transfusions appear to be useful; in one group of 49 suicidal patients from Colombia, corticosteroids did not prevent coma or death from hepatic injury.50 In another group of 15 patients with hepatic encephalopathy, 3 of 5 patients treated with exchange transfusions survived, as compared to 3 of 10 untreated patients.50 Red phosphorus is nonvolatile, insoluble, not absorbed through the gastrointestinal tract, and, therefore, relatively harmless when ingested.84

Barium carbonate is a highly toxic soluble salt previously used as a rodenticide. Another toxic soluble barium salt, barium sulfide is currently used as a male depilatory.82 Insoluble forms of barium, such as the barium sulfate commonly used in radiographic procedures, are harmless. But, soluble forms of barium—such as the acetate, carbonate, chloride, hydroxide, nitrate, and sulfide forms— cause profound weakness and gastrointestinal, neurologic, cardiovascular, pulmonary, and possibly renal dysfunction.67,94 Most of the toxic effects of barium result from its direct stimulation of all types of muscle, including cardiac muscle, and from its ability to cause a profound reduction in serum potassium together with an increase in intracellular potassium.76,82,94 Death results from hypokalemia, cardiac dysrhythmias, congestive heart failure, and pulmonary toxicity. A similar mechanism has been proposed for the hypokalemic paralysis that results from barium poisoning, chronic potassium deficiency, and thyrotoxicosis:45 the large, active and passive influx of extracellular potassium into the muscle turns off the Na+K+-ATPase pump causing depolarization and paralysis. However, in 1 case report involving barium carbonate, the degree of weakness correlated with the plasma barium concentrations and not the potassium concentrations.67 The author suggests that barium itself is responsible for membrane depolarization by causing release of acetylcholine83 and by competitively reducing the permeability of all membranes to potassium,45 with the resultant intensity of neuromuscular blockade correlating directly with the plasma barium concentrations. One case of renal toxicity and acute renal failure following ingestion of a teaspoonful of barium chloride may have resulted from treatment with intravenous MgSO4, saline, and furosemide (in addition to the previously recommended oral MgSO4).94 The intravenous combination of medications may have caused barium sulfate to precipitate out into the renal tubules. Treatment for the ingestion of soluble forms of barium includes emesis, if it can be accomplished rapidly outside of the hospital, or orogastric lavage with 5–10 g of sodium sulfate added to the lavage solution in the hope of converting the barium carbonate to barium sulfate.5,65 Instilling MgSO4 30 g, through a nasogastric tube in 1 instance appears to have been effective in precipitating the barium as the insoluble sulfate.55 The most important aspect of management is rapid, aggressive potassium replacement intravenously as indicated by frequent serum potassium monitoring,34,65,94 together with vigilance for subsequent hyperkalemia

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resulting from rhabdomyolysis and extracellular return during recovery.82

Vacor (N–3-pyridylmethyl-N′p-nitrophenyl urea, PNU)

The quest for a safe, highly effective single-dose rodenticide occasionally leads to the introduction of extremely toxic substances with tragic consequences to humans who are exposed to them. One of the most unfortunate examples is N–3-pyridylmethyl-N′-pnitrophenyl urea (Vacor, PNU), which was introduced in 1975 with labeling indicating that it was safe for human consumption. Shortly after its introduction, 7 South Koreans died after eating Vacor-contaminated rice. In the United States, more than 100 poisonings and at least 12 deaths caused by Vacor occurred between 1975 and 1980, with deaths resulting from the ingestion of as little as a single (30-g) package. The manufacturer withdrew Vacor from sale in June 1979, with a request to return all unsold Vacor, but no public recall was ever issued. Information in this section regarding the management of Vacor poisoning may also be applicable to pentamidine, alloxan, and streptozotocin exposures, all of which destroy pancreatic  cells. Although more than 20 years have elapsed since Vacor was withdrawn from the market, AAPCC/TESS continues to report between 1 and 7 Vacor exposures annually with adverse outcomes rated from none to moderate, but no major adverse effects or deaths. These continuing reports of Vacor exposures without the serious sequelae seen in the 1970s suggest either an overreporting of unconfirmed exposures or a large reservoir of Vacor packets in the environment. The last confirmed exposure to Vacor reported in the medical literature occurred in 1986, when a patient ingested the contents of a package that had been sold and placed many years earlier; at the time of the exposure, the recommended antidote, niacinamide was no longer available.38 Vacor is a structural analogue of alloxan and streptozotocin and, as noted above, all three destroy pancreatic  cells.42 Pentamidine toxicity also results in islet cell necrosis without an accompanying lymphocytic infiltrate.33 Vacor, alloxan, and streptozotocin all interfere with niacinamide metabolism in pancreatic  cells, liver, and brain cells.36,41,46 In vitro studies demonstrate that these toxins are incorporated into various intracellular nucleotides, which are then unable to act as hydrogen carriers in oxidoreductase systems, thereby inhibiting the activities of certain enzyme systems. When these nucleotides are substituted for niacinamide in the synthesis of nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH), major abnormalities of the pentose phosphate pathway result, causing defects in intermediary metabolism and RNA production.36 Recently, investigators who incubated mitochondria and submitochondrial particles from beef, rat heart, and rat liver with various concentrations of Vacor demonstrated that it specifically inhibits the NADH-ubiquinone reductase activity of respiratory complex I in mammalian mitochondria, in turn correlating quantitatively with the inhibition of insulin release from insulinoma cells and pancreatic islets. This inhibition was entirely consistent with

the dose effects of Vacor that had been reported in human poisonings.29 In other rat experiments, electron microscopy of the thickened glomerular basement membranes that developed within 7 days of Vacor ingestion revealed increased collagen, laminin, fibronectin, neutral polysaccharides, and chondroitin sulfate proteoglycan.79 Electrophysiologic studies on a peripheral motor nerve-skeletal system of Vacor-treated rats showed decreased amplitude of muscle action potential with corresponding structural studies demonstrating degenerative changes in the axon terminal at the neuromuscular junction.1 Humans who ingested Vacor developed, within hours, an insulin-deficient hyperglycemia or diabetic ketoacidosis, accompanied by severe postural hypotension and sensorimotor peripheral and autonomic neuropathies.41,46,54,70,72 Reported deaths were caused by ketoacidosis, gastrointestinal perforation, cardiac dysrhythmias, and pneumonia. Patients who survived Vacor ingestions after manifesting symptoms, almost invariably required insulin therapy to manage their newly acquired diabetes. The major long-term management problem however, was the neuropathy, especially the resultant postural hypotension which is both severe and extremely resistant to therapy. Based on the in vitro studies noted and on an in vivo rat study, a treatment plan for acute Vacor (and presumably, alloxan and streptozotocin) ingestions was formulated, calling for 500 mg of niacinamide (nicotinamide) IM or IV, immediately followed by 100–200 mg IM or IV every 4 hours for up to 48 hours, increased to every 2 hours if signs of toxicity develop. Under this treatment plan, the maximum total dose of niacinamide is 3 g/d for an adult. For small children, approximately one-half of the adult dose was recommended. When the patient was able to take oral medications, 100 mg of niacinamide was recommended 3–5 times daily for 2 weeks. Fludrocortisone was frequently necessary for persistent postural hypotension. In the past, investigators cautioned against substituting niacin (nicotinic acid) for niacinamide (nicotinamide), out of concern that (a) the vasodilatory effects of nicotinic acid would exacerbate the hypotensive effects of Vacor;46 (b) niacin is less effective than niacinamide; and (c) niacin causes and exacerbates glucose intolerance.56 However, when intravenous niacinamide became unavailable in this country, substituting niacin as the only available alternative was advocated. Niacinamide in capsule form may still be found at various nutritional supplement outlets. In addition to giving niacinamide (nicotinamide), emesis, or orogastric lavage, activated charcoal and cathartic administration were recommended. Ketoacidosis should be managed with insulin, and silent, nonpainful, gastrointestinal perforation should be anticipated and rigorously searched for. The reasons that Vacor continues to be of more than historical interest over two decades after its withdrawal include the insights it provides into the limitations of product testing techniques and of postmarketing surveillance: Because of widely varying LD50s, perhaps resulting from a common gene not shared by other animals, rats and humans appear to be the most susceptible to Vacor toxicity.34 Vacor is also providing new insights into possible environmental etiologies of diseases—in this case, diabetes mellitus—just as MPTP (see Chap 62) has demonstrated a link between environmental toxins and parkinsonism. Vacor poisoning may be a biochemical paradigm for the metabolic induction of insulin-dependent diabetes mellitus, as well as

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some of its associated vascular and neurologic problems: Vacorinduced diabetes mellitus closely mimics the “naturally occurring” disease. Of 18 patients who had developed diabetes mellitus after Vacor ingestions, 44% also developed retinopathy, 28% developed proteinuria, and all developed (muscle) capillary membrane thickening similar to that seen in insulin-dependent diabetes after a mean duration of 6.2 years postingestion.31

MODERATELY TOXIC RODENTICIDES (SIGNAL WORD: “WARNING”) Moderately toxic rodenticides, those with an LD50 of 50–500 mg/kg body weight, include the “selective” rodenticide ANTU and cholecalciferol (vitamin D3), one of the newest and increasingly popular rodenticides.


-Naphthyl-Thiourea

ANTU kills rats by causing pulmonary edema and pleural effusion, probably because of damage to the lung capillaries resulting in increased permeability.10,75 Young rats and rats exposed initially to small, nonlethal doses are relatively resistant to the lethal effects of ANTU, possibly by developing pulmonary cell hyperplasia in response to the small doses.8 The heart appears to be unaffected by ANTU.10,75 There are no well-documented cases or series of human ANTU ingestions from which human toxicity can be accurately determined. In several older series of combined ANTU + chloralose ingestions, it appears that the respiratory symptoms were more severe from the combination than from chloralose alone, suggesting pulmonary effects of ANTU in humans. Of the 14 patients poisoned by the combination, 11 required intubation because of tracheobronchial hypersecretion.30,34 Recommended treatment for ANTU ingestions is orogastric lavage followed by administration of activated charcoal.58

Cholecalciferol

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Cholecalciferol (vitamin D3) was first registered and marketed in the United States in late 1984. It is now widely used by professional pest control operators as Quintox, and by the general public as Rampage. Cholecalciferol mobilizes calcium from the bones of rodents and rabbits and in toxic doses produces hypercalcemia, osteomalacia, and metastatic calcification of the cardiovascular system, kidneys, stomach, and lungs; death typically occurs in 2–5 days.51–53 All animals are susceptible to the effects of cholecalciferol, but because of their size, rats and mice succumb to much lower doses than do larger animals such as cats and dogs.51–53 Cholecalciferol appears to be an effective rodenticide either when a large amount is consumed in one meal or when smaller amounts are consumed over a 2–3-day period.53,71 Because death is not immediate and the cholecalciferol does not impart unusual characteristics to the bait, the bait shyness seen with zinc phosphide, ANTU, strychnine, and other rodenticides does not occur with cholecalciferol.51–53 The closely related calciferol (vitamin D2 or ergocalciferol) has been used as a rodenticide in Europe and Canada since 1978, with no genetic resistance reported to date.51–53 Although rats manifest the signs of severe acute hypercalcemia, including lethargy and ultimately death from myocardial infarction in 2–5 days,71 no serious human toxicity or death from the rodenticide form of cholecalciferol has been reported to date. All of the advice for managing human ingestions is based on experience with treating therapeutic forms of vitamin D poisoning and hypercalcemia. One case of cholecalciferol poisoning in an industrial setting may be particularly relevant because, as in the case of a child who might repeatedly ingest small amounts of rodenticide, the exposure described was two small doses over a 32-day period and resulted in prolonged hypercalcemia.39 Immediate intervention after a large acute ingestion should include gastric emptying by emesis or orogastric lavage followed by gastric decontamination with activated charcoal and possibly sorbitol. Repetitive dosing of activated charcoal has been recommended, but data are insufficient to confirm its usefulness. Treatment for moderate to severe degrees of hypercalcemia (greater than 11.5 mg/dL) include IV fluid therapy with 0.9% sodium chloride solution if the patient is hypovolemic and can tolerate a fluid load. Potassium and magnesium levels should be monitored and maintained. Furosemide should be administered. Prednisone (0.5–1.0 mg/kg daily) appears to be particularly effective for hypercalcemia secondary to vitamin D poisoning. Calcitonin (salmon calcitonin, Calcimar) 4–8 IU/kg SC or IM every 6–12 hours may reduce serum calcium levels by 1–3 mg/dL over a few hours by inhibiting osteoclastic bone resorption while promoting calciuria. Bisphosphonates (such as pamidronate) can be used concomitantly with calcitonin to produce a prolonged effect. A normal serum calcium level obtained 48 hours after an acute ingestion almost certainly excludes any significant toxicity.

LOW-TOXICITY RODENTICIDES (SIGNAL WORD: “CAUTION”) The remaining rodenticides, with one exception, are of low toxicity (LD50, 500–5000 mg/kg). This category includes red squill (Urginea maritima) and norbormide, along with the “warfarintype” anticoagulant rodenticides, which are still the most commonly used rodenticides today.

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Red Squill

sue anoxia.58 In vitro norbormide promotes calcium entry into smooth-muscle cells, inducing a myogenic contraction selective for the small vessels in rats, whereas in the arteries of other mammals (and in the rat aorta), norbormide behaves like a calcium channel entry blocker.11 Although emesis and catharsis may be considered if they can be easily performed, it is probably quite sufficient to achieve gastric decontamination with activated charcoal and possibly a cathartic, especially when dealing with an uncooperative patient.

Anticoagulants

Red squill is a naturally occurring rodenticide found in the sea onion plant Urginea maritima of the Liliaceae family. It contains scillaren A and B, which are cardiac glycosides. The effects of red squill on humans are chiefly gastrointestinal: abdominal pain, nausea, and vomiting. Red squill is considered to be so potent an emetic in humans, that the expected cardiotoxicity (ie, ventricular irritability, premature ventricular contractions, ventricular fibrillation, and so on) is rarely, if ever, seen as a result of ingesting the commercial rodenticide. However, a 1995 case report of a human who ingested two bulbs of the plant, documents the subsequent nausea, vomiting, seizures, hyperkalemia, atrioventricular block, ventricular dysrhythmias, and death that would be expected after a massive cardiac glycoside poisoning.90 Evaluation should include cardiac monitoring, electrolyte (particularly potassium) analysis, and a digoxin assay with which these cardiac glycosides may cross-react. There are no specific data indicating the degree of cross-reactivity demonstrated by red squill, but this concept and the consequent utility of obtaining a “digoxin” level is discussed for many other plant and animal cardiac glycosides in Chap. 48. When present, the cardiotoxicity of red squill is probably best treated with digoxin-specific antibody fragments [see Antidotes in Depth: Digoxin-Specific Antibody Fragments (Fab)].78

Norbormide

Norbormide, the irreversible smooth-muscle constrictor, appears to be specific for rats and has no known human toxicity. Rats die as a result of intense generalized vasoconstriction, resulting in tis-

The anticoagulant, or warfarin-type rodenticides are far and away the most commonly implicated in rodenticide related calls to poison centers (see Chapter 116 and p. 1752). Prior to the 1980s, both human and rodent toxicity from the anticoagulant rodenticides depended on repeated exposure to relatively small doses. Although there was virtually no toxicity to humans after a single exposure from this type of rodenticide, the inability to ensure repetitive ingestions by rats made warfarin-type anticoagulants less effective as rodenticides. In addition, a selection process led to the prevalence of resistant rats (“super rats”) in some areas. For both of these reasons, more toxic rodenticides continued to be used and introduced. In the 1980s, newer types of anticoagulant rodenticides were marketed that are both lethal to rats and toxic to humans after a single acute ingestion. Use of these potent long-acting anticoagulant rodenticides continues to increase. A single ingestion of a “superwarfarin” rodenticide such as difenacoum or brodifacoum, may result in marked anticoagulation effects for up to 7 weeks. The case presented at the beginning of this chapter demonstrates the severity and duration of brodifacoum toxicity.12 Chapter 42 has a

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detailed discussion on the classification, mechanism of action, diagnosis, and treatment of warfarin and long-acting anticoagulants. Appropriate management of patients exposed to anticoagulant rodenticides begins with an appreciation of the time required before clinical effects become apparent. Because acute single-dose ingestions of currently available anticoagulant rodenticides typically do not result in immediate toxic effects, initially there are no clinical findings. The history then becomes essential in attempting to exclude or diagnose an exposure; if the details of the history are in doubt, baseline complete blood count (CBC) and PT determinations are important. Additionally, when an acute exposure to a long-acting anticoagulant is under consideration, a factor analysis for factors II and VII may be very useful, if available. An abnormal PT or INR and/or diminished levels of factors II and VII will serve to identify either the chronic ingester of a short-acting anticoagulant or a patient who presents several hours or days after exposure to a long-acting coumarin.7 In either case, an abnormal PT or INR and/or decreased factor levels should prompt a careful search for bleeding complications. For patients with active blood loss, fresh-frozen plasma (FFP) is the initial treatment of choice, followed by Vitamin K1 for long-term control of the PT or INR.

and severe myoclonic jerks with flexion of major muscle groups. The patient was intubated, attached to a respirator and lavaged; he was given phenytoin, mannitol, dexamethasone, and diazepam. Blood and urine analyses were positive for his prescribed fluoxetine in therapeutic levels and negative for carisoprodol and ethanol. EEG demonstrated only bihemispheric slowing with a normal head computed tomography (CT) scan. After 24 hours, the patient responded to noxious stimuli and was free of tremors and myoclonus. He was discharged 2 days later.14 Because there is no known antidote for bromethalin, it is hoped that the symptomatic and supportive care provided to the patient described above will prove to be sufficient to achieve a good outcome after other significant human exposures. In rats, administration of a commercially available extract of Gingko biloba immediately after 1.0 mg/kg ingestion of bromethalin resulted in a statistically significant decrease in the severity of adverse neurologic effects.24

Bromethalin

For the patient exposed to an unknown rodenticide, the approach is more complicated than for a patient who ingests a known common commercial rodenticide such as warfarin or cholecalciferol. First, as always, adequate breathing and circulation must be assured and the patient briefly examined. If the patient is initially stable, the next priority is to make every effort to fully identify the type and quantity of rodenticide ingested. If the rodenticide and its package material are not brought with the patient, someone should be sent to bring them back to the ED. Identifying a harmless rodenticide ingestion early on is more cost effective and less traumatic to the patient than treating for an unknown ingestion. If the rodenticide container is labeled, and the information is telephoned back to the ED, care should be taken to obtain the full name, not just the brand name. For example, until 1986, there was a line of rodenticides all carrying the “Pied Piper” name on a variety of very different products: Pied Piper for Rats and Mice contained ANTU and warfarin; whereas Pied Piper Kwik-Kill Mouse Seed contained strychnine; and Pied Piper Rodenticide contained red squill. Many manufacturers still use similar names for dissimilar poisons. While awaiting full identification of the rodenticide, a careful physical examination should be performed, searching for toxic signs that indicate specific rodenticides:

Bromethalin is the newest rodenticide and is considered to be of low toxicity in its commercial product (LD50 of >500 mg/kg in rats.) Bromethalin was registered with the EPA in 1982, became available in 1986, and is currently available commercially in the United States as green pellets mixed with cornmeal (which gives it a fresh corn odor) and Bitrex. Of all the currently used rodenticides, less is known about bromethalin, marketed as Assault or Vengeance, than about any of the other rodenticides. From the time bromethalin became available, concern was expressed about its potential toxicity.51 However, the first possible bromethalininduced case of human toxicity was not reported until 1996,14 perhaps because as late as 1997 bromethalin had been registered in only 6 states; in 2 of these states, California and New York, bromethalin first became available in 1996. Bromethalin is considered to be a highly effective, single-feeding rodenticide with a mode of action reportedly involving the uncoupling of oxidative phosphorylation in the mitochondria, resulting in decreased ATP production, increased fluid accumulation, and consequent increased pressure on nerve axons interrupting nerve impulse conduction.52 The pathologic changes resulting from a 1.5 mg/kg oral dose of bromethalin administered to cats, included spongy changes, hypertrophied fibrous astrocytes, and hypertrophied oligodendrocytes in the white matter of the cerebrum, cerebellum, brainstem, spinal cord, and optic nerve.24,26 Prior to sacrifice of the animal, the clinical manifestations of bromethalin poisonings included ataxia, focal motor seizures, decerebrate posture, decreased proprioception, and depressed level of consciousness. Dogs given oral doses of 6.25 mg/kg of bromethalin developed hyperexcitability, tremors, seizures, depression, and death within 15–63 hours of exposure.25 Death in animals is also usually preceded by paralysis and loss of tactile sensation.91,92 In 1996, the first case of possible bromethalin-induced human toxicity was reported. A 28-year-old male was found unconscious with open packages of two different rat poisons—Velsicol (diphacinone 0.005%) and Vengeance (bromethalin 0.01%), carisoprodol, and alcohol. Tactile stimulation produced muscle tremors

MANAGING THE PATIENT EXPOSED TO AN UNKNOWN RODENTICIDE

■ Gastrointestinal symptomatology, paresthesias, and the late onset of hair loss are characteristic of thallium. ■ Irritability or “apprehension” followed by seizures, coma, and death from respiratory failure or ventricular tachycardia and fibrillation are produced by SMFA and fluoroacetamide. ■ Central nervous system stimulation, opisthotonos, prolonged recurrent motor seizures or convulsions, and medullary paralysis followed by death suggest strychnine poisoning. ■ Hypotension, vomitus with a rotten or “fishy” odor, cardiopulmonary collapse, coma, renal damage, and leukopenia suggest zinc phosphide poisoning. ■ Oral and skin burns, luminescent “smoking” vomitus, and stools with a garlic odor, and gastrointestinal and biliary damage characterize yellow phosphorus poisoning.

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■ Dysphagia, muscle cramps, seizures, hematemesis, and bloody diarrhea followed by cardiovascular collapse suggest arsenic. ■ The combination of striking hyperglycemia with or without ketoacidosis, and severe postural hypotension, autonomic and peripheral neuropathies, ileus, and esophageal or GI perforation characterize PNU or Vacor poisoning. ■ Muscle tremors, myoclonic jerks with flexion of major muscle groups, and unresponsiveness may be the human manifestations of bromethalin poisoning. ■ Dyspnea, rales, pulmonary edema, pleural effusions, and hypothermia are seen with massive ingestions of ANTU. ■ Nausea, vomiting, diarrhea, and abdominal pain will probably be the only effects of ingesting red squill, but when those effects are combined with signs of ventricular irritability (premature ventricular contractions and ventricular fibrillation), then this potent emetic and cardiac glycoside is certainly identified. ■ Signs or symptoms of a bleeding disorder and abnormal PT or INR, or low levels of coagulation factors, point to either a large acute ingestion of a superwarfarin rodenticide, such as brodifacoum, or repeated (chronic) ingestion of a regular warfarin-type rodenticide. ■ Finally, evidence of hypercalcemia following (massive or chronic) rodenticide ingestion suggests a new and popular product, cholecalciferol (vitamin D3 ).

If a toxic syndrome is identified, aggressive management, including the use of specific antidotes, may be necessary (see Table 90–1). Immediately following an ingestion and prior to the development of signs and symptoms of toxicity, there is no rodenticide currently in use for which lavage followed by activated charcoal, and possibly a cathartic, is contraindicated, although they may be unnecessary for the older warfarin-type rodenticides and most unintentional exposures. After the patient is symptomatic, however, orogastric lavage, activated charcoal, and catharsis must be individualized according to the specific toxin and the patient’s clinical condition. If every effort to identify the rodenticide fails, the following diagnostic evaluation may be indicated: A CBC or hemoglobin (Hgb)/hematocrit (Hct) determination and INR (prothrombin time) will help diagnose and manage repetitive ingestions of the older warfarin-type rodenticide, chronic ingestions of the newer superwarfarin anticoagulant rodenticides, and a large single ingestion of a superwarfarin a few days after ingestion. Repetitive ingestions of the otherwise harmless older warfarins is an important consideration for children who have pica, as well as for institutionalized, emotionally disturbed adults who may nibble grainlike rodenticides repeatedly. Serum glucose, potassium, and bicarbonate determinations will identify hyperglycemia and ketoacidosis caused by Vacor, and an elevated serum calcium concentration suggests cholecalciferol (vitamin D3 ) ingestion. Liver enzymes, blood urea nitrogen (BUN), and creatinine are useful baseline determinations for rodenticides that cause renal or hepatic damage (eg, zinc phosphide, yellow phosphorus, cholecalciferol). A serum sample and 50 mL of urine should be obtained and sent to the toxicology laboratory with the request to hold it for possible heavy metals screening, especially if the patient is vomiting. Finally, if indicated by history or symptomatology, additional specimens may be collected for specific rodenticide determinations (eg, thallium, strychnine); chest and abdominal radiographs may be useful because of

the radiopaque nature of some of the uncommonly used rodenticides (Chap. 8). If there is any doubt about either the nature of the rodenticide or the reliability of the patient (or parents) after the diagnostic evaluation, the patient may be admitted or held in the ED for observation. No matter what type of rodenticide was ingested, a determination should be made as to whether the ingestion was unintentional, a suicide gesture or attempt, or a manifestation of abuse or neglect.7 A psychiatric assessment is, of course, indicated for any possible suicide attempt. If the patient is a child or infant, the emergency physician should review the principles of poison prevention with the parents (Chap. 4) and should consider the possibility that the incident represents child abuse or neglect. The emotional state of the parents must be taken into consideration when the physician is contemplating sending the child home for continued observation in the absence of history, physical, or laboratory evidence suggesting a serious exposure. In summary, the key to managing the patient who ingested a rodenticide is to identify the rodenticide, the quantity ingested, its potential toxicity, and any available specific antidote. Toxic ingestions should be excluded or treated immediately; conversely, patients with the most common acute anticoagulant or cholecalciferol exposures should not be overtreated.

ACKNOWLEDGMENTS Mary Ann Howland, PharmD, and Richard S. Weisman, PharmD, contributed to this chapter in a previous edition.

REFERENCES 1. Ahn JS, Lee TH, Lee MC: Ultrastructure of neuromuscular junction in Vacor-induced diabetic rats. Korean J Intern Med 1998;13:47–50. 2. Amr MM, Abbas EZ, El-Samra M, et al: Neuropsychiatric syndromes and occupational exposure to zinc phosphide in Egypt. Environ Res 1997;73:200–206. 3. Anderson AH: Experimental studies on the pharmacology of activated charcoal: III. Absorption from gastrointestinal contents. Acta Pharmacol 1948;4:275–284. 4. Anderson AH: Experimental studies on the pharmacology of activated charcoal: I. Absorption power of charcoal in aqueous solutions. Acta Pharmacol 1946;2:69–78. 5. Arena JM, Drew RH: Rodenticides, fungicides, herbicides, fumigants and repellents. In: Arena JM, Drew RH, eds: Poisoning: Toxicology, Symptoms, Treatment, 5th ed. Springfield, IL, Charles C Thomas, 1986, pp. 222–251. 6. Arneson D, Chi’en LT, Chance P, Wilroy RS: Strychnine therapy in nonketotic hyperglycinemia. Pediatrics 1979;63:369–373. 7. Babcock J, Hartman K, Pedersen A, et al: Rodenticide-induced coagulopathy in a young child. A case of Münchausen syndrome by proxy. Am J Pediatr Hematol Oncol 1993;15:126–130. 8. Barton CC, Bucci TJ, Lomax LG, et al: Stimulated pulmonary cell hyperplasia underlies resistance to alpha-naphthylthiourea. Toxicology 2000;143:167–181. 9. Ben-Assa B: Indirect thallium poisoning in a Bedouin Family. Harefuah 1962;62:378–380. 10. Bohm GM: Changes in lung arterioles in pulmonary oedema induced in rats by alpha-naphthyl-thiourea. J Pathol 1973;110:343–345. 11. Bova S, Travis L, Debetto P, et al: Vasorelaxant properties of norbormide, a selective vasoconstrictor agent for the rat microvasculature. Br J Pharmacol 1996;117:1041–1046.

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12. Bruno CR, Howland MA, McMeeking A, Hoffman RS: Long-acting anticoagulant overdose: Brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med 2000;36:262–267. 13. Boyd RE, Brennan PT, Deng JF, et al: Strychnine poisoning: Recovery from profound lactic acidosis, hyperthermia, and rhabdomyolysis. Am J Med 1983;74:507–512. 14. Buller G, Heard J, Gorman S: Possible bromethalin-induced toxicity in a human [abstract]. A case report. J Toxicol Clin Toxicol 1996; 34:572. 15. Chefurka W, Kashi KP, Bond EJ: The effect of phosphine on electron transport in mitochondria. Pestic Biochem Physiol 1976;6:65–82. 16. Chenoweth MB: Monofluoroacetic acid and related compounds. Pharm Rev 1949;1:383–424. 17. Chenoweth MB, Kandel A, Johnson LB, Bennett DR: Factors influencing fluoroacetate poisoning: Practice treatment with glycerol monoacetate. J Pharmacol Exp Ther 1951;102:31–49. 18. Chi CH, Chen KW, Chan SH, et al: Clinical presentation and prognostic factors in sodium monofluoroacetate intoxication. J Toxicol Clin Toxicol 1996;34:707–712. 19. Chi CH, Lin TK, Chen KW: Hemodynamic abnormalities in sodium monofluoroacetate intoxication. Hum Exp Toxicol 1999;18: 351–353. 20. Chugh SN, Aggarwal HK, Mahajan SK: Zinc phosphide intoxication symptoms: Analysis of 20 cases. Int J Clin Pharmacol Ther 1998;36: 406–407. 21. DeBacker W, Zachee P, Verpooten GA, Majelyne W: Thallium intoxication treated with combined hemoperfusion-hemodialysis. J Toxicol Clin Toxicol 1982;19:259–264. 22. Desenclos JC, Wilder MH, Coppenger GW, et al: Thallium poisoning: An outbreak in Florida, 1988. South Med J 1992;85:1203–1206. 23. Diaz-Rivera RS, Collazo PJ, Pons ER, et al: Acute phosphorus poisoning in man: A study of 56 cases. Medicine 1950;29:269–298. 24. Dorman DC, Cote LM, Buck WB: Effects of an extract of Gingko biloba on bromethalin-induced cerebral lipid peroxidation and edema in rats. Am J Vet Res 1992;53:138–142. 25. Dorman DC, Simon J, Harlin KA, Buck WB: Diagnosis of bromethalin toxicosis in the dog. J Vet Diagn Invest 1990;2:123–128. 26. Dorman DC, Zachary JF, Buck WB: Neuropathologic findings of bromethalin toxicosis in the cat. Vet Pathol 1992; 29:138–144. 27. Ecobichon DJ: Toxic effects of pesticides. In: Klaassen CD, ed. Casarett and Doulls’ Toxicology: The Basic Science of Poisons, 5th ed. New York, McGraw-Hill, 1996, pp. 681. 28. Edmunds M, Sheehan TMT, Van’t Hoff W: Strychnine poisoning: Clinical and toxicological observations on a non-fatal case. J Toxicol Clin Toxicol 1986;24:245–255. 29. Esposti MD, Myers MA: Inhibition of mitochondrial complex I may account for IDDM-induced by intoxication with the rodenticide Vacor. Diabetes 1996;45:1531–1534. 30. Favarel-Garrigues JC, Boget JC: Intoxications aigues parles raticides a’ base de chloralose et d’ANTU. Concours Med 1968; 90:2289– 2298. 31. Feingold KR, Lee TH, Chung MY, Sipehstein MD: Muscle capillary basement membrane width in patients with Vacor-induced diabetes mellitus. J Clin Invest 1986;78:102–107. 32. Gajdusek DC, Luther G: Fluoroacetate poisoning: A review and report of a case. Am J Dis Child 1950;79:310–320. 33. Hauser L, Sheehan P, Simpkins H: Pancreatic pathology in pentamidine-induced diabetes in acquired immunodeficiency syndrome patients. Hum Pathol 1991;22:926–929. 34. Hayes WJ: Pesticides Studied in Man. Baltimore, Williams & Wilkins, 1982. 35. Heath A, Ahlmen J, Branegard B, et al: Thallium poisoning: Toxin elimination and therapy in three cases. J Toxicol Clin Toxicol 1983; 20:451–463. 36. Herken H: Antimetabolic action of 6-amino-nicotinamide on the pentose phosphate pathway in the brain. In: Aldridge N, ed: Mechanism of Toxicity. London, St. Martin’s, 1970, p. 189.

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37. Heiser JM, Daya MR, Magnussen AR, Norton RL: Massive strychnine intoxication: Serial blood levels in a fatal case. J Toxicol Clin Toxicol 1992;30:269–283. 38. Howland MA, Weisman R, Sauter D, Goldfrank L: Nonavailability of poison antidotes. N Engl J Med 1986;314:927–928. 39. Jibani M, Hodges NH: Prolonged hypercalcemia after industrial exposure to vitamin D3. Br Med J 1985;290:748–749. 40. Kamerbeek HH, Rauws AG, Ham MT, et al: Dangerous redistribution of thallium by treatment with sodium diethyldithiocarbamate. Acta Med Scand 1971;189:149–154. 41. Karam JH, LeWitt PA, Young CH, et al: Insulinopenic diabetes after rodenticide (Vacor) ingestion: A unique model of acquired diabetes in man. Diabetes 1980;29:971–978. 41a. Katz J, Prescott K, Woolf AD: Strychnine poisoning from a Cambodian traditional remedy. Am J Emerg Med 1996;14:475–477. 42. Kenney RM, Michaels IAL, Flomenbaum NE, Yu GSM: Poisoning with N-3-pyridylmethyl-N′-p-nitrophenyl urea (Vacor). Arch Pathol Lab Med 1981;105:367–370. 43. Kosnett MJ, Becker CE: Dimercaptosuccinic acid: Utility in acute and chronic arsenic poisoning [abstract]. Vet Hum Toxicol 1988; 30:369. 44. Kuno M, Weakly JN: Quantal components of the inhibitory synaptic potential in spinal mononeurones of the cat. J Physiol (Lond) 1972; 224:287–303. 45. Layzer RB: Periodic paralysis and the sodium-potassium pump. Ann Neurol 1982;11:547–552. 46. LeWitt PA: The neurotoxicity of the rat poison Vacor: A clinical study of 12 cases. N Engl J Med 1980;302:73–77. 46a. Libenson MH, Yang JM: Weekly clinicopathological exercises: Case 12–2001: A 16-year-old boy with an altered mental status and muscle rigidity. N Eng J Med 2001;344:1232–1239. 47. Lisella FS, Long KR, Scott HG: Toxicology of rodenticides and their relation to human health. J Environ Health 1970;33:231–237. 48. Lisella FS, Long KR, Scott HG: Toxicology of rodenticides and their relation to human health. J Environ Health 1970;33:361–365. 49. Lovejoy FH: Thallium. Clin Toxicol Rev 1982;5:1–2. 50. Marin GA, Mantoya CA, Sierra JL, Senior JR: Evaluation of corticosteroid and exchange transfusion treatment of acute yellow phosphorous intoxication. N Engl J Med 1961;284:125–128. 51. Marsh R: Personal communication, June 29, 1993. 52. Marsh RE: Currrent (1987) and future rodenticides for commensal rodent control. Bull Soc Vector Ecol 1988;13:102–107. 53. Marsh R, Tunberg A: Characteristics of cholecalciferol: Rodent control—Other options. Pest Control Technol 1986;14:43–45. 54. Miller LV, Stokes JD, Silpipat C: Diabetes mellitus and autonomic dysfunction after Vacor rodenticide ingestion. Diabetes Care 1978;1: 73–76. 55. Mills K, Kunkel D: Prevention of severe barium carbonate toxicity with oral magnesium sulfate [abstract]. Vet Hum Toxicol 1993; 35:342. 56. Molner GD, Berge KG, Rosenveas JW, et al: The effect of nicotinic acid in diabetes mellitus. Metabolism 1974;13:181–189. 57. Moore D, House I, Dixon A, et al: Grand rounds, Guy’s Hospital— Thallium poisoning. Br Med J 1993;306:1527–1529. 58. Morgan DP: Recognition and Management of Pesticide Poisonings, 4th ed. Washington, DC, United States Environmental Protection Agency, 1989. 58a. Nelson LS, Perrone J, DeRoos F, et al. Aldicarb poisoning by an illicit rodenticide imported into the United States: Tres Pasitos. J Toxicol Clin Toxicol 2001;39:447–452. 59. Nogué S, Mas A, Parés A, et al: Acute thallium poisoning: An evaluation of different forms of treatment. J Toxicol 1982;19:1015–1021. 60. Oberpaur B, Donoso A, Claveria C, et al: Strychnine poisoning: An uncommon intoxication in children. Pediatr Emerg Care 1999;15: 264–265. 61. O’Callaghan WA, Joyce N, Counihan HE, et al: Unusual strychnine poisoning and its treatment: Report of 8 cases. Br Med J 1982; 285:478.

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62. Omara F, Sisodia CS: Evaluation of potential antidotes for sodium fluoroacetate in mice. Vet Hum Toxicol 1990;32:427–431. 62a. Palatnick W, Meatherall R, Sitar D, Tenenbein M: Toxicokinetics of acute strychnine poisoning. J Toxicol Clin Toxicol 1997;35:617–620. 63. PDR for Herbal Medicines, 2nd ed. Montvale, NJ, Medical Economics, 2000. 64. Pedersen RS, Olesen AS, Freund LG, et al: Thallium intoxication treated with long-term hemodialysis, forced diuresis and Prussian blue. Acta Med Scand 1978;204:429–432. 65. Pelfrene AF: Synthetic rodenticides. In: Hayes WJ, Laws ER, eds: Handbook of Pesticide Toxicology. San Diego, Academic Press, 1991, pp. 1271–1316. 65a. Perper JA: Fatal strychnine poisoning–a case report and review of the literature. J Forensic Sci 1985;30:1248–1255. 66. Peters RA: Lethal synthesis. Proc Roy Soc Lond 1952;13:139–143. 67. Phelan DM, Hagley SR, Guerin MD: Is hypokalaemia the cause of paralysis in barium poisoning? Br Med J 1984;289:882. 68. Pietras RJ, Stavrakos C, Gunnar RM, Tobin JR: Phosphorus poisoning stimulating acute myocardial infarction. Arch Intern Med 1968; 122:430–434. 69. Plunkett LM: Do current FIFRA testing guidelines protect infants and children? Lead as a case study. Federal Insecticide, Fungicide, and Rodenticide Act. Regul Toxicol Pharmacol 1999;29:80–87. 70. Pont A, Rubino JM, Bishop D, Peal R: Diabetes mellitus and neuropathy following Vacor ingestion in man. Arch Intern Med 1979;139: 185–187. 71. Product Information Sheet. Quintox. Madison, WI, Bell Laboratories, 1985. 72. Prosser PR, Karm JH: Diabetes mellitus following rodenticide ingestion in man. JAMA 1978;239:1148–1150. 73. Reigart JR, Brueggeman JL, Keil JE: Sodium fluoroacetate poisoning. Am J Dis Child 1975;129:1224–1226. 74. Reigart JR, Roberts JR: Recognition and Management of Pesticide Poisonings, 5th ed. Washington, DC, United States Environmental Protection Agency, 1999. 75. Richter CP: The development and use of alpha-naphthyl-thiourea (ANTU) as a rat poison. JAMA 1945;129:927–931. 76. Roza O, Berman LB: The pathophysiology of barium, hypokalemia and cardiovascular effects. J Pharmacol Exp Ther 1971;177:433–439. 77. Rubitsky HJ, Myerson RM: Acute phosphorus poisoning. Arch Intern Med 1949;83:164–178.

78. Sabouraud AE, Ortizberea M, Cano N, et al: Specific anti-digoxin Fab fragments: An available antidote for proscillaridin and scilliroside poisoning. Hum Exp Toxicol 1990;9:191–193. 79. Seon YD, Lee TH, Lee MC: Changes of glomerular basement membrane components in Vacor-induced diabetic nephropathy. Korean J Intern Med 1999;14:77–84. 80. Sgaragli GP, Mannaioni PF: Pharmacokinetic observations on a case of massive strychnine poisoning. Clin Toxicol 1973;6:533–540. 81. Shum S, Whitshead J, Vaughan L, et al: Chelation of organoarsonate with dimercapton succinic acid. Vet Hum Toxicol 1995;37:239–242. 82. Sigue G, Gamble L, Pelitere M, et al: From profound hypokalemia to life-threatening hyperkalemia. A case of barium sulfide poisoning. Arch Intern Med 2000;160:548–551. 83. Silinsky EM: On the role of barium in supporting the asynchronous release of acetylcholine quanta by motor nerve impulses. J Physiol 1978;274:157–171. 84. Simon FA, Pickering LK: Acute yellow phosphorus poisoning. JAMA 1976;235:1343–1366. 85. Singh M, Vijayaraghavan R, Pant SC, et al: Acute inhalation toxicity study of 2-fluoroacetamide in rats. Biomed Environ Sci 2000;13: 90–96. 86. Smith BA: Strychnine poisoning. J Emerg Med 1990;8:321–325. 87. Taitelman U, Roy A, Hoffer E: Fluoroacetamide poisoning in man: The role of ionized calcium. Arch Toxicol Suppl 1983;6:228–231. 88. Talley RC, Linhart JW, Trevino AJ, Moore L: Acute elemental phosphorous poisoning in man: Cardiovascular toxicity. Am Heart J 1972; 84:139–140. 89. Teitelbaum DT, Ott JE: Acute strychnine intoxication. Clin Toxicol 1970;2:267–273. 90. Tuncok Y, Kozan O, Caudar C, et al: Urginea maritima (squill) toxicity. J Toxicol Clin Toxicol 1995;33:83–86. 91. Van Lier RBL, Ottosen D: Studies on the mechanism of toxicity of bromethalin, a new rodenticide. Theoret Toxicol 1981;1:114. 92. Velsicol Chemical Corp: Vengeance Rodenticide Technical Manual. St. Louis City, Michigan 1986, p. 19. 93. Weiss S, Hatcher RA: Studies on strychnine. J Pharm Exper Therap 1922;14:419–482. 94. Wetherill SF, Guarino MJ, Cox RW: Acute renal failure associated with barium chloride poisoning. Ann Intern Med 1981;95:187–188.

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HERBICIDES Rebecca L. Tominack / Susan M. Pond

A 22-year-old 60-kg male was brought to the Emergency Department (ED) at 2 AM, about 1 hour after deliberately swallowing about 200 mL of an unknown herbicide. He was drinking heavily and had not eaten for about 12 hours. He vomited several times soon after the ingestion and was found by relatives, who brought him to the hospital. In the ED, he was cooperative but restless and agitated. He complained of burning in the mouth, throat, and stomach and shortness of breath. He kept repeating “I want to die.” His pulse was 105 beats/min, blood pressure 170/70 mm Hg, respiratory rate 24 breaths/min, and temperature, 97.3°F (36.3°C). Physical examination was normal except for superficial buccal ulcerations, pharyngeal erythema, and epigastric and abdominal tenderness. An intravenous line was inserted. Gastrointestinal decontamination was initiated with 100 g of activated charcoal mixed into a slurry with 100 mL of 70% sorbitol by mouth. The patient vomited most of the dose and became increasingly agitated and uncooperative. To proceed further with therapy, the patient was paralyzed, intubated, and ventilated with room air. Another dose of charcoal/ sorbitol was administered via a nasogastric tube. He was transferred to the Intensive Care Unit (ICU). The admission chest radiograph was normal, and the electrocardiogram (ECG) showed sinus tachycardia. The complete blood count revealed a moderate leukocytosis, serum electrolytes were normal except for a potassium level of 3.4 mEq/L, liver enzymes were abnormal with a slight increase in alanine aminotransferase and an increased lactate dehydrogenase. An arterial blood gas on room air showed pH 7.43, PCO2 29 mm Hg, PO2 98 mm Hg, and bicarbonate 21.5 mEq/L. At 10 AM an upper gastrointestinal (GI) endoscopy was performed. The pharynx was edematous and inflamed. There were erythema and superficial ulcerations, some oozing blood, in the esophagus and stomach. The treatment plan was aggressive supportive care. By 5 PM, his blood pressure had fallen precipitously to 80/50 mm Hg but responded to a bolus of intravenous 0.9% NaCl and vasopressors. However, arterial oxygenation deteriorated at this time, requiring increasing inspired oxygen tensions to maintain an acceptable PO2 level above 60 mm Hg. Crackles were heard at the lung bases, and acute lung injury was diagnosed. Positive endexpiratory pressure was added to the ventilator settings. His blood

pressure fell again to 70/30 mm Hg and urine output declined to less than 5 mL/h. A Swan-Ganz catheter was inserted to manage his fluid status,which revealed a low cardiac output despite a normal intravascular volume. The peripheral vascular resistance also decreased over the ensuing hours. The patient died at 9 PM from cardiogenic shock, 19 hours after admission.

INTRODUCTION Definitions and Regulations

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Herbicides are chemical agents intended to kill unwanted vegetation or regulate some aspect of the growth cycle of plants. In the United States, the Environmental Protection Agency (EPA) regulates all pesticide products, including herbicides, which are sold or distributed in commerce under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). Table 91–1 demonstrates the EPA toxicity classification. Registration is based on scientific studies that demonstrate that these agents can be used without posing unreasonable risks to people or the environment. Aspects of regulation cover all facets of pesticide development and use, including approval to use on a crop-by-crop basis, usage rates, labeling, protective measures for workers, and whether actual application is restricted to those who are specially certified by training in proper handling techniques (“restricted-use pesticides”). In addition, the EPA establishes tolerances (maximum levels) of pesticide residues in raw agricultural commodities and in food or feed products under the Federal Food, Drug, and Cosmetic Act. Under the Food Quality Protection Act of 1996, when establishing tolerances the EPA must consider the higher vulnerability of children to pesticide residues, aggregate exposures of the public to residues from all sources, and sum the effects of agents with a common mechanism of toxicity. Other Federal Agencies (Food and Drug Administration, US Department of Agriculture) and individual states cooperate with the EPA in various aspects of regulation of pesticides. Most of the developed world operates equally stringent pesticide approval and registration systems. Because of this intense, ongoing regulatory oversight, pesticide chemicals are among the best-studied chemicals in modern society.

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TABLE 91–1. Category and Signal Word I Danger Poison II Warning III Caution IV None

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

EPA Toxicity Classifications Oral LD50 (mg/kg)

Dermal LD50 (mg/kg)

Inhalation LC50 (mg/L)

0–50

0–200

0–0.05

50–500

200–2000

0.05–0.5

500–5000

2000–20,000

0.5–5.0

>5000

>20,000

>5.0

Eye Irritation

Skin Irritation

Corrosive: corneal opacity not reversible within 21 days

Corrosive

Corneal opacity reversible within 8–21 days; irritation persisting for 7 days Corneal opacity; irritation reversible within 7 days

Severe irritation at 72 hours Moderate irritation at 72 hours Mild or slight irritation at 72 hours

Irritation cleared within 24 hours

History, Chemistry, and Epidemiology Before the increase in knowledge of organic chemistry in the late 1800s, farmers had few options for weed control. Often there was no attempt to control weeds at all; crop seeds were scattered in a field, nature took its course, and separation of mature weeds from crop was done at the harvest. Smothering weeds before planting by turning the soil with a plough was a standard agricultural practice that only recently is being replaced with an alternative “notill” practice. In the early 1700s farmers began sowing seed in rows to facilitate mechanical weed removal after the crop emerged. However, pulling weeds by hand or chopping them with a hoe are prohibitively labor-intensive solutions, particularly for field crops. The first serious attempts to find chemical agents for weed control originated in the success of Bordeaux mixture (copper sulfate and lime) and Paris Green (copper acetoarsenite) in controlling fungal diseases affecting the French vineyards. Heavy metal salts such as iron sulfate, copper nitrate, and arsenates and various inorganic chemicals such as borates and chlorates were investigated and found marginally acceptable, primarily to control broadleaf weeds among cereal grain crops on small, intensively cultivated farms. Thus, before the second World War, only a limited number of chemicals were available as herbicides, and these were of relatively low potency, relatively high toxicity to nontarget species, and undesirably persistent in the environment. In the 1940s the first herbicidal chemical based specifically on plant physiology was discovered, 2,4-dichlorophenoxyacetic acid (2,4-D). This agent interferes with growth-regulating compounds called auxins produced by the plant. It was a great success because of its efficiency against broadleaf weeds in crops, low cost, higher potency, lower toxicity, and lack of persistent residues. Since this success in the 1940s there has been a steady introduction of active herbicide ingredients into the marketplace. At present, there are approximately 180 chemical agents registered for use as herbicides in the United States, 55 introduced in the 1990s alone. Typical classification schemes organize herbicides by mechanism of action on the plant and subcategorize by general chemical structure. Agents within the same chemical group usually share qualitatively similar toxicologic profiles. Most contemporary herbicides are organic chemicals, and some of a herbicide’s behavior in plants, animals, and the environment can be predicted from its organic chemistry. Aliphatic chain structures with polar, nonhalogen substitutions (N, O, P, S) tend to be readily degraded in the environment by microbiota. Aromatic structures, particularly if halogenated, tend to be more difficult to

degrade and might persist in the environment. Although some degree of herbicide persistence may be desirable for crops with a long growing season, persistence from one growing season to another or any bioaccumulation is generally undesirable. Many herbicide structures include an organic acid or other polar groups that can participate in salt formations. The parent acids are often not sufficiently water soluble for water-based application. Organic salts, often amine, ammonium, sodium, or potassium ionize in water and are more often encountered commercially. Salts are also relatively nonvolatile, which prevents loss to the atmosphere and adds an increased margin of safety against inhalation exposure by the applicator. The worldwide use of herbicide active ingredients is estimated to have been 2.25 billion pounds in 1997. Thus, herbicides account for approximately 40% of the worldwide total pesticide use of 5.68 billion pounds. The United States market accounted for 25% of world herbicide use (568 million pounds). The largest sector of US use is agriculture, accounting for 83% of total herbicide poundage applied. The highest-use agricultural herbicides in pounds for 1997 were atrazine, 78 million pounds; metolachlor, 66 million; glyphosate, 36 million; acetochlor, 33 million; and 2,4-D, 31 million pounds. In the home and garden market, much smaller by poundage but significant for potential human exposures, the top-use herbicides were 2,4-D, 8 million pounds; glyphosate, 6 million; dicamba, 4 million; mecoprop, 4 million; and trifluralin, 2 million pounds.2

FORMULATIONS AND ADJUVANTS Herbicide formulations generally require multiple ingredients to allow mixing, dilution, application, and stability of the herbicidal chemical. Formulation ingredients are generally not individually disclosed on the label, material safety data sheet (MSDS), or other product information. In the United States, they are lumped under the FIFRA designation “inert ingredients” or “other ingredients.” Although often significantly less toxic than active ingredients, they can be present in quantities that pose some risk of adverse health effect. Surfactants, organic solvents, and preservatives should be considered in any exposure, whether a large volume intentional ingestion of product concentrate or a topical exposure to products diluted with water for use. In addition, tank mix additives are adjuvant ingredients sold separately for addition to a commercial herbicide formulation by the applicator at the time of dilution

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and use. Particularly in occupational exposures, it is important to inquire about tank mix additives in order to assess the entire spectrum of potential toxic or irritant action. A variety of formulation types are marketed, including emulsifiable or water-soluble solution concentrates, suspension or microencapsulated concentrates, gels, wettable powders, waterdispersible granules, dusts, pellets, and other novel formulations. Most are concentrated liquids or solids that produce solutions, suspensions, or emulsions of the active ingredient when diluted with water for spray. These concentrates carry high proportions of active ingredients (25–65%) and adjuvants compared to the concentrations in the intended use dilution. The toxic and irritant properties of the water dilution are usually more benign than those of the original concentrate. Prediluted products (“ready to use”) are purchased at the proper use concentration and invariably contain some type of preservative to prevent mold or bacterial growth. Thus, they may carry some risk of allergic contact dermatitis. Wettable powders and water-dispersible granules form water based suspensions for spray application. Dusts and granules are broadcast by application directly out of the bag by hand or by mechanized distribution. They characteristically contain relatively low concentrations of the active ingredient (2–25%) because they are not further diluted before use. However, they are dusty,which increases exposure risk to the worker.

Solvents Aqueous solution concentrates and gels use water as the primary solvent and occasionally alcohols or glycols as cosolvents. Lipidsoluble active ingredients to be delivered in liquid formulations such as emulsifiable concentrates generally require an organic solvent system comprised of a primary solvent and one or more cosolvents. Organic solvents may impart flammability risk as well as their own vapor and ingestion toxicity risk to a formulation. Common solvent classes include vegetable oils, various aromatic and aliphatic hydrocarbons, esters, alcohols, ketones, methyl esters of C8–18 fatty acids, and solvents with low vapor pressure such as cyclohexanone, isophorone, alkyl pyrrolidones, and alkyl biphenyls.

Surfactants and Emulsifiers Herbicides intended for land-based plants (not natural waterways) usually contain surface-active agents or require surfactant tank mix additives. The health professional must assume the presence of significant surfactant in any herbicide concentrate until proven otherwise. Surface-active agents are critical to the formation and stability of the diluted spray and to enhance the biologic activity of the herbicide by aiding the spread of the spray droplets onto the leaf surface to maximize the area of contact. Because tropical vegetation is often protected by a very thick waxy cuticle, the surfactant content of herbicides used in tropical areas may be markedly increased compared to those used in temperate climates. Nonionic surfactants are the most commonly used class, followed by anionic agents; cationic surfactants are hardly used at all. Many nonionic surfactants can be easily recognized by their ethoxylated structure. Anionic surfactants can be easily recognized by a sulfate, sulfonate, or phosphate moiety as well as a cation for salt formation. Surfactants can be irritating on skin and eye exposure and cause irritant contact dermatitis with prolonged or repeated exposures. Ethoxylated nonionic surfactants rapidly oxidize on storage and with exposure to air or to hydroperoxides,

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peroxides, and a variety of aldehydes, including formaldehyde, to levels that are capable of inducing or inciting allergic contact dermatitis.46 Surfactants are considered to contribute significantly to the overall clinical picture of large volume ingestions of an herbicide concentrate as occurs in suicidal gestures. Systemic surfactant effects include pharyngeal, esophageal, and gastrointestinal irritation and ulceration, hypotension, hypoxemia, and acute lung injury.

Preservatives and Others Preservatives to deter mold, fungal, and bacterial growth in the formulation include isothiazolones, parabens, propionic acid, sodium sulfite, sorbic acid, and carbamates, some of which are contact sensitizers. The manufacturer may reduce the concentration of a sensitizing preservative below the guinea pig sensitization threshold. However, because many of the agents are in widespread use across a number of product classes, it is possible for the patient to be sensitized from another source and then react to the low levels in any particular herbicide product. Other adjuvants provide a variety of functions on an as-needed basis in a particular formulation. Such functional additions include structured polymers, dispersants, binders, wetting agents, disintegrants, fillers and carriers, acid scavengers, hydrotropes, milling aids, densifiers, crystal promoters, effervescents, bittering agents, dyes and dye stabilizers, pH adjusters and buffers, seed preservatives, nitrogen fertilizers, and antifreeze agents.

REGULATORY STATUS OF FORMULATION ADJUVANTS IN THE UNITED STATES Over a decade ago the EPA initiated a graduated Inerts Regulatory Strategy. This is a major effort aimed to reduce the potential for adverse effects to public health and the environment from pesticides containing potentially toxic inert ingredients. It requires data showing the safety of the material in the amounts and patterns of expected use. Inert ingredients present in pesticide formulations under registration at the time were placed in one of four lists: List 1, Inerts of Toxicologic Concern; List 2, Potentially Toxic Inerts with High Priority for Testing; List 3, Inerts of Unknown Toxicity; and List 4, Minimal-Risk Inerts. Once a material is on List 4, it can be used without additional regulatory burden. Data on the materials on Lists 1, 2, and 3 are being systematically reviewed to either reclassify the material to List 4 or to cancel its use as an inert in pesticides. Once an ingredient is canceled from List 1 or 2, it will likely never be approved for use in the future. New additions to List 4 desired by a manufacturer will eventually require submission and review of a data package. The long-term goal is to have only List 4 inerts in registered pesticides. List 1 inerts (Toxicologic Concern) were so designated for known carcinogenicity, reproductive or developmental toxicity, neurologic or other chronic effects, ecologic effects, or bioaccumulation. Most were voluntarily withdrawn by manufacturers, and those desired for continued use must have data provided that support the safety of their use. List 2 inerts (Potentially Toxic, High Priority for Testing) have similar structures to chemicals on List 1. Supporting safety data will be also required to move these items to List 4b.

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List 3 inerts (Unknown Toxicity) were so designated because of lack of data to classify them on other lists. Their ultimate disposition is reclassification or, of course, attrition or withdrawal. List 4 inerts (Minimal Risk) were subdivided into List 4a, GRAS (generally recognized as safe), such as cookie crumbs and corn cobs, and 4b, sufficient data to substantiate that current patterns of use in pesticide products will not adversely affect public health and the environment. List 4b contains chemicals such as isopropyl alcohol, petrolatum, and the majority of surfactants used. Current categorized lists of the inerts by Chemical Abstracts Service (CAS) number as well as changes over time in the lists can be accessed on the EPA’s web page (www.epa.gov/opprd001/inrts/ lists.html).

HERBICIDE FORMULATION INFORMATION RESOURCES In the United States, the label will usually identify only the active ingredient, often by its full chemical name rather than a common name. The MSDS usually repeats the ingredient information found on the label. However, any material on the SARA 313 Hazardous Materials List must be identified in the MSDS if it is present at >1% in the formulation or at >0.1% for a carcinogen. Check the hazard identification section of the MSDS for this. A call to the manufacturer is unlikely to yield a full accounting of the formulation. The persons attempting to answer the inquiry may not themselves have access to the Confidential Statement of Formulation (CSF) that represents the recipe and variations approved by the EPA. A state law in Iowa requires that the manufacturer, within 15 minutes of the call, reveal to a health professional or poison center the exact composition of the pesticide formulation in the event of a human exposure. If the exposure occurs in an occupational setting, the OSHA Hazard Communication Standard, CFR 1910. 1200 (i), requires the manufacturer to reveal the exact identify of all chemicals in the product that may pose a health hazard for the purposes of emergency patient assessment and care. This includes any material claimed to be a trade secret, and it must be revealed immediately on request. However, the manufacturer may require the health care professional to keep the trade secrets as secret and may make that request in writing after the urgent situation has passed. For nonemergency inquiries regarding an occupational exposure to a material with trade secret chemicals, the request may have to be made in writing, following the guidelines issued in the standard. Some global hazard information may be gleaned from the socalled “signal word” (Danger, Caution, Warning) plus other hazard statements on a pesticide label. The EPA requires a signal word appropriate to the classification of the most severe toxic effect found in animal testing of skin irritancy, eye irritancy, or lethality (oral LD50, dermal LD50, or inhalation LC50). Keep in mind that the categories refer only to the concentrated product before dilution. A herbicide product that is Category I for eyes will not be corrosive once it is diluted for spray use. When assessing any exposure to a pesticide, a series of standard questions often yields useful information in assessing the hazard and risk to the particular patient as well as in forming the treatment options (see Table 91–2). In dermal or eye exposure, the primary concern will be local irritation. Allergic contact is possible if the formula contains a sen-

TABLE 91–2 Questions that Should Be Asked About Exposure to a Pesticide Product Name of product and manufacturer Type of formulation if known (such as emulsifiable concentate, wettable powder) Concentration of active ingredient Presence and concentration of significant inerts, especially surfactants, solvents, preservatives Dilution to which patient was exposed (may differ significantly from the product in the bottle) Amount ingested or other quantification of dermal or inhalation exposures Name and amount of any additives used at the time of mixing, if diluted Route(s) of exposure Circumstances of exposure, especially unintentional or suicidal Time since exposure Timing and extent of vomiting after ingestion Age and prior medical conditions of the patient Any first-aid measures taken by the patient before medical contact

sitizing active or adjuvant ingredient or an ethoxylated surfactant that has formed sensitizing aldehydes and other oxidation products. The results of the guinea pig sensitization test are not necessarily to be relied on in evaluating such a possibility. Because most herbicide active ingredients are water soluble, their penetration through the skin is usually minimal. In potential spray exposure, the droplet size generated by the equipment is a primary consideration in evaluating extent of airborne exposure. Spray equipment and nozzles used in agriculture are intended to deliver relatively large droplets, which fall quickly to minimize spray drift onto nontargeted plants. Generally more than 95% of droplets generated are larger than 100 µm and are not considered respirable particles, capable of being retained by the lung.32 Most particles over 10 µm are filtered out by impacting in the nasopharynx and large airways. However, during heavy, prolonged, or overhead spraying, sufficient numbers of large mist droplets can enter the nose and mouth and may result in symptoms such as bad taste and irritated nose and throat. These symptoms are usually self-limiting. Use of an inexpensive, easily obtainable dust/mist respirator will reduce this problem. Ingestion of most herbicides that have been diluted with water for use is unlikely to cause severe toxicity, even in relatively large quantity. Ingestion of concentrated formulations that carry high loads of active ingredient, solvent, surfactant, and other adjuvants may result in significant toxicity that may be life-threatening. Target organ damage inherent to the active ingredient as well as systemic surfactant effects must be anticipated.

PARAQUAT Paraquat is the classic example of a herbicide that is safe when used as directed but is capable of dramatic toxicity when misused. Because of its low cost, rapid action, and favorable environmental characteristics, it remains a widely used herbicide throughout the world. The combination of ready availability and high toxicity results in continued appearance of severe and fatal poisonings, many from suicidal intent. Once the free radical–initiated pulmonary fibrosis is under way, even heroic medical interventions fail to salvage the patient. Poor worker protection practices are also problematic in subacute and chronic toxicity.

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Characteristics Paraquat (1,1′-dimethyl-4,4′-bipyridylium dichloride, CAS 1910–42–5) was synthesized in 1882. As methyl viologen it has been used as a color indicator for oxidation-reduction reactions since 1932. This indicator use is based on its reduction to a blue radical by alkaline sodium dithionite,14 which is also the basis for a colorimetric urine screen for paraquat exposure. Paraquat’s herbicidal action was serendipitously recognized when a field observation in the 1950s recorded that a quaternary salt used as a surfactant for a test herbicide was itself herbicidal.13 Synthesis of more active compounds led to the rediscovery of both paraquat and diquat and their introduction to the market in the early 1960s.13 Paraquat is a nonselective contact herbicide, desiccant (harvest aid), defoliant, and plant growth regulator primarily used on field crops, fruit and nut crops, and nonagricultural areas such as airports, commercial buildings, and storage yards. Paraquat rapidly damages and kills plants through contact action by intercepting electrons moving through photosystem I, the photosynthesis pathway in plants that generates reducing equivalents. In the presence of light, it generates reactive oxygen radicals including hydrogen peroxide that disrupt cell membrane integrity. It is rapidly inactivated by adsorption to soil. Because only the contacted leaves are affected, regrowth can occur from the roots of perennials. Paraquat dichloride is marketed most commonly as an aqueous solution concentrate containing 200 g paraquat dichloride/L (20% w/v), sometimes in combination with diquat or other herbicides. In the United States, paraquat is registered as a Restricted Use Pesticide available in concentrations from 23 to 43.5% dichloride salt. Spray dilutions are typically in the range of 1 to 5 g/L (0.1 to 0.5% w/v). The aqueous concentrates also contain appropriate adjuvant agents as described above and sometimes deterrent adjuvants to prevent unintentional ingestion or reduce the amount swallowed and absorbed. If no blue dye is added, the concentrate is dark brown like cola, for which it can be mistaken, especially if decanted into a soft drink bottle.

Epidemiology Most cases of paraquat poisoning result from the deliberate ingestion of one of the liquid formulations containing 20 to 40% paraquat.73 Thousands of deaths have been reported since paraquat was first marketed in 1962, mostly in adults with intentional ingestions. Unintentional ingestions can occur, particularly when the product has been handled or stored incorrectly.30,73 Death has also been reported from homicidal use, massive dermal exposure, intravenous administration, and prolonged occupational spraying.20,30,48,73,100 Suicidal ingestion of paraquat has been a disproportionate problem in some countries including the United Kingdom, Western Samoa, Fiji, Sri Lanka, Malaysia, and Japan.73 Measures taken by the manufacturer and by regulatory agencies have curbed the incidence of unintentional ingestions and reduced the mortality rate.107 These have included thickened or gel formulations with reduced paraquat concentration, capping the maximum concentration allowed in commerce and for spray application, restrictions on open sale and availability, improved product labeling, education programs about correct use, marker blue dyes, pyridine stenchant additives to make the product smell bad and taste worse, and emetics. Comparing the 4-year periods immediately before and

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after the 1988 institution of the color change from brown to blue and addition of a stenchant and emetic to paraquat formulations in the United States, there was a nearly 50% decline in the proportion of all pesticide exposures represented by paraquat ingestion. This indicates that such measures indeed have an impact on unintentional exposures. However, they are unlikely to influence those truly intent on suicide.

Toxicokinetics Absorption. Splash or diluted spray mist exposure to skin, eyes, and upper airways leads to minimal systemic absorption despite the risk of local tissue damage. Repeated or continuous dermal contact, especially to a concentrated solution, may lead to some absorption into the bloodstream if the integrity of the stratum corneum is impaired.4,67,100 Following ingestion, systemic absorption of paraquat begins rapidly but is incomplete (20 mL of 20% concentrate in a 70-kg person) usually die within 1 to 5 days after ingestion from multiorgan failure, shock, or tissue destruction in the GI tract. Death from esophageal perforation and mediastinitis can occur within 2 to 3 days of the ingestion. If a history of paraquat ingestion is unsuspected, the diagnosis can be missed. Such patients have been treated for spurious illness such as diphtheria, as was the case in three patients who presented with prominent membranes on the tongue and pharynx.88

Diagnostic Testing Urine and plasma should be sent to the laboratory promptly for qualitative and, if available, quantitative determination of paraquat concentrations. If possible, specimens should be shipped in plastic containers because paraquat binds to glass. Treatment of the patient should continue until the results are available. Rapid, qualitative analysis in urine is performed by reducing paraquat to its blue monocation radical with sodium dithionite under alkaline conditions and comparing the result with appropriate positive and negative controls.11,14 A fresh alkaline sodium dithionite solution is made by adding 100 mg of sodium dithionite (nonoxidized) to 5 mL of 5 M NaOH. An aliquot sample (250 µL) of this solution is added to 1 mL urine. If paraquat is present in a

Clinical Features of Paraquat Poisoning By Organ System

Cardiovascular Hypovolemia, shock, dysrhythmias Central nervous Coma, convulsions, cerebral edema Dermatologic Corrosion of skin, nails, cornea, conjunctiva, and nasal mucosa Endocrine Adrenal insufficiency caused by adrenal necrosis as part of multiple organ failure Gastrointestinal Oropharyngeal ulceration and corrosion; nausea, vomiting, hematemesis, diarrhea, dysphagia, perforation of esophagus, pancreatitis, centrilobular hepatic necrosis, cholestasis

Genitourinary Oliguria or nonoliguric renal failure caused by acute tubular necrosis; proximal tubular dysfunction Hematopoietic Polymorphonuclear leukocytosis early, anemia late Respiratory Cough, aphonia, prominent pharyngeal membranes (pseudodiphtheria), mediastinitis, pneumothorax, hemoptysis, pulmonary edema, and hemorrhage, pulmonary fibrosis

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concentration of 2 µg/mL or greater, a concentration-dependent blue to black color is evident. Diquat is reduced similarly to form a yellow-green color. Plasma or urine paraquat concentrations can be measured quantitatively by a variety of techniques, the most common being radioimmunoassay, gas chromatography, spectroscopy, and highperformance liquid chromatography.11,26,84 It is usually relatively easy to identify a laboratory that can perform the spot test but more difficult to find one to do the quantitative measurements. Many manufacturers support a 24-hour emergency service that should provide this information for each country. The telephone number for the service can be found either on the product label or via a poison center or other emergency facility. In many countries and areas, quantitative assays are not available in a timely manner to assist with management of the patient. In this case, the management must be guided by the clinical and other laboratory findings. Clinical chemistry abnormalities reflect the development of acute renal tubular necrosis and necrosis of the liver, lung, pancreas, and muscle.87 Monitoring plasma creatine kinase is useful in diagnosing the delayed onset of type 1 skeletal muscle fiber damage.91 If paraquat concentrations in blood exceed about 10 mg/L, measured values of creatinine and LDH may be elevated artificially because of interference with the colorimetric methods used to measure them.24 Hematologic abnormalities, if any, are usually nonspecific and related to bleeding, infection, or stress. Methemoglobinemia with hemolysis has been reported65 but was thought to be caused by the monolinuron in the formulation, not the paraquat.75 Tissue destruction injury to the esophagus and mediastinum can be associated with pneumomediastinum and pneumothorax.20 The changes in the lung parenchyma are obvious on the chest radiograph, first as cystic and linear opacities and later as consolidation, particularly in the perihilar regions.42 A chest radiograph, taken on the ninth day after the ingestion of paraquat in a patient who died 3 days later, is shown in Fig. 91–2. It shows diffuse consolidation most marked in the perihilar regions.

Management Early treatment is a very important determinant of survival in paraquat-poisoned patients. Therefore, any patient who has been exposed to paraquat should be treated as a medical emergency, even if there are no symptoms or signs of toxicity at the time of presentation. This is particularly true when the patient has been exposed to one of the concentrated liquid formulations or there has been an ingestion either alone or as a component of a splash exposure with dermal or ocular contact. An accurate history should be taken as for any agrichemical ingestion. If there has been dermal exposure, either primarily or secondarily from contact with contaminated vomitus, the clothing should be removed immediately and the skin washed gently but thoroughly with soap and water. Harsh scrubbing should not be conducted because the resultant skin abrasion could actually increase the transdermal absorption of paraquat. If the eyes have been splashed, ocular irrigation with copious amounts of water should continue for 15 minutes. These patients should be seen by an ophthalmologist for further management. Gastric Emptying. If paraquat was ingested only minutes earlier, measures to remove it or prevent its absorption from the gastrointestinal tract should be instituted immediately. Spontaneous vomiting is a near certainty in significant ingestions of paraquat concentrate because of its irritant effects and the emetic added to many formulations. If it has not yet occurred, consideration should be given to inducing vomiting, assuming there are no contraindications. Alternatively, a slurry of activated charcoal, Fuller’s earth, bentonite, or garden clay can be considered in the field as a first aid measure, especially if there will be a substantial delay in reaching a medical facility. In most developed countries, resorting to nonpharmaceutical clay will not need to be seriously considered. Even if the patient has already vomited, further gastrointestinal decontamination should be considered. Once the patient has presented for medical care, induced emesis with syrup of ipecac should not be employed because of the time delay involved between its administration and subsequent emesis. This time is better spent by administering an oral adsorbent as quickly as possible.64 Adsorbents. Oral adsorbent options include 1 to 2 g/kg of activated charcoal, 1 to 2 g/kg of Fuller’s earth in a 15% (w/L) aqueous suspension, or 1 to 2 g/kg bentonite in a 7% (w/v) aqueous slurry. All three adsorbents bind and retain paraquat effectively, but activated charcoal is used most frequently because of its ready availability. In some countries, the manufacturer provides hospitals or local company representatives with kits containing Fuller’s earth and a cathartic. The adsorbent may be given with a cathartic such as a magnesium salt or 70% sorbitol (2 mL/kg). If the patient vomits the first dose of the adsorbent, another should be given, through a nasogastric tube if necessary. Rapid control of repeated vomiting with antiemetics and promotility agents is essential when the patient cannot retain the adsorbent.

Figure 91–2. Chest radiograph taken 9 days after the ingestion of 70 mL of 20% paraquat, demonstrating diffuse alveolar consolidation, most marked in the perihilar regions.

Lavage. Naso- or orogastric lavage may be relatively ineffective in reducing absorption. Spontaneous vomiting may have already emptied the stomach, leaving little for lavage to affect. Paraquat, in liquid formulation, empties into the small bowel relatively rapidly and may be substantially out of reach by the time lavage can be performed. During the time spent in lavage, paraquat ab-

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sorption is proceeding rapidly from the bowel. In cats, absorption of paraquat was reduced more by an oral adsorbent than by lavage.19 In addition, substantial mucosal damage in the esophagus and stomach caused by paraquat formulation places these structures at risk for perforation by the large-bore lavage tube.

Extracorporeal Removal. Methods to maintain or increase the rate of elimination of paraquat from the body should be considered. Forced diuresis and peritoneal dialysis are not effective.10 Hemodialysis can equal or exceed renal clearance of paraquat, particularly when renal function is impaired, but has not reduced mortality.34 Therefore, hemodialysis should be performed for the usual indications in patients with acute renal failure and considered only when hemoperfusion is not available.22 Hemoperfusion, across a cartridge containing activated charcoal, enhances elimination of paraquat from the blood. When hemoperfusion was performed once in dogs 2 to 12 hours after an LD50 or LD100 dose of paraquat, mortality was reduced significantly.33,105 On the other hand, there is no clinical evidence that hemoperfusion is efficacious in humans.34 Many factors may account for this. Most patents ingest many multiples of a potentially fatal dose; even if hemoperfusion removes an amount equivalent to several fatal doses, many fatal doses still remain in the body. Many patients present hours after ingestion; during this time the paraquat is actively removed from the blood and sequestered in the lung, where it is inaccessible to hemoperfusion. When renal function is normal, hemoperfusion contributes very little additional clearance, so it has proportionately less effect on survival. Likewise, most of the absorbed dose is eliminated by the kidneys during the first 12 hours after the ingestion; hemoperfusion after this time has little proportional effect on total clearance. Last, the slow redistribution phase from the muscles and lung to plasma limits the removal rate of paraquat.71 Because of these factors, we recommend that charcoal hemoperfusion be begun and continued for 6 to 8 hours only if it can be initiated within 4 hours of ingestion. Based on current clinical and experimental evidence, there is no indication for repeated hemoperfusion. Although continuous arteriovenous hemofiltration can reduce the marked rebound in plasma paraquat concentrations that occurs after hemoperfusion as a result of redistribution of paraquat from the tissues,70 no clinical benefit of this procedure has been demonstrated.

Fluids and Oxygen. Fluids and electrolytes should be administered IV in sufficient volume to replace GI tract losses and maintain high normal urine output and normal hemodynamics. Supportive and palliative care are most important components of the management of paraquat-poisoned patients. Attention should be paid to analgesia for the pain associated with the mucosal ulceration. Patients should be monitored frequently for the development and progression of renal and respiratory failure. Supplemental oxygen is a two-edged sword in that it accelerates paraquat-induced oxygen radical toxicity as it temporarily relieves the distress of hypoxia. Generally, supplemental oxygen is withheld until the arterial oxygen tension falls below 50 mm Hg and/or the patient expresses respiratory distress. Its potential contribution to the pathologic process and the ultimate decline of the patient should be acknowledged.

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Investigational Management Strategies None of the proposed “antidotes” for paraquat toxicity have demonstrable clinical efficacy.5,7 Failed treatments examined experimentally, and in some cases clinically, include those that could prevent the accumulation of paraquat by the lung (various polyamines, d-propranolol), increase efflux of paraquat from the lung (cyclophosphamide, d-propranolol), reduce or prevent the consequences of the redox cycling (reduction of FIO2, vitamin E, superoxide dismutase, ascorbic acid, deferoxamine, selenium, niacin, or N-acetylcysteine), or reduce the extent of pulmonary fibrosis (corticosteroids, immunosuppressive agents, fibrinolytic agents, colchicine, and radiotherapy). Some groups administer vitamin C (4000 mg/d) and vitamin E (250 mg/d) routinely;95 these have very few contraindications or side effects, even if efficacy is unproved. Few controlled trials of these approaches have been performed. In one study, when 33 patients given high doses of cyclophosphamide and dexamethasone were compared prospectively with 14 patients given standard therapy (gastrointestinal decontamination and fluids) there was no significant difference in the mortality in the two groups (63 and 61%, respectively).68 In another study, 16 patients comparable to 17 conventionally treated control patients in age, gender, urine dithionite results, and time since ingestion were given pulse therapy with cyclophosphamide and methylprednisolone. The pulsedtherapy group had a 25% mortality compared to the group treated conventionally (71%).57 Despite having theoretical benefit or demonstrated effectiveness in animal models,25,77 reduction of inspired oxygen concentration in paraquat-poisoned patients has not been demonstrated to be effective clinically. Low-dose inhaled nitric oxide reduces the intrapulmonary shunt in a paraquat-poisoned patient, and anecdotal survival cases exist in which the multifaceted treatment included nitric oxide inhalation. These findings are preliminary and do not justify use of nitric oxide; it may actually add to the toxicity by reacting with the superoxide anion forming the peroxynitrite anion and the hydroxyl radical.6,23,61 Paraquat-specific IgG antibodies and their paraquat Fab reduce the in vitro uptake and toxicity of paraquat in type II pneumocytes.18 However, in vivo use of intact antibodies or Fab fragments is complicated by their reduction of the renal clearance of paraquat because of the protein–paraquat complex formation and the protein load of antibody required to reduce or prevent toxicity. Assuming that a 70-kg patient ingested 30 mg paraquat ion/kg, the absorbed dose to be “neutralized” (5% absorption) would be 105 mg. Thus, a stoichiometric dose of paraquat Fab would be 28 g. If less than a stoichiometric dose can shift the patient’s position on the dose toxicity curve to the left, sufficiently far to prevent death, the dose would be less. It would be even less for a recombinant, single-chain antibody (sFv), which is half the molecular weight of Fab. The volume of a 14-g (0.2 g/kg) dose of a sFv corresponds to 200 mL of plasma. In addition, compared to intact IgG and Fab, the volume of distribution (Vd) and renal clearance of sFvs are larger.21 These kinetic properties would be advantageous for treatment of paraquat poisoning because of its large Vd and high renal clearance. It may be possible to deliver lower doses of anti-PQ sFv by inhalation, more or less topically to the target cells. Unfortunately, such therapy with sFvs has not been developed clinically to date because of the prohibitive costs of manufacturing sufficient amounts of such recombinant products even to test in animals.

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Any efficacy of such antibody therapy, however, will be limited by the practical issues such as the length of time before the patient presents to a medical facility. The “window of opportunity” for any effective treatment of paraquat poisoning is very short, only a few hours at most.

Lung Transplantation Lung transplantation has been performed in a few patients, but only one has survived.44,63,80,102 In that case, a single lung was transplanted 44 days after paraquat ingestion; recovery was complicated by subsequent removal of the other poisoned native lung, and severe myopathy prevented weaning from mechanical ventilation.102 Therefore, single or bilateral lung transplantation can be considered if a patient survives for 3 weeks or longer with endstage respiratory failure and otherwise meets criteria for transplantation. In this context of prolonged medically supported survival, other serious, long-term effects of paraquat are revealed. For example, patients given lung transplants who survived for several months after paraquat exposure have developed progressive toxic myopathy, which proved fatal in one case.80,102

Prognosis Not all patients who ingest paraquat die, but the mortality in some series of patients has been as high as 75%.7,83,100 Typically a patient who survives does not develop pulmonary injury and has no residual effects. There have been a few survivors reported with residual pulmonary fibrosis, and some have progressively improved over time.9,40 The outcome is dose-dependent. Patients who ingest paraquat intentionally usually take a higher dose than those who ingest it unintentionally and therefore have a worse prognosis. Similarly, the incidence of death is higher the more concentrated the formulation ingested. Plasma concentrations of paraquat measured within 28 hours after the ingestion are useful in estimating the prognosis according to the nomogram presented in Fig. 91–3.36,74 This nomogram was derived empirically from clinical data and not by statistical means. Thus, it is not infallible. Patients with higher concentrations than those expected from the nomogram to be associated with survival have survived; conversely, some with lower concentrations have died.74 When experience with the nomogram in 166 cases was reviewed, it correctly predicted the outcome in 93% of cases who died and in 64% who survived.74 Therefore, reports in the literature of unexpected survival in individual patients as determined on the nomogram should be attributed only with caution to one or another innovative treatment because of the imperfections of the predictive line. The extension of this nomogram beyond 28 hours83,84 has similar predictive efficacy. It appears that whenever the initial plasma concentration of paraquat exceeds 3 mg/L, mortality is 100%.34 The mode of death is cardiogenic shock within 24 hours of the ingestion in those whose paraquat levels exceed 10 µg/mL.74 Additionally, concentrations of paraquat in urine obtained within the first 24 hours of ingestion can be used to estimate prognosis.83,84 Of 53 patients studied, 15 who had urinary concentrations of paraquat below 1 µg/mL within the first 24 hours survived. Urinary concentrations in those who died within 24 hours ranged from approximately 10 to 10,000 µg/mL; concentrations in those who died later from pulmonary fibrosis were between 1 and 1000 µg/mL.

Figure 91–3. Nomogram showing the relationship among the plasma concentrations of paraquat on the ordinate (µg/mL), time after ingestion on the abscissa, and the probability of survival. (Reprinted, with permission, from Hart RB, Nevitt A, Whitehead A: A new statistical approach to the prognostic significance of plasma paraquat concentrations [Letter]. Lancet 1984;2:1222–1223.)

Several compilations of indices using physiologic and clinical data76,84,90 have been proposed and have predictive efficacy comparable to the nomogram of plasma paraquat level against time. The rate of increase in plasma creatinine over a 5-hour period has also been proposed as a predictor of outcome but has not yet been subsequently validated.76 One group prospectively studied routine lung scintigraphy changes in 13 paraquat-poisoned patients using 97 Tc-labeled diethylenetriamine pentaacetate aerosol inhalation compared to volunteer controls. The four patients showing normal alveolar permeability survived, and the nine with abnormal alveolar permeability died.45 Several factors can moderate the amount of paraquat absorbed and thus the plasma and urinary concentrations. When paraquat is swallowed on a full stomach, its absorption is reduced because of delayed gastric emptying and the adsorption of the herbicide by the food.8 The presence of ulceration in the upper gastrointestinal tract is a poor prognostic sign because it may reflect the concentration and the dose of paraquat in the formulation. In one series of patients who had upper GI endoscopy between 3 hours and 3 days after the ingestion, 9 of 14 patients with gastric and esophageal ulcerations died.8 Conversely, all six who had no gastric ulcerations survived. The development of renal failure heralds a poor prognosis. Of 20 patients in one series who developed renal failure, 19 died.8

DIQUAT Diquat (1,1′-ethylene-2,2′-dipyridylium dibromide)12 is used agriculturally for the same purposes as paraquat as well as for the control of aquatic weeds; it is combined with paraquat in several formulations. The LD50 of the two compounds in animals is of the same order of magnitude.89 In terms of caustic effects, kinetics, and mechanisms of toxicity, diquat is similar to paraquat89 with

CHAPTER 91

one important exception. Diquat lacks the structural features necessary for active transport by the polyamine uptake pathway into the lungs. Therefore, the extent of pulmonary injury and fibrosis in patients who take toxic doses of diquat is much less than that after paraquat. In comparison to paraquat, there have been relatively few cases of diquat poisoning. In a review of 11 cases the lethal adult human dose of diquat was 6 to 12 g.8 Effects from massive ingestion include severe gastrointestinal damage, airway compromise, respiratory failure, renal failure, seizures, and hemodynamic collapse. Most died despite treatment such as forced diuresis, hemoperfusion, and the administration of antioxidants.35,60,72,85,101,106 In one fatal case, the serum diquat level 4 hours after ingestion of 60 g of diquat cation was 64 µg/mL. The patient exhibited progressive anuria, coma, and seizures and died 26 hours after ingestion from cardiovascular collapse. Extracorporeal removal techniques yielded 1.09 g of diquat. Postmortem analysis revealed marked renal tubular damage.45 Another patient ingested 200 mL of diquat dibromide diluted to 1.84% and remained asymtomatic until 8 hours afterward. He subsequently developed esophagitis, epiglottitis, and acute renal failure, from which he slowly recovered.98 Intravaginal instillation of 20 mL of concentrated diquat formulation resulted in local corrosion, renal failure, diffuse slowing on EEG, and a 3-month spastic tetraparesis, from which she eventually recovered.78 Treatment of diquat-exposed patients proceeds along the same lines as for those exposed to paraquat regarding gastric decontamination, adsorbents, hemodialysis and perfusion, and supportive care. Diquat may introduce an artifact in the laboratory assay for serum creatinine.85

GLYPHOSATE

History and Epidemiology Glyphosate (N-phosphonomethyl glycine) was originally synthesized by a French chemist and logged into a chemical bank. In the late 1960s an American company acquired and screened this bank of compounds and discovered glyphosate’s remarkable herbicidal activity. After nearly 30 years of commercial availability, glyphosate is one of the most widely used and studied herbicides in the world. Growth in use has averaged approximately 20% per year. Use continues to increase largely because of its suitability for “no-till” soil preparation before planting of crops. This conservation measure preserves topsoil; over half of the world’s 650 million arable acres will use no-till planting by 2002. Glyphosate is also one of the nonselective herbicides for which genetically engineered resistant crops have been developed, and this may eventually become the largest driver to further increase in use. Glyphosate is registered for use in over 100 countries. The original glyphosate formulation concentrate (Roundup Herbicide,

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Monsanto) contained the isopropylamine salt of glyphosate (41% w/v), a polyethoxylated tallow amine surfactant (15.4% w/v), and water. Over 100 different brand names comprised of many formulations have been sold worldwide by this company. In addition, other companies may now market the glyphosate molecule, and it is estimated to appear in thousands of other herbicide products. Some products contain the original isopropylamine salt, but some contain the monoammonium, sodium sesqui-, or other salts of glyphosate. Some products are dry formulations; some contain different surfactant systems, or greater or lesser amounts of total surfactant, or no surfactant at all. Glyphosate may also be sold in combination with other herbicides including various chlorphenoxy compounds, simazine, linuron, and picloram or with a fertilizer to boost plant growth, thereby enhancing lethality. A related chemical is glyphosine [N,N-bis(phosphonomethyl) glycine], which is a plant growth regulator. It is a dimer of glyphosate.

Agronomic Mechanism and Toxicity Glyphosate is applied after the plant has emerged from the soil (“postemergent”) and is nonselective in its action, killing any green plant. It inhibits the enzyme 5-enolpyruval shikimic acid 3-phosphate (EPSP) synthetase, which is important in the biosynthesis of aromatic amino acids. The lethal effects in the plant can be reversed by supplying L-phenylalanine and L-tyrosine. There is no equivalent enzyme in animal systems; thus, this is the mechanism of its selective toxicity. In addition, it has a minor activity as a nonspecific metal chelator, an effect that does not appear important clinically. Glyphosate’s environmental profile is considered quite favorable. It displays a relative lack of volatility, lack of residual soil activity, lack of soil migration, rapid environmental biotic degradation to basic elements (t1/2 in soil = 60 days), and no bioaccumulation. Its mammalian safety profile is also quite favorable. It is noncarcinogenic (US EPA category E), nonmutagenic, and devoid of developmental toxicity. There is no serious chronic toxicity in 2-year animal feeding studies, and its acute oral toxicity is relatively low (rat oral LD50 = 5600 mg/kg). The formulated glyphosate is practically devoid of systemic toxicity from dermal exposure. The moderate skin irritation of the original Roundup formulation is caused by the polyethoxylated tallow amine surfactant, which is corrosive to skin in animal tests when applied without dilution. As the surfactant content is progressively reduced in the concentrated formulation or by dilution, the potential for irritation declines.

Toxicokinetics Absorption. Glyphosate kinetics and metabolic fate have been extensively characterized in animals, and human clinical data appear to follow the same general patterns. Rats orally dosed with 14 C-labeled glyphosate acid in water absorbed 20 to 30% and excreted the remainder in the feces. A 10-fold higher dose resulted in 30-fold higher blood concentrations, suggesting an enhanced absorption ratio at higher doses. Pretreatment of rats with surfactant and glyphosate in drinking water did not increase the subsequent absorption of the labeled glyphosate.16 Dermal absorption has been determined experimentally in an in vitro human skin model using 14C-labeled glyphosate in formulated herbicide. After 16 hours, not more than 2.3% of the applied dose was recovered in the plasma receptor fluid. In vivo dermal

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absorption studies in rhesus monkeys confirmed poor absorption; total urinary recovery of labeled glyphosate was only 0.4% of applied dose in 24 hours and 2% in 7 days. Water or soap and water washing removed the applied glyphosate; 50% was still recoverable by washing at 24 hours.104 Several worker-biomonitoring studies verify poor dermal absorption by failing to find detectable levels of glyphosate in the urine.43,55 Elimination. Glyphosate is not metabolized in mammalian systems; a minor metabolite, aminomethyl phosphonic acid, may be detected in amounts 200 mL) and those developing acute lung injury or cardiogenic shock are at more risk of a fatal outcome. In a series of 50 patients evaluated with upper endoscopy, esophageal injury was noted in 68%, gastric injury in 72%, and duodenal injury in 16%. Severity of esophageal injury (Zagar grade 2 or 3) was correlated with length of hospital stay and complication rate.17 In a series of 53 patients evaluated by laryngoscopy, 36 (68%) showed significant laryngeal injury, which was correlated with longer length of hospital stay and risk of aspiration pneumonitis.41 Oral and gastrointestinal irritation (burning of mouth and throat, vomiting, abdominal pain) develop rapidly after ingestion. Hypotension may develop within hours of very large ingestions. Some patients may appear to be relatively stable for the first 8 to 12 hours and then develop hypotension and respiratory distress. It is difficult to correlate ingested amount with severity of clinical effect because of the unmeasured loss through vomiting. However, in general, severity follows a dose-related trend. In one large series, there were 11 fatalities among 41 cases (27%) who ingested an estimated 150 mL or more of concentrated formulation (41% isopropylamine glyphosate, 15% ethoxylated tallow amine surfactant) but none among 51 who ingested 24 per minute Pulse >70% of the maximum heart rate for age; eg, age 20; 140 beats/min; age 50; 120 beats/min Blood pressure Diastolic >105 mm Hg Temperature 99.5°F (37.5°C) Skin Dermatitis Recent medical history Nausea, vomiting, diarrhea, fever, upper respiratory infection, heat illness, or substantial alcohol intake within past 72 hours; new prescription medications taken within past 2 weeks or nonprescription medications taken within past 72 hours; any alcohol within past 6 hours; pregnancy Modified with permission from the Advanced Hazmat Life Support Provider Manual 2nd ed. Tucson, AZ, Arizona Board of Regents, 2000.

■

■ ■ ■ ■

tact dispatch to send a hazmat response team to the ED while the patient waits outside the ED in an area of limited patient traffic. Notify hospital security to provide ED security and deny entry of contaminated patients unless the attending emergency physician makes a conscious decision to allow entry after considering the risks and benefits. Notify the chemical spill coordinator, the ED director, and the clinical supervisor, who will notify the on-call administrator. Review current ED status and staffing and assign personnel to care for all ED patients. Provide liaison to hospital security, the administrator on call, and the chemical spill coordinator. Notify public affairs.

Additional recommendations for the care of contaminated hazmat patients in emergency departments are excerpted from the Annals of Emergency Medicine and used here with permission:16 No medical consensus exists for the minimum level of personal protection required for hospital decontamination. This is especially true regarding respiratory protection, which is only necessary when toxic vapors are at concentrations high enough to cause potentially harmful effects to staff. After clothing removal, a contaminated patient poses minimal inhalation risk when decontamination is performed outside the ED. However, if a patient is placed in a poorly ventilated treatment room (enclosed space), personnel without respiratory protection could have symptoms from inhalation of off-gassing vapors from clothing, skin, or vomitus. Selecting the appropriate protective equipment depends on the specific hazardous substance identified. Surgical masks never provide adequate protection from toxic vapors.16 Legal requirements do apply to hospital-based decontamination. All EDs incorporated in an emergency response plan for hazardous materials incidents through Local Emergency Planning Committees, an agreement with a facility or hazardous waste site, or other means, must meet OSHA requirements [29 CFR 1910.120(q)] for both training and response to hazardous materials, because it is likely they will be faced with chemically exposed patients without previous decontamination at some time. Under these regulations, emergency medical personnel who would decontaminate victims exposed to a hazardous substance should be trained

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at a minimum to the first-responder operations level. . . For response to an unknown hazard, OSHA regulations require level B protection, which includes a positive-pressure selfcontained breathing apparatus and splash-protective chemical resistant clothing. However, these regulations should not be interpreted to require the use of this equipment for treatment of contaminated patients in all hospitals. Use of self-contained breathing apparatus can itself pose significant problems to ED staff. These hazards include increased weight, improper use of the equipment, problems with donning and doffing, and decreased dexterity. Other options include having the patients decontaminate themselves if they are capable, designating a local fire department hazardous materials teams to assist in or perform the decontamination, or proceeding with decontamination with less than level B protection if assistance is not available within a suitable time interval based on the patient’s condition. Hospitals frequently receiving contaminated casualties or in high-risk areas may need to consider additional training and equipment, such as specialized chemical-resistant clothing and respirators.16

Medical Management of Hazmat Victims Decontamination. Decontamination has two important functions: altering absorption for the patient and preventing secondary contamination of others. Primary goals at any hazmat incident are protecting emergency responders, preventing secondary contamination, and decreasing morbidity and mortality of hazmat victims.6,12,16,18,28,38,45–47,70,77 Exposure solely to gases, such as simple asphyxiants, generally requires no skin or mucous membrane decontamination to prevent secondary contamination of others. However, exposure to highly water-soluble irritant gases, such as ammonia, can cause skin and mucous membrane irritation and chemical burns that are treated with copious water irrigation. This effort of decontamination treats the patient rather than prevents secondary contamination of healthcare providers. When indicated by the presence of adherent solids or liquids on a patient, skin decontamination should be performed in the field, in the decontamination zone. This is a two-step procedure. First remove all clothing, jewelry, and shoes. Bag and tag these possessions. The patient’s possessions should be left at the scene, stored, and may need to be disposed of as hazardous waste. Any adherent solid particles should be brushed away from the patient. Gently blot away any obvious adherent liquid. Step two is meticulous washing with large quantities of water. Also use a mild liquid detergent if the adherent solids or liquids are not water-soluble or if the identity of the material is unknown. Most decontamination solutions are made for equipment, not people. Do not use these potentially irritating solutions on people. Pay close attention to all exposed skin and in particular the skin folds, the axillae, the genital area, and the feet. Use luke-warm water with gentle water pressure to reduce the risk of hypothermia. Apply water systematically from head to toe, protecting the patient’s airway. Exposed, symptomatic eyes should be continuously irrigated with water throughout the patient contact, including transport, if possible. Remember to check for and remove contact lenses. Use of Morgan therapeutic lenses is the most efficient method to decontaminate a patient’s eyes, but this requires using an ocular topical anesthetic such as proparacaine.

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Primary Survey and Resuscitation: The Basics. In general, the primary patient assessment and resuscitation are performed only after any necessary skin decontamination in the warm zone. The only two procedures that are commonly performed before any necessary skin decontamination are opening the patient’s airway and spine precautions. Common sense dictates that if liquid or solid contamination involves only the patient’s eyes or a small body part, such as a hand, then supportive care may be performed while decontamination is in progress. This procedure will also depend on the toxicity of the hazardous material. The primary survey and resuscitation is described by the mnemonic A, B, C, D, E: Airway with cervical spine control, if necessary, Breathing; Circulation, Disability (nervous system), Exposure with environmental control. Hazmat Patient Assessment. Hazmat patient assessment includes a history and physical examination. History is guided by the AMPLE mnemonic: Allergies, Medications, Past medical history, Last normal menstrual period, Last tetanus shot, Last meal, and Events. Determine the events that led up to the hazmat incident. Who was involved in the hazmat incident? Are there other patients who need to be searched for and rescued? What is the exact identity of the hazardous material? Is there more than one hazardous material? What was the route of exposure? Where did the hazmat incident occur? Was there a confined–space exposure? When did the hazmat incident occur? How long was the exposure? How and why did the hazmat incident occur? Was there an explosion? Was there a fire? Is this hazmat incident an act of terrorism? Secondary Survey. After the primary survey and resuscitation, hazmat patient assessment involves a secondary survey. This hazmat secondary survey focuses on identifying poisoning complications, recognizing preexistent problems that have the potential for exacerbation, assessing for accompanying trauma or burns, and recognizing toxic syndromes (toxidromes). There are five fundamental hazmat toxidromes or hazidromes: the irritant gas toxidrome, the asphyxiant toxidrome, the cholinergic toxidrome, the corrosive toxidrome, and the hydrocarbon and halogenated hydrocarbon toxidrome (Table 93–6). The hazmat patient assessment secondary survey also includes determining whether the patient has complications from poisoning. These complications can involve derangements of the Airway, Breathing, Cardiovascular system, Disability (the nervous system), or the organs of Elimination (the liver and kidneys). For example, the respiratory system (Airway and Breathing) can react in only a limited number of ways to various insults. The upper airway can become obstructed from edema caused by thermal or chemical burns. Ventilatory insufficiency can be caused by loss of central nervous system respiratory drive or by neuromuscular blockade with muscular weakness or paralysis caused by an organic phosphorus compound or carbamate poisoning. Aspiration pneumonitis can be caused by emesis with an unprotected airway. Acute lung injury (ALI) can be caused by direct damage to the alveolar-capillary membrane because of the local toxic effects of poorly water-soluble irritant gases such as phosgene and nitrogen dioxide, or ALI can be caused by other insults such as prolonged hypoxia or hypoperfusion. Patient assessment emphasizes that we must treat the patient, not the poison. Knowing what the patient was exposed to does not

necessarily mean that the patient was poisoned. Although knowledge about the poison is important, knowledge about the patient’s condition, derived from the primary survey and continual reassessments, is even more important. Even if the patient has been poisoned, preservation of the patient’s vital functions with a primary survey and resuscitation, ie, basic supportive care, is the cornerstone of treatment, taking precedent over administering any antidote. Poisoning Treatment Paradigm. The poisoning treatment paradigm (Alter absorption, Antidote administration, Basics, Change catabolism, Distribute differently, and Enhance elimination) is an important AHLS mnemonic (A, B, C, D, E).79 Altering absorption (decontamination) is the cornerstone of toxicologic treatment. Hazmat antidotes are limited in number (Table 93–7). Basics, ie, the primary survey and resuscitation, are fundamental to the care of all patients, including hazmat victims. Poisonings caused by some hazardous materials can be treated effectively by changing their catabolism, distributing them differently, or enhancing their elimination. An example of changing catabolism is the antidote sodium thiosulfate accelerating the catabolism of highly toxic cyanide to its relatively nontoxic metabolite thiocyanate. An example of enhancing elimination is ventilating with 100% oxygen to enhance exhalation of carbon monoxide. Many inhaled toxicants, including gases such as carbon monoxide, are eliminated by exhalation. All the antidotes discussed are found in great detail in the appropriate Antidotes in Depth elsewhere in the text.

PART II: PREHOSPITAL AND INTERHOSPITAL CONSIDERATIONS Whether a patient with a toxicologic emergency is one of many from a hazmat incident or, more typically, is the sole victim of a single exposure, once that patient is in the care of the EMTs and paramedics, the prehospital issues are, for the most part, the same. As noted in the beginning of this chapter, the vast majority of hazmat incidents do not generate patients, and when they do, usually there are only a few victims. Because paramedics and EMTs are capable of providing highquality care for critically ill patients, the facilities may be able to utilize EMTs and paramedics to transfer seriously ill victims of carbon monoxide poisoning to hyperbaric oxygen facilities, victims of envenomations to antivenom treatment centers, and victims of drug overdoses and poisonings to designated poison treatment centers and other hospitals capable of providing necessary hemodialysis and/or hemoperfusion. Appropriate pre- and interhospital care of the poisoned or overdosed patients begins with a knowledge of those aspects of management described in detail in Chapters 3, 31, and 95. Unfortunately, there is a dearth of sound scientific information regarding management of poisonings and overdoses in the prehospital setting, and many of the recommendations that follow have been extrapolated from similar situations that arise in the hospital setting.

Personal Danger to EMTs and Paramedics When hazmat incidents occur, the danger to rescue personnel is often recognized immediately, and the series of protective measures detailed earlier in this chapter will generally protect the

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TABLE 93–6.

Predominant Route of Exposure

Typical Toxicants

Irritant gas: High water-solublity

Ammonia, formaldehyde, hydrogen chloride, sulfur dioxide Chlorine

Inhalation

Phosgene, nitrogen dioxide

Inhalation

Carbon dioxide, methane, propane Isobutyl nitrite, carbon monoxide, hydrogen cyanide, hydrogen sulfide, hydrogen azide Acids (hydrochloric, nitric, sulfuric) Alkalis (ammonium, potassium hydroxide, or sodium) Organic phosphorus pesticides, carbamate insecticides Organic phosphorus nerve agents

Inhalation

Chloroform, gasoline, propane, toluene

Inhalation

Irritant gas: Intermediate water-solubility Irritant gas: Poor water-solublity Asphyxiant: Simple Asphyxiant: Systemic (chemical)

Cholinergic

Cholinergic

Hydrocarbon and halogenated hydrocarbons

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Primary Hazmat Toxidromes or Hazidromes

Hazidrome

Caustic

HAZMAT INCIDENT RESPONSE

Pathophysiology Effects

Site of Toxicity

Irritant and corrosive local effects; readily dissolves in the water of exposed mucous membranes and the upper airway Irritant and corrosive local effects; dissolves in the water of exposed mucous membranes and the upper and lower airways Irritant and corrosive local effects by slowly dissolving in the water of the alveolarcapillary membrane of the lung Displacement of oxygen from the ambient atmosphere Interferes with oxygen transportation and/or utilization

Airway

Skin and mucous membranes

Irritant and corrosive local effects

Airway, Cardiovascular

Skin

Excess acetylcholine accumulation at both muscarinic and nicotinic receptors in the peripheral and central nervous system

Disability

Inhalation

Inhalation

Inhalation and/or skin

Airway, Breathing

Breathing

Cardiovascular, Disability Cardiovascular, Disability

Disability

Inhalation causes lethargy to coma and cardiac irritability

Cardiovascular Disability

Modified with permission from the Advanced Hazmat Life Support Provider Manual, 2nd ed. Tucson, AZ, Arizona Board of Regents, 2000.

EMT or paramedic from subsequent primary or secondary exposure and illness. Much more problematic, however, is the solitary exposure victim. Victims of deliberate poisonings and patients who have taken drug overdoses with suicidal intent are often unable or unwilling to describe accurately the extent of the ingestion or exposure (Chaps. 3 and 31). Conversely, after a suicide “gesture” the patient may deliberately exaggerate the nature of the overdose or exposure or suggest that there is a widespread danger to others. When dealing with an actual or possible source of danger, EMTs and paramedics must protect themselves from exposure to poisons or inhalation of toxic chemicals and fumes by using appropriate protective equipment and providing adequate ventilation within enclosed places suspected of containing high concentrations of toxic gases. Many toxic gases are colorless and odorless, and some chemicals (eg, organic phosphorus compounds) can be absorbed through intact skin. Paramedics and EMTs must also be aware of the danger of mouth-to-mouth resuscitation for patients suspected of having cyanide poisoning.8 Overdose victims who are conscious or who have an altered level of consciousness other than coma present other difficulties in the prehospital setting. They may be combative, placing themselves and paramedics or EMTs at risk, or they may be unwilling to accept medical care, particularly transport to the hospital. Prehospital care providers must maintain their objectivity and compassion and not allow these factors to alter acceptable standards of care such that the patient is placed at greater risk.

As with all patient interactions, care must be taken to avoid blood and body fluid contamination. Patients using illicit drugs intravenously are especially prone to blood-borne infections (HIV and hepatitis), and great care must be taken to avoid contamination during treatment and handling of drug paraphernalia. Initial Prehospital Management of a Poisoned or Overdosed Patient. Prehospital personnel should be mindful that the patient’s condition may deteriorate rapidly and unpredictably. For an unconscious patient, definitive control of the airway with endotracheal intubation and establishment of an IV line should be considered early in the management. A properly secured airway not only ensures adequate ventilation and oxygenation but may limit further aspiration of gastric contents. Indications for the use of D50W, thiamine, naloxone, and oxygen in a patient with an altered level of consciousness are generally consistent with their use in the ED as described in Chapters 3 and 31. However, the value of the empiric use of naloxone and D50W in the prehospital setting has been questioned in two retrospective studies; the findings are summarized in the antidote section below.35,36

The Role of the EMT or Paramedic in Establishing a Diagnosis of Poisoning or Overdose One of the most important functions an EMT or paramedic can perform in managing a patient with a toxicologic emergency is to evaluate the patient’s environment to the extent permitted by the

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TABLE 93–7.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Hazmat Antidotes

Antidote in Depth Citation

Antidote

Poisoning

Common Adult Dosesa

Common Pediatric Doses

See p 1353

Atropine

1–2 mg IV bolus; titrate with repeated doses.

0.02–0.04 mg/kg IV bolus, never less than 0.1 mg, titrate with repeated doses

See p 1341

Calcium gluconate

Calcium gluconate

See p 1341

Calcium chloride

See p 1511

Cyanide antidote kit: amyl nitrite Cyanide antidote kit: sodium nitrite

10–20 mL of 10% solution (1–2 amps). IV slowly; repeat doses may be required. Topical application of 2.5 to 10% topical gel or solution 5–10 mL of 10% solution (0.5–1 amp) IV slowly; repeat doses may be required By inhalation

0.2–0.3 mL of 10% solution/kg IV slowly; repeat doses may be required

See p 1341

Organic phosphorus compounds, carbamates, nerve agents Systemic hydrofluoric acid or fluoride poisoning Hydrofluoric acid skin burns Systemic hydrofluoric acid or fluoride poisoning Cyanide, nitriles Cyanide, nitriles

10 mL of 3% solution (1 amp) slow IV bolus, over 5 minutes

Cyanide, nitriles

See p 1450

Cyanide antidote kit: sodium thiosulfate Methylene blue

See p 1492

Oxygen

See p 1361

Pralidoxime (2-PAM)

Simple asphyxiants, systemic asphyxiants, methemoglobinforming compounds, carbon monoxide, cyanides, azides, hydrozoic acid, hydrogen sulfide Organic phosphorus nerve agents

50 mL of 25% solution (1 amp) slow IV bolus 1–2 mg/kg (0.1–0.2 mL/kg of 1% solution) slow IV bolus over 5 minutes; repeat doses may be required 100%, by inhalation

See p 667

Pyridoxine

See p 1511

See p 1511

Methemoglobin-forming compounds

Hydrazines

1–2 g slow IV infusion, over 10 minutes, then 500 mg/h continuous IV infusion 25 mg/kg IV

Topical application 0.1–0.2 mL of 10% solution/kg IV slowly; repeat doses may be required By inhalation 0.12–0.33 mL/kg of 3% solution slow IV bolus over 5 minutes, up to a maximum dose of 15 mg/kg in a nonanemic child 1.65 mL/kg slow IV bolus of 25% solution up to a maximum of 50 mL (1 amp) 1–2 mg/kg (0.1–0.2 mL/kg of 1% solution) slow IV bolus over 5 minutes; repeat doses may be required 100%, by inhalation

20–40 mg/kg slow IV infusion over 10 minutes, then 10–20 mg/kg/h continuous IV infusion 25 mg/kg IV

a

These are commonly used doses for hazmat poisonings. Specific doses for a given patient must always be determined by the treating clinician. See other chapters and specifically the individual Antidotes in Depth for additional information including indications, contraindications, and complications of each agent. Modified with permission from the Advanced Hazmat Life Support Provider Manual, 2nd ed. Tucson, AZ, Arizona Board of Regents, 2000.

patient’s condition. For example, an elderly patient brought in unconscious from home may be suffering from hypoglycemia, hyperosmolar coma, diabetic ketoacidosis, sepsis, poisoning, overdose, intoxication, etc. However, if the EMT notices an unvented space heater in the corner of the room and reports this finding to the emergency physician, the diagnosis of carbon monoxide (CO) poisoning can be pursued expeditiously. This consideration is especially important because oxygen administration en route may begin to treat the signs and symptoms before the patient is examined in the ED, thereby potentially obscuring the etiology of the patient’s initial altered consciousness. Reporting the presence of the space heater to the local health department or EPA will allow appropriate personnel to seek out and eliminate the CO source before others die from the exposure. In addition to noting empty pill bottles, suicide notes, or illicit drug paraphernalia found with a patient, prehospital personnel should be aware of any unusual smells, sources of toxic gases, and

evidence of toxic chemicals in the patient’s environment. Chemicals in the workplace, for example, may present a difficult diagnostic challenge that is made easier if the EMT notes the few specific chemicals that are available. Prehospital evaluation and care should include transport to the ED of containers (labeled or not), pills and pill bottles, and any possible ingested plant material for definitive identification. Some prehospital personnel carry “patient belongings” bags in the ambulance for this purpose. If possible, an animal at the scene, which may be either a source or a victim of poisoning, should be restrained or contained and transported later by appropriate personnel such as the ASPCA. Finally, recognition of the possibility of concomitant trauma to the victim is essential for appropriate and timely management. Many overdose patients also become victims of blunt or penetrating trauma. Conversely, many trauma victims are also inebriated or overdosed on medications or drugs.

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Gastric Decontamination in the Prehospital Setting No method of gastric decontamination has been adequately proven to alter morbidity or mortality.2 Therefore, routine use of gastric decontamination is no longer a standard of care, and its use in selected oral ingestions should be carefully considered and justified.2 Administration of syrup of ipecac to alert patients after a recent oral ingestion may be considered. In some types of poisoning, gastric emptying (most typically by emesis) may be possible only early in the clinical course, before the resultant toxicity precludes such intervention, as in colchicine or a heavy metal poisoning. Especially when transport time is long, therefore, syrup of ipecac may have to be administered at home as directed by a regional poison center or by prehospital personnel if it is to be administered at all. Arguments against prehospital administration of syrup of ipecac include (1) that a patient who starts vomiting en route to the hospital may be difficult to position properly, and (2) that controlling the airway in the back of a moving ambulance may be difficult, with the added danger that the patient may lose the gag reflex before vomiting. Orogastric lavage, which may be an appropriate alternative form of gastric emptying, has not gained widespread use in the prehospital setting. Prehospital administration of activated charcoal (AC) may offer a relatively safe and attractive alternative to both emesis and lavage. In an area where ambulance transport time was relatively short (about 10–12 minutes on average), the authors of one pilot study were able to demonstrate that prehospital, AC could be administered in an average of 5.0 minutes from the first encounter with paramedics versus 51.4 minutes when AC was delayed until arrival in the ED.23 In another retrospective review of prehospital charts of adults with the diagnosis of “drug overdose,” gastrointestinal decontamination was initiated with ipecac in only 6 of 361 (2%) patients. No patient received AC despite a median transport time of 25 minutes. The median time to administration of AC in the ED was 82 minutes.82 Even when no form of gastric decontamination is offered in the prehospital setting, ambulance transportation to the ED by itself appears to result in decreased time to gastric decontamination. In a retrospective review of 167 overdose patients receiving gastric lavage or activated charcoal, the median interval from presentation to gastric decontamination for the 105 patients who arrived by ambulance was 55 minutes compared to 73 minutes for the nonambulance patients.83 The authors concluded that although ambulance-transported overdose patients waited a shorter time than nonambulance patients for gastrointestinal decontamination, the delay was unacceptably long in either case. The findings of this study support the argument that some form of gastrointestinal decontamination should be initiated prehospital. It is virtually impossible to design a protocol that takes into consideration all of the factors relevant to the very large number of substances that may be involved in an overdose or poisoning. In addition, variations in transport time in different regions of the country (eg, urban vs rural settings) may make gastric emptying essential or lifesaving in one case and unnecessary or dangerous in another case involving the same drug or toxin. For these reasons, EMTs and paramedics must be able to contact a physician located in a hospital ED, regional poison center, or base station telemetry unit to tailor options in gastric decontamina-

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tion or gastric emptying to the individual patient. The various methods of gastric emptying and indications and contraindications for their use are described in Chapter 31. Specific issues regarding gastric decontamination are thoroughly discussed in Chapter 5.

The Role of Antidotal Therapy in Prehospital Care: Recommendations for Specific Antidotes that EMTs and Paramedics Should Carry The list of antidotes available to hospital-based care providers is quite extensive when compared to lists of medications that paramedics typically carry in their drug boxes or vehicles (see Tables 3–1 and 93–8). Several considerations must be addressed before an antidote is made available for use in the prehospital setting: (1) the vast majority of poisonings and overdoses require care directed by clinical presentation as opposed to care for a known or presumed drug or toxin (Chaps. 3 and 31); (2) there are space limitations in the prehospital setting, restricting the total number of medications and the amount of equipment that can be carried; (3) antidotes that are rarely used may have to be restocked, often at considerable cost, to comply with manufacturers’ expiration dates, loss of potency, deterioration to harmless or toxic substances (eg, the cyanide antidote kit); (4) medications that must be refrigerated or prepared (mixed) for each shift are impractical; (5) antidotes used inappropriately may be extremely toxic or lethal to a patient (eg, the cyanide antidote kit). Some prehospital care systems address this last issue by providing only nontoxic or relatively nontoxic antidotes, or the nontoxic component(s) of TABLE 93–8. Medications Commonly Carried by Paramedics that Can Also Be Used as Antidotesa,b Medication

Antidotal Use

Atropine

β-Adrenergic antagonist, calcium channel blocker, and cardiac glycoside (digoxin) overdoses; muscarinic mushroom (Clitocybe, Inocybe) poisoning; organic phosphorus and carbamate insecticide poisoning Stimulants Calcium channel blocker overdose (causing hypotension and bradydysrhythmias), hydrofluoric acid Extrapyramidal reactions from antipsychotics or antiemetics β-Adrenergic antagonists, calcium channel blocker overdoses Carbon monoxide, cyanide, hydrogen sulfide poisoning (1) Cyanide, methanol, ethylene glycol (reversal of metabolic acidosis) (2) Salicylates, chlorpropamide, phenobarbital, formic acid, chlorphenoxyherbicides (enhanced elimination) (3) Cyclic antidepressants, quinine, carbamazepine, type IA and IC antidysrhythmics, cocaine, some phenothiazines (reversal of type IA ECG effects)

Benzodiazepinesc Calcium chloride

Diphenhydramine Glucagon Oxygen Sodium bicarbonate

a

Use of medications outside of protocols may not be permissible in some areas, even with on-line medical control. b Table does not include medications such as D50W, thiamine and naloxone primarily intended to be used as standard component of overdose management antidotes for an altered level of consciousness. c Usually administered with D50W and oxygen to avoid masking hypoglycemia and hypoxia.

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multistep antidotes such as only the sodium thiosulfate from the cyanide antidote kit. Few organized attempts to study the use of antidotes in the prehospital setting have been conducted to date, and virtually all of the studies that have been published are retrospective analyses.2–4,12,23,25,36,69,84 One such study investigating the safety of the prehospital use of 0.4 to 0.8 mg of naloxone in 813 patients found it to be a safe component of paramedic treatment protocols for patients with an acute loss of consciousness.84 However, another retrospective study of the empiric use of naloxone by paramedics in 730 patients with acute alterations in mental status found that selective administration based on the presence of pinpoint pupils, bradypnea, or circumstantial evidence of drug use correctly identified “narcotized” patients with a sensitivity of 92% and a specificity of 76%. The authors concluded that implementing a screening strategy for naloxone use based on these historical and physical findings could reduce naloxone administration by 75% while achieving cost savings, faster prehospital care, and fewer iatrogenic effects of naloxone.35 Interestingly, these same authors reviewed 340 records retrospectively in an attempt to identify a subset of prehospital patients at risk for hypoglycemia by utilizing the clinical findings of tachycardia, diaphoresis, and a history of diabetes. In stark contrast to the results of their naloxone study, they found that only 76% of hypoglycemic patients were identified, and with a specificity of only 54%36. Thus, the prehospital use of hypertonic dextrose could be reduced by only 46%, and this would have the effect of withholding it from 25% of hypoglycemic patients. In marked contrast to their conclusions regarding naloxone, the authors concluded here that selective use of D50W for AMS would be feasible only with concomitant field use of a rapid, accurate test of serum glucose.36 Uncommon or unusual poisonings present additional problems in the use of antidotes in the prehospital setting. One way of dealing with uncommon poisonings is to have protocols, treatments, and antidotes readily available for use after an identified index case or cases indicate the possibility of a large number of exposures. Examples of such poisonings may be found in the hazmat portion of this chapter and include CO and cyanide exposures as well as lethal drugs or combinations that may affect a particular population, such as sudden widespread availability of fentanyl, unexpectedly potent opioids, or opioid substitutes and combinations. Finally, EMTs and paramedics should be mindful that almost all prehospital care protocols are sign- or symptom-driven; few, if any, ambulances routinely carry all available specific antidotes to treat all potential poisonings. Moreover, even when an antidote (such as glucagon) is available because the medication is also used in other ALS protocols, its dosage as an antidote may differ (see Table 93–7).56–58 For these reasons, rather than applying a series of protocols over a prolonged period of time to treat a variety of signs and symptoms, EMTs and paramedics should initiate early telemetry contact with a base station physician, and a rational decision should be made regarding any further treatment or immediate transport of the patient to a facility where a specific antidote is available.

The Optimal Position for Transporting a Poisoned or Overdosed Patient In one attempt to identify the optimal transport position for a poisoned or overdosed patient, volunteers were given 80 mg/kg of

acetaminophen to simulate an overdose, and five different (stationary) body positions commonly used in prehospital and emergency department settings were examined over a 2-hour period.76 Although the difference did not reach statistical significance, initial drug absorption was lowest in the left lateral decubitus position, a position that also offers advantages in preventing aspiration, enhancing oropharyngeal drainage, and maximizing patient observation in an ambulance.76

The Role of the EMT or Paramedic in Transferring a Poisoned or Overdosed Patient for Definitive Care Certain poisonings and overdoses require specific treatments not available at a community hospital or not available soon enough to help a particular patient (Table 93–9). Emergency physicians must sometimes weigh the benefits and risks of transferring ill, poisoned, or overdosed patients to tertiary care centers. In general, a patient presenting with a toxicologic emergency should be moved to another facility only if the primary hospital does not have the necessary therapy and if there is no acceptable alternative treatment available. Hyperbaric Oxygen for Carbon Monoxide Poisoning. Criteria for determining which patients may benefit from hyperbaric oxygen treatment (HBO) are discussed in detail in Chapter 97. A CO poisoning victim should be provided with 100% oxygen while being transported to a hyperbaric chamber; assisted ventilation should be provided to any patient who is not breathing spontaneously. A physician or paramedic able to administer advanced cardiac life support should accompany the patient. Attention to the patient’s ongoing cardiorespiratory needs is critical. The safety of transferring CO-poisoned patients for HBO was addressed in a 10-year retrospective study of 297 consecutive COpoisoned patients requiring HBO.69 The authors concluded that CO-induced cardiac or respiratory arrests, myocardial infarctions, and worsening mental status are not likely to occur during transport to the hyperbaric chamber if they did not occur before the decision to perform HBO, and, therefore, transfer need not be deferred for fear of these occurrences. However, dysrhythmias, hypotension, seizures, agitation, and emesis as well as repeat cardiac arrests and near arrests can occur; therefore, complete prepared-

TABLE 93–9. Patients with Poisoning or Overdose Who May Require Transfer to Special Treatment Centers Poisoning/Overdose

Type of Care

Carbon monoxide (high levels and/or serious clinical sequelae) Snake or spider venom Lithium, salicylates, theophylline, methanol, or ethylene glycol Acetaminophen (with significant hepatic damage) Myocardial depressants (massive amounts that cannot be metabolized or dialyzed or otherwise treated, such as lidocaine, calcium channel blockers) Infants with serious poisonings or drug overdoses from a variety of sources

Hyperbaric oxygen Antivenom treatment Hemodialysis and/or hemoperfusion Hepatic transplantation Cardiopulmonary bypass

Neonatal and pediatric intensive care unit

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ness for cardiac resuscitation, airway control, and volume expansion during transport was recommended.69 Transfer principles for referral to a hyperbaric treatment center are outlined in Tables 93–10 and 97–2. Hemoperfusion and/or Hemodialysis. Transferring a patient to a facility capable of hemodialysis or hemoperfusion is most commonly required for poisoning with methanol or ethylene glycol and serious overdoses of lithium, salicylates, or theophylline (Chaps. 33, 39, 61, and 66). All initial treatment should be instituted before, and continued during, interhospital transport. Patients sick enough to require hemodialysis or hemoperfusion should ideally be transported in an advanced life-support ambulance and with an accompanying physician. Antivenom Treatment Centers for Envenomations. Because envenomations are relatively rare and may be extremely serious or lethal, victims may require transportation to a specialty center for treatment. Table 93–11 outlines the New York City snake bite protocol, which includes a section on patient transport.

Legal Considerations in Transferring Poisoned or Overdosed Patients Incorrect interpretation of the United States Federal EMTALA and COBRA legislation72 adopted and implemented to prevent inappropriate transfers of indigent patients (patient dumping) may hinder or prevent transporting a patient who, though medically “unstable,” may nevertheless require specialized treatment or facilities. Nothing in the legislation precludes such a transfer provided that: (1) the treatment is considered necessary; that is, the benefits of the transfer outweigh the risks; (2) the sending and receiving institutions are in agreement regarding the necessity of the transfer and the medical care being provided to accomplish it; (3) the transfer is effected in accordance with accepted medical practice; and (4) the transfer is not for economic reasons. As with any patient transfer between institutions, care must be taken to ensure that before transport the patient has been medically stabilized as much as possible within the time constraints dictated by the nature of the exposure. With respect to the level of care during transport, a physician accompanying a patient would be ideal, but in most situations properly trained and qualified paramedics

TABLE 93–10. Suggested Protocol for Transferring a Patient to Hyperbaric Treatment A physician at the sending facility must perform a basic physical examination and laboratory assessment including: History (past medical history, medications, complaints) COHb (in carbon monoxide cases) Chest radiograph Electrocardiogram Blood tests—chemistry profile, toxicology tests (if applicable) Pregnancy test (for women of childbearing age) Neurologic examination (including mental status exam) Formal ENT examination for smoke inhalation, noting any indicators of respiratory involvement including stridor, hoarseness, carbonaceous sputum, and singed nasal hairs Any patient requiring transfer for hyperbaric treatment is best considered unstable; therefore, the sending institution should consider the need for physician accompaniment when indicated.

TABLE 93–11.

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Snakebite Protocol for New York City

Identification of snake Record verbal description of snake, time of bite, description of wound(s), and signs and symptoms of envenomation. If snake is identified as poisonous or symptoms warrant proceed with first-aid measures and transportation. If snake is identified as nonpoisonous, treat as any other animal bite First-aid measures for poisonous snakebite to be instituted by EMS or other trained medical personnel DO NOT EMPLOY TOURNIQUET, CUT AND SUCTION, OR CRYOTHERAPY If snake has been identified as an elapid (cobra, mamba, coral snake, sea snake, krait, tiger snake, taipan), apply an Ace bandage on the affected extremity, encompassing the wound(s) and extending up the entire extremity. Do not apply an Ace bandage if the snake has been identified as a crotaline (rattlesnake, copperhead, cottonmouth, fer-de-lance, puff adder, Gaboon viper). Splint the affected extremity to decrease mobility in all bites. Begin a large-bore IV in an unaffected extremity and start an infusion of 0.9% sodium chloride or lactated Ringer solution. Transport immediately. EMS or 911 Ambulance unit should have a trained paramedic, capable of intubation and CPR if necessary, when transferring a patient from another hospital. Helicopter transport is available through EMS (or 911) if deemed necessary Receiving hospital ED must be informed of estimated time of arrival and method of transportation.

and vehicles equipped to provide advanced life support may be acceptable, especially if the alternative (ie, not transporting the patient) would probably result in morbidity or mortality.

SUMMARY The use of D50W, thiamine, naloxone, oxygen, activated charcoal, possibly syrup of ipecac or orogastric lavage, and benzodiazepines, as well as many other therapeutic modalities discussed elsewhere in this text, are also applicable to prehospital management. There are, however, certain unique and important considerations for the prehospital setting: ■ Initial management should incorporate concern for and elimination of any possible risk to rescue personnel at the scene. ■ Without compromising patient care, paramedics and EMTs should try to note and collect evidence at the scene that may be essential to establish a definitive diagnosis. ■ Specific antidotes must be used appropriately; conversely the lack of availability of other antidotes (antivenom) or treatment (HBO) at particular hospitals must be considered in deciding the best time for subsequent transport or rapid evacuation to a specialized treatment facility. ■ Appropriate use of paramedics or EMTs and well-equipped vehicles will facilitate safe transport of poisoned or overdosed patients to specialty or tertiary care centers. Pitfalls to avoid in providing prehospital care to victims of poisonings or overdoses include these:

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■ Not recognizing or acting on index cases to prevent further exposures or deaths: the opportunity to prevent large-scale hazmat incidents. ■ Relying on sign- or symptom-driven standing protocols to treat a patient for a prolonged period of time or using standard advanced-life-support dosages of medications when only a larger dose of medication or a specific antidote, not available at the scene, will save the patient.

ACKNOWLEDGMENTS Theodore I. Benzer contributed to this chapter in a previous edition.

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CHAPTER

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METHEMOGLOBINEMIA Dennis Price

Methemoglobin (Met Hb) Normal level: 1%, slightly higher in infants Action level: 20%: Asymptomatic patient 10–20%: Symptomatic patient Values greater than or equal to the action level usually necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical condition of the patient.

A 27-year-old man was brought to the Emergency Department (ED) by ambulance with a complaint of shortness of breath. The patient had a history of acquired immunodeficiency syndrome (AIDS), complicated by Candida esophagitis and two episodes of Pneumocystis carinii pneumonia. His medical regimen included zidovudine and dapsone. The patient said that he had recently become depressed over the death of a close friend and took “all of his medications” in a suicide attempt 3 hours before arrival. He vomited once at home and began getting short of breath about 2 to 3 hours later. On physical examination, the patient appeared cachectic and acutely short of breath. His vital signs were: blood pressure 90/40 mm Hg, pulse 140 beats/min, respiratory rate 40 breaths/min, rectal temperature 100.2°F (37.9°C). A pulse oximeter indicated 88% saturation on room air. The skin was diaphoretic with old track marks. Examination was remarkable for perioral cyanosis. His neck was supple and without jugular venous distention. The chest was clear to auscultation with good airflow. Cardiac examination revealed a tachycardia with normal S1 and S2 heart sounds and a grade 1/6 systolic ejection murmur heard best at the left lower sternal border. The abdomen was nontender with good bowel sounds and no hepatomegaly. Examination of extremities revealed no clubbing or edema, but the nail beds were markedly cyanotic. His neurologic examination was normal. A 100% nonrebreathing oxygen mask was applied, and the patient was attached to a cardiac monitor. An intravenous (IV) line was inserted, and blood samples were obtained for a complete blood count, electrolytes, BUN, glucose, and acetaminophen level. After a few minutes of oxygen therapy, the patient’s heart rate decreased to 128 beats/min, but he was still cyanotic and tachypneic, and the pulse oximeter continued to indicate 86 to 88% oxygen saturation. Arterial blood gas analysis was obtained while the patient was receiving supplemental oxygen, but the house officer thought that it might be a venous specimen because it was so darkly colored. The results were: pH 7.34, PCO2 30 mm Hg, PO2 400 mm Hg calculated oxygen saturation 99%. The patient was given 60 g of activated charcoal in a slurry of water and 50 mL of 70% sorbitol orally. The electrocardiogram (ECG) showed a sinus tachycardia with normal axis, intervals, ST segments, and T waves. The chest radiograph was normal. A serum acetaminophen level was zero. All other laboratory test results were unremarkable. Cooximetry of an arterial specimen revealed: total hemoglobin 8.4 g/dL, oxyhemoglobin

64%, methemoglobin 33%, deoxyhemoglobin 1%, carboxyhemoglobin 2%. The patient received 60 mg of methylene blue (0.1 mL/kg of 1% solution) IV over 20 minutes. Pulse oximetry indicated a drop to 73 to 75% for several minutes with no change in his clinical symptoms. About 40 minutes after the methylene blue infusion, the patient was less cyanotic, and a repeat methemoglobin level was 6%. Three hours later he was again short of breath and cyanotic, and his methemoglobin had risen to 24%. Another 60 mg of methylene blue was infused and led to an improvement in his color and tachypnea within 20 minutes. His repeat methemoglobin level was 4%. Over the first 24 hours, the patient required a total of three doses of methylene blue therapy. His hemoglobin subsequently fell to 6.2 g/dL, and he was transfused with 2 units of packed red blood cells. While in the hospital, the patient was evaluated by a psychiatrist and enrolled in an AIDS support group. The patient was discharged 6 days after admission with a hemoglobin of 9.7 g/dL and normal cooximetry values.

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1438

Biologic systems constantly need to protect themselves from oxidants in order to survive. Cellular components such as enzyme systems and structural elements become oxidized spontaneously and have increased rates of oxidation when exposed to exogenous oxidants. When hemoglobin becomes oxidized, it forms methemoglobin. This occurs when the iron atom in hemoglobin loses one electron to an oxidant, and the ferrous (Fe2+) state of iron is transformed into the ferric (Fe3+) state. Some oxidation of hemoglobin occurs normally during oxygen transport, and this oxidation is increased in the presence of some hereditary conditions; however, oxidizing compounds from the environment and drugs are the major source of oxidant stress to the individual. Although it is typically not life threatening, methemoglobinemia may produce symptoms because of cellular hypoxia and should be considered in a complete differential diagnosis of the cyanotic patient with no apparent cardiovascular cause. Methylene blue, an exogenous electron carrier, will reduce oxidized hemoglobin.

CHAPTER 94

HISTORY AND EPIDEMIOLOGY Physicians became aware of methemoglobin in the latter half of the 19th century. Methemoglobin was first described by Felix Hoppe-Seyler in 1864.25 He was a physiologic chemist who studied blood in the laboratory. Subsequently, in 1891, a case of druginduced methemoglobinemia that resolved on its own was described.53 In the late 1930s methemoglobinemia was recognized as a predictable adverse effect of the use of sulfanilamide, and the use of methylene blue was recommended to treat the ensuing cyanosis.34 Concurrent use of methylene blue was also recommended by some authors when these drugs were utilized.82 In 1948 an enzyme defect was reported in twin brothers that caused cyanosis in the absence of cardiopulmonary disease; the cyanosis responded to ascorbic acid therapy.27 In the past half-century, the biochemistry, genetic predisposition, and treatment modalities for methemoglobinemia were greatly elucidated. Computerized searches today produce thousands of articles dealing with methemoglobin. Methemoglobinemia can be hereditary or acquired. The hereditary types are exceedingly rare, with only several hundred cases reported to date in the literature.5,36,48,49,67 Even acquired methemoglobinemia, although more common than hereditary methemoglobinemia, occurs only infrequently. This is in part because of increased federal regulation of industrial manufacturing methods and food processing,62 major historic causes of acquired methemoglobinemia, and in part because of the limited clinical manifestations at the lower methemoglobin concentrations. The AAPCC data annually show fewer than 100 uses of methylene blue as an antidote (Chap. 116 and page 1752).

ETIOLOGIES Nitrates and nitrites are powerful oxidizing agents that represent two of the most common methemoglobin-forming compounds. Sources of nitrates and nitrites include drinking well water, food, industrial compounds, and pharmaceuticals. The contamination of drinking water occurs mainly with nitrates because nitrite is easily oxidized to nitrate in the environment. Nitrates are very soluble and easily contaminate shallow rural wells by way of the runoff of water containing nitrogen-based fertilizers and nitrogenous waste from animal and human sources. Foods such as cauliflower, carrots, spinach, and broccoli have high nitrate content, and nitrates enter the food chain as preservatives in meat products such as hot dogs and sausage.1,2,13 The oxidation reaction of nitrates that occurs in vivo and in vitro is complex and poorly understood. Ingested nitrates are reduced to nitrites by bacteria in the intestinal tract (especially in infants) and can then be absorbed, ultimately leading to methemoglobin production. This conversion is not essential, however, because nitrates themselves can oxidize hemoglobin.23,32,76 In the past, nitrates were a too common cause for well water contamination, and infant fatalities were associated with methemoglobinemia.15,51 A number of reports from the Midwest United States demonstrated the problems of poorly constructed shallow wells that permit contamination by surface waters containing chemicals, pesticides, fertilizers, and microorganisms.54 In several South Dakota studies, 20 to 50% of wells contained both coliform bacteria and water that exceeded the Environmental Protection Agency (EPA) standards for permissible quantities of nitrogen as

METHEMOGLOBINEMIA

1439

nitrates (10 ppm or 10 mg/L).40 In New York State, 419 wells from rural farms demonstrated elevated levels of nitrogen compounds, and 15.7% were found to have nitrate levels greater than 10 mg/L.26 Nitroglycerin (glyceryl trinitrate) and organic nitrates are more effectively absorbed through mucous membranes and intact skin than from the gastrointestinal (GI) tract. The onset of action is also more rapid, and the total effect is much greater, through the former.16,20,64 Aromatic amino and nitro compounds may indirectly produce methemoglobin. These agents do not form methemoglobin in vitro and are therefore assumed to do so by chemical conversion to some extremely active in vivo intermediate compounds.10,77 Methemoglobin and carboxyhemoglobin levels are found in victims of fires and automobile exhaust fume poisoning.7,38,41,46,73 Heat-induced hemoglobin denaturation in burn patients and the inhalation of nitrogen oxides from smoke inhalation are suggested to be causative factors for methemoglobin formation. Topical anesthetics such a prilocaine and benzocaine regularly produce methemoglobinemia.30,44,59 These agents are ubiquitous and are found in the various topical and local anesthetics used for medical procedures. Because of its use by AIDS patients, dapsone is increasingly implicated as a cause of methemoglobinemia. Cases of prolonged methemoglobinemia from dapsone ingestion have been reported and are related to its long half-life and the methemoglobin-forming potential of its metabolites.19 The bladder anesthetic pyridium (phenazopyridine) is another commonly reported oxidizing agent.14,21,29,56,74 Other causes of methemoglobinemia are listed in Table 94–1.

HEMOGLOBIN PHYSIOLOGY AND METHEMOGLOBIN Hemoglobin consists of four polypeptide chains noncovalently attracted to one another. Each of these subunits carries one heme molecule deep within the structure. The polypeptide chain protects the iron moiety of the heme molecule from inappropriate oxidation (Fig. 94–1). The iron is held in position by six coordination bonds. Four of these bonds are between iron and the nitrogen atoms of the protoporphyrin ring, with the fifth and sixth bond sites lying above and below the protoporphyrin plane. The fifth site is occupied by histidine of the polypeptide chain. Changes in the amino acid sequence of the polypeptide chain, as occur in hemoglobin M, influence this protective “pocket,” allowing easier iron oxidation (Fig. 94–2). This process is referred to as hemoglobin autooxidation. The sixth coordination site is where most of the activity within hemoglobin occurs. Oxygen transport occurs here, and this site is altered with formation of methemoglobin or carbon monoxide poisoning (Fig. 94–3). It is at this site that an electron is lost to toxic oxidants transforming iron from its ferrous to its ferric form, producing oxidized hemoglobin: methemoglobin. Hemoglobin will transport an oxygen molecule only when its iron atom is in the reduced ferrous state (Fe2+). During oxygen transport the iron atom actually transfers an electron to oxygen, thus transporting oxygen as a superoxide charged particle Fe3+O2. When oxygen is released, the ferrous state is restored, and hemoglobin is ready to accept another oxygen molecule. Interestingly, a

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PART D

TABLE 94–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Common Etiologies of Methemoglobinemia

Hereditary Hemoglobin M NADH methemoglobin reductase deficiency (homozygote and heterozygote) Acquired A. Medications Amyl nitrite Benzocaine Dapsone Lidocaine Nitroglycerin Nitroprusside Phenacetin Phenazopyridine Prilocaine (local anesthetic) Quinones (chloroquine, primaquine) Sulfonamides (sulfanilamide, sulfathiazide, sulfapyridine, sulfamethoxazole) B. Chemical agents Aniline dye derivatives (shoe dyes, marking inks) Butyl nitrite Chlorobenzene Fires (heat-induced denaturation) Food adulterated with nitrites Food high in nitrates Isobutyl nitrite Naphthalene Nitrophenol Nitrous gases (seen in arc welders) Silver nitrate Trinitrotoluene Well water (nitrates) Pediatric Reduced NADH methemoglobin reductase activity in infants (< 4 months) Associated with low birth weight, prematurity, dehydration, acidosis, diarrhea, and hyperchloremia

small percentage of oxygen is released from hemoglobin with its shared electron (forming superoxide O2
) and leaving iron oxidized. This sixth coordination site becomes occupied by a water molecule. This abnormal unloading of oxygen contributes to the steady-state level of methemoglobin of approximately 1% found in normal individuals. In summary, the differences between hemoglobin and methemoglobin are subtle and involve only a small part of the hemoglobin molecule but make methemoglobin incapable of oxygen transport.

METHEMOGLOBIN PHYSIOLOGY AND KINETICS Because of the spontaneous and environmentally induced oxidation of hemoglobin, the erythrocyte has developed multiple mechanisms to maintain the normal level of methemoglobin at less than 1%.8 All of these systems donate an electron to the oxidized iron atom. The half-life of methemoglobin acutely formed as a result of exposure to oxidants is between 1 and 3 hours.39,52 If there is continuous adsorption of the oxidant, or if the metabolites of the oxi-

his Fe++

O2−

his

O2− Fe++

Fe++ his

Fe++

O2−

O2−

his

Figure 94–1. The hemoglobin molecule is symbolically represented with its heme center being surrounded by the globin portion of the molecule.

dant are themselves oxidants, then the half-life of methemoglobin will be prolonged. Quantitatively the most important reductive system requires nicotinamide adenine dinucleotide (NADH), which is generated in the Embden Meyerhof glycolytic pathway (Fig. 94–4). This electron donor, along with the enzyme NADH methemoglobin reductase, reduces the oxidized ferric (Fe3+) iron or heme to the more functionally favorable ferrous (Fe2+) iron state. There are numerous cases of hereditary deficiencies of the enzyme NADH methemoglobin reductase.36,49,67 Homozygotes for this enzyme deficiency usually have methemoglobin levels of 10 to 50% under normal conditions without any clinical provocations, whereas heterozygotes do not ordinarily demonstrate methemoglobinemia except when subject to oxidant stresses. Additionally, because this enzyme system lacks full activity until about 4 months of age, infants are more susceptible than adults to oxidizing stresses.57,84 Oxidized iron can be reduced nonenzymatically using ascorbic acid and reduced glutathione as electron donors, but this method is much slower and quantitatively less important under normal circumstances.

Tyrosine

H

O

H

Figure 94–2. Hemoglobin M occurs when histidine is replaced by tyrosine in the amino acid sequence of the polypeptide chain. Hemoglobin M is more easily autooxidized (as shown) to methemoglobin.

CHAPTER 94

Heme

Fifth Coordination Site

Sixth Coordination Site N

N Fe

Histidine

CO

Carboxyhemoglobin

O2–

Oxyhemoglobin

H O H Methemoglobin

N N

Figure 94–3. The heme molecule is depicted with its bonding sites. Oxyhemoglobin, carboxyhemoglobin, and methemoglobin all involve the sixth coordination bonding site of iron.

Within the red cell there is another enzyme system for reducing oxidized iron that is dependent on the nicotinamide-adenine dinucleotide phosphate (NADPH) generated in the hexose monophosphate shunt pathway (Fig. 94–5). This NADPH reduces only a small percentage of methemoglobin under normal circumstances, whereas the NADH-dependent methemoglobin reductase system plays the major role. Because of its relatively minor role in methemoglobin reduction, patients with a deficiency of NADPH methemoglobin reductase do not exhibit methemoglobinemia under normal circumstances.72 When the NADPH methemoglobin reductase system is provided with an exogenous electron carrier such as methylene blue, this system is accelerated to reduce oxidized hemoglobin.23 Methylene blue is reduced to leukomethylene blue by NADPH-dependent methemoglobin reductase, using NADPH as the electron donor; leukomethylene blue directly reduces the heme iron (see Antidotes in Depth: Methylene Blue).

CLINICAL MANIFESTATIONS The clinical manifestations of methemoglobinemia are related to impaired oxygen delivery to the tissue. The manifestations of toxicity of acquired methemoglobinemia are usually more severe than those produced by a corresponding degree of anemia. This discordance occurs because methemoglobin not only decreases the available oxygen carrying capacity but also increases the affinity of the

Figure 94–4. The role of glycolysis in the Embden-Meyerhof pathway in the reduction of methemoglobin.

METHEMOGLOBINEMIA

1441

unaltered hemoglobin for oxygen. This shifts the oxygen hemoglobin dissociation curve to the left, which further impairs oxygen delivery.16 This effect is attributed to the formation of heme compounds intermediate between normal reduced hemoglobin (all four iron atoms are ferrous) and methemoglobin, in which one or more of the iron moieties are in the ferric state.5,17 The degree to which this high-oxygen-affinity hemoglobin reduces oxygen delivery to the tissue from arterial blood is unclear because the work was done at partial pressures of oxygen found in venous blood.17 Because the symptomatology associated with methemoglobinemia is related to impaired oxygen delivery to the tissue, concurrent diseases such as congestive heart failure, chronic obstructive pulmonary disease, or pneumonia may greatly increase the clinical effects of methemoglobinemia. Anemia has profound effects as well (see Fig. 94–6). Predictions of symptoms and recommendations for therapy are based on methemoglobin concentrations in previously healthy individuals with normal hemoglobin levels. Cyanosis is a consistent physical finding in methemoglobinemia. Cyanosis occurs when just 1.5 g/dL of methemoglobin is present. This represents only a 10% conversion of hemoglobin to methemoglobin if the baseline hemoglobin is 15 g/dL. In contrast, it takes 5 g/dL of deoxyhemoglobin (which represents 33% of hemoglobin) in the deoxygenated form to produce the same degree of cyanosis. Sulfhemoglobin, another darkly pigmented hemoglobin, also produces a detectable bluish color when its level is only 0.5 g/dL (this represents only 3% of hemoglobin converted to sulfhemoglobin). In summary, a wide range of levels of pigment produce the same degree of cyanosis. In previously healthy individuals, methemoglobin concentrations of 10 to 20% usually result in cyanosis without apparent adverse clinical manifestations. At 20 to 50% methemoglobin concentration, dizziness, fatigue, headache, and exertional dyspnea may develop. At about 50% methemoglobin, lethargy and stupor usually appear; and the lethal concentration is probably greater than 70% (Table 94–2). The cyanosis associated with methemoglobinemia is generalized, being both peripheral and central. Patients often appear in less distress or less ill than patients with cyanosis secondary to cardiopulmonary causes. Some patients may have a mixed etiology for their cyanosis, such as cardiopulmonary-induced hypoxia together with methemoglobinemia. The blood oxygen-carrying capacity in such situations may be drastically reduced (Fig. 94–6; see Chap. 20 for a discussion of O2 content of blood). Symptomatology of methemoglobinemia is determined not only by the absolute concentration of methemoglobin but also by its rates of formation and elimination. Levels of methemoglobin that may be clinically benign when caused by hereditary defects or maintained chronically are likely to produce more severe signs when acutely acquired. Healthy subjects lack the compensatory mechanisms that develop over a lifetime in individuals with hereditary compromise, such as erythrocytosis and increased 2,3-diphosphoglyceric acid. Certain compounds characteristically produce prolonged methemoglobinemia. For instance, dapsone has a very long halflife in overdose situations.18,19 Aniline and numerous toxic metabolites of aniline are capable of oxidizing hemoglobin. In the presence of renal failure, drugs such as phenazopyridine (Pyridium) are slowly eliminated and cause prolonged methemoglobinemia.

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PART D

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Figure 94–5. The role of hexose monophosphate shunt in the reduction of methemoglobin by methylene blue.

Some compounds producing oxidant stress may have associated toxicities unrelated to the development of methemoglobinemia, such as seizures caused by benzocaine and lidocaine or hypotension caused by nitrates.61

DIAGNOSTIC TESTING For those individuals in whom methemoglobinemia is suspected, a source for the oxidant stress should be sought. Arterial blood gas sampling may reveal blood with a characteristic chocolate brown color. The arterial PO2 should be normal reflecting the adequacy of pulmonary function to deliver dissolved oxygen to the blood. However, the arterial PO2 does not measure the more important

Functional Hemoglobin

14 12 10 8

physiologic parameter, the hemoglobin oxygen saturation (SaO2) or content of the blood. When the partial pressure of oxygen is known, and oxyhemoglobin and deoxyhemoglobin are the only species of hemoglobin, oxygen saturation can be calculated accurately from the arterial blood gas. If, however, other hemoglobins are present, such as methemoglobin, sulfhemoglobin, or carboxyhemoglobin, then the fractional saturation of the hemoglobin must be determined by the cooximeter. The cooximeter is a spectrophotometer that identifies the absorptive characteristics of several hemoglobin species at different wavelengths. Because oxyhemoglobin, deoxyhemoglobin, methemoglobin, and carboxyhemoglobin all have different absorptions at the different measuring points of the cooximeter, their proportions and concentrations can be determined. Some newer instru-

A Normal B Hypoxia

D Methemoglobinemia and Anemia

6

Hemoglobin g/dL

4 2 Oxyhemoglobin

0 Deoxyhemoglobin

2

Methemoglobin

4

High-Oxygen Affinily Hemoglobin

6 8

Methemoglobinemia C

Methemoglobinemia, Hypoxia, and Anemia E

10 Dysfunctional Hemoglobin

Figure 94–6. Clinical manifestations of methemoglobinemia depend on the level of methemoglobin as well as host factors such as preexisting disease, anemia, and hypoxemia. Five examples of arterial blood gas analyses are presented. A. Blood gas from a normal individual with 14 g/dL of hemoglobin. Almost all hemoglobin is saturated with oxygen. B. Blood gas from a patient with cardiopulmonary disease producing cyanosis in which only 9 g/dL of hemoglobin is capable of oxygen transport. C. Methemoglobin concentration of 28% in an otherwise normal individual will reduce hemoglobin available for oxygen transport to less than 9 g/dL (approximately 4 g/dL of methemoglobin and 1.3 g/dL of high-oxygen-affinity hemoglobin because of the left shift of the oxyhemoglobin dissociation curve). D. The same degree of methemoglobin as in C but in a patient with a hemoglobin of 10 g/dL. Only 6 g/dL of hemoglobin would be capable of oxygen transport. E. Methemoglobinemia and anemia to the same degree as D but in a hypoxic patient.

CHAPTER 94

TABLE 94–2. Signs and Symptoms Typically Associated with Methemoglobin Concentrations in Healthy Patients with Normal Hemoglobin Concentrations Methemoglobin Concentration (%) 1–70

Signs and Symptoms None Possibly none Slate gray cutaneous coloration Pulse oximeter will read low SaO2 Cyanosis Chocolate brown blood Dyspnea Exercise intolerance Headache Fatigue Dizziness, syncope Weakness Tachypnea Metabolic acidosis Dysrhythmias Seizures CNS depression Coma Grave hypoxic symptoms Death

METHEMOGLOBINEMIA

1443

deal with methemoglobin interference. The clinician, therefore, needs to understand both how the particular pulse oximeter in use handles methemoglobin and that cooximetry determination is needed when methemoglobinemia is suspected. The pulse oximeter reading in patients with methemoglobinemia may not be accurate, but it may be helpful when it is compared with that of the arterial blood gas: if there is a difference between the measured oxyhemoglobin of the pulse oximeter (SaO2) and the calculated oxyhemoglobin of the arterial blood gas (PO2), then a “saturation gap” exists. The calculated PO2 will be greater than the measured SaO2 if methemoglobin is present (Table 94–3). Hyperlipidemia also interferes with accurate cooximetry determination. Triglyceride levels above 500 mg/dL cause the instrument to indicate falsely elevated methemoglobin levels. When triglycerides are present, lipemic serum should be washed free of this interfering substance in order to evaluate for methemoglobinemia.55,78 Methylene blue causes a transient decrease in the pulse oximetry reading because of its blue color and excellent absorption at 660 mm.45,47,83

ACQUIRED METHEMOGLOBINEMIA AND INFANCY ments have expanded the spectrum at which they read and are also able to read fetal hemoglobin and sulfhemoglobin.22,86 The pulse oximeter applied to a patient’s finger at the bedside was developed to estimate oxygen saturation trends in critically ill patients. The device takes advantage of the unique absorptive characteristics of oxyhemoglobin and deoxyhemoglobin and the different concentrations of these two hemoglobin species during different phases of the pulse. Each manufacturer has calibrated its oximeter using volunteers breathing progressively hypoxic gas mixtures.68,75,81 In other words, the oxygen saturation values displayed by the pulse oximeter are derived from comparison with these experimentally derived tables. Methemoglobin interferes with pulse oximetry in a complicated fashion. Like the cooximeter, the pulse oximeter reads absorbance of light at wavelengths of 660 nm and 940 nm, which are chosen to efficiently separate oxyhemoglobin and deoxyhemoglobin. However, methemoglobin absorption at these wavelengths is greater than that of either oxyhemoglobin or deoxyhemoglobin.3,60 Therefore, when methemoglobin is present, tables that do not take into account the presence of methemoglobin are inaccurate. The degree of inaccuracy is unique for each brand of instrument. In the dog model, the pulse oximeter oxygen saturation (SaO2) values drop with increasing methemoglobin levels. This fall in (SaO2) is not exactly proportional to the fraction of methemoglobin, however, as the pulse oximeter overestimates the level of real oxygen saturation. For example, in the case when the methemoglobin level measured in the blood using a cooximeter was 20%, the pulse oximeter indicated an SaO2 of 90%. However, as the methemoglobin concentration approached 30%, the pulse oximeter saturation values approached 85% and then leveled off regardless of how high the methemoglobin level increased.3,80 From our experience and that of others,30,79 much lower levels of oxygen saturation (SaO2) than 85% can occur by pulse oximetry when methemoglobin levels rise above 30%. These differences result from variations in the way different model pulse oximeters

Infants are more susceptible to methemoglobinemia than adults. An infant’s NADH methemoglobin reductase is not fully active until 4 to 6 months of age.61 Infants who are bottle-fed may be exposed to nitrates and nitrites in well water, and additionally, infants have a relatively large body surface area, making adsorption of oxidants more of a threat to them than adults. Methemoglobinemia of unknown origin is often reported in infants.66,71,85 The patients are usually ill for other reasons such as dehydration, acidosis, diarrhea, and hyperchloremia with an associated methemoglobinemia.31 These infants can have methemoglobin levels in the 20 to 67% range with severe consequences. Most of these patients are very young (under 6 months), and many are small for their age.37

METHEMOGLOBINEMIA AND HEMOLYSIS The enzyme defect responsible for oxidant-induced hemolysis is glucose-6-phosphate dehydrogenase deficiency. A review of hemolysis shortly after the discovery of this enzyme defect addressed the confusion regarding the relationship of hemolysis and methemoglobinemia.6 The review, which stressed the distinctness of these disease entities, was reaffirmed in 1991 (E. Beutler, personal communication). Confusion persists today for a number of reasons. Both hemolysis and methemoglobinemia are caused by oxidant stress, and hemolysis can occur following episodes of methemoglobinemia. Additionally, certain erythrocyte protective mechanisms against oxidants (NADPH production) are the same in two disorders. Furthermore, methylene blue treatment of methemoglobin is reported to produce hemolysis,28,35 although it is not clear if the methylene blue or the oxidant ingested contributes to the methemoglobinemia.

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PART D

TABLE 94–3.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Hemoglobin Oxygenation Analysis

Measuring Device

Source

What is Measured

How Are Data Expressed?

Benefits

Pitfalls

Insight

Blood gas analyzer

Blood

Partial pressure of dissolved oxygen in whole blood

PO2

Also gives information about pH and PCO2

If gap exists between ABG and pulse oximeter, an abnormal Hb form may exist

Cooximeter

Blood

SaO2 % MethHb, %CoHb, %OxyHb, %DeoxyHb

Measures hemoglobin species directly

Pulse oximeter

Monitor

Directly measures absorptive charateristics of oxyhemoglobin, deoxyhemoglobin, methemoglobin, carboxyhemoglobin at different wavelength bands in whole blood Absorptive characteristics of oxyhemoglobin in pulsatile blood assuming the presence of only Oxy- and Deoxyhemoglobin in vivo

Calculates SaO2 from the partial pressure of oxygen in serum; inaccurate if forms of Hb other than OxyHb and DeoxyHb are present Provides data on hemoglobin only; most instruments will not measure sulfhemoglobin, HbM, and some other forms of Hb

% Oxy Hb

Moment-tomoment bedside data

Inaccurate data if interfering substances are present: methemoglobin, sulfhemoglobin, carboxyhemoglobin, methylene blue

Maximum depression 75–85% regardless of how much methemoglobin is present

However, oxidants damage the erythrocyte at different locations in the two disease entities. Hemolysis occurs when oxidants damage the erythrocyte by acting directly as electron acceptors or through the formation of hydrogen peroxide or other oxidizing free radicals. Oxidants forming irreversible bonds with sulfhydryl groups of hemoglobin cause denaturation and precipitation of the protein. These precipitates are sufficient quantitatively to form Heinz bodies within the red cell. Cells with large numbers of Heinz bodies are removed by the reticuloendothelial system, producing hemolysis. Alternatively, some oxidants can destroy the erythrocyte membrane directly, causing non–Heinz body hemolysis. Methemoglobinemia does not necessarily progress to hemolysis if unchecked. Numerous cases describe the occurrence of hemolysis following methemoglobinemia, although most poisonings with these compounds do not in fact manifest both types of toxicity. This is reported with dapsone,18,19,58 phenazopyridine (Pyridium),14,21,29,56,74 amyl nitrite,11 and aniline.33,40,50 These instances of combined occurrences may represent the incidental toxicity of an oxidizing agent or represent the depletion of all cellular defenses against oxidants. Currently it is not possible to predict when hemolysis will follow methemoglobinemia with any level of certainty; however, clearly there is an increased incremental risk. Another source of confusion concerning hemolysis and methemoglobinemia is that reduced glutathione (GSH) is required to protect against both. Erythrocytes are able to withstand hemolytic oxidant damage as long as they can maintain adequate levels of reduced glutathione, the principal cellular antioxidant. Glutathione is maintained in its reduced form by using NADPH as its reducing agent. Cells with reduced capacity to produce NADPH (ie, eryth-

Most accurate method to determine oxygen content of blood

rocytes of patients with G-6-PD deficiency or cells with depleted reduced glutathione/NADPH) are thus susceptible to hemolysis. In the presence of methemoglobinemia, reduced glutathione plays a minor role as a reducing agent, but NADPH is necessary for successful antidotal therapy. This codependence on the reducing power of NADPH generated by the hexose monophosphate shunt links the two disorders. Competition for NADPH by oxidized glutathione and exogenously administered methylene blue is postulated to be the cause of methylene blue–induced hemolysis, ie, competitive inhibition of glutathione reduction. The clinical importance of this phenomenon is uncertain. It may be easier to consider hemolysis and methemoglobin formation as subclasses of disorders of oxidant stress. They should be considered separate clinical entities sharing limited characteristics.

MANAGEMENT For most patients with mild methemoglobinemia, no therapy is necessary other than withdrawal of the offending agent and oxygen administration, as reduction of the methemoglobin will occur by means of intact normal reconversion mechanisms (NADH methemoglobin reductase). In the clinical setting, continued absorption, prolonged half-life, and toxic intermediate metabolites may prolong methemoglobinemia. Patients should be examined carefully for signs of physiologic stress related to decreased oxygen delivery to the tissue (Fig. 94–7). Obviously, changes in mental status, such as stupor or lethargy, or ischemic chest pain necessitates immediate treatment, but subtle changes in behavior or inattentiveness also may be signs of global hypoxia and should

CHAPTER 94

Figure 94–7.

METHEMOGLOBINEMIA

1445

Toxicologic assessment of the cyanotic patient.

be treated as well. Abnormal vital signs, such as tachycardia and tachypnea, thought to be caused by tissue hypoxia or the functional anemia of methemoglobinemia, should also be treated aggressively. Patients who develop lactic acidosis or ischemic ECG changes should be treated as well. A methemoglobin level alone is generally not an adequate indication of need for therapy. The most widely accepted treatment of methemoglobinemia is the administration of methylene blue, 1 to 2 mg/kg body weight as a 1% solution, infused IV over 5 minutes. This is 0.1 to 0.2 mL/kg of a 1% solution. The 5-minute infusion helps prevent painful

local responses from rapid infusion. When a painful reaction occurs, it can be minimized by flushing the IV rapidly with at least 15 to 30 mL of fluid following the infusion. Improvement should be noted within 1 hour of methylene blue administration. If cyanosis has not disappeared within 1 hour of the infusion, a second dose should be given, and other factors considered (Fig. 94–8). The use of methylene blue in patients with G-6-PD deficiency is controversial. Deficiency of this enzyme is estimated to be present in 200 million people worldwide. Its incidence in the United States is highest among African Americans (11%).4 For this rea-

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PART D

Figure 94–8.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Management algorithm for patients with suspected methemoglobinemia unresponsive to initial therapy.

son, G-6-PD–deficient patients have been excluded from most treatment protocols because methylene blue is a mild oxidant and case reports have suggested methylene blue’s toxicity. However, because of the lack of immediate availability of the test for G-6PD deficiency, most patients with no known history of G-6-PD deficiency who need treatment receive methylene blue therapy before their G-6-PD status is known. Although many patients with G-6-PD deficiency have undoubtedly been treated unknowingly, few case reports of toxicity have actually been reported. Methylene blue itself is an oxidant, but in an assessment of the hemolytic potency of varied drugs, methylene blue in doses of 390 to 780 mg proved to be only a moderate hemolytic agent.43 Even the authors of the review most frequently cited as a rationale for withholding methylene blue treatment were unsure that the methylene blue that had been given to their G-6-PD–deficient patient produced hemolysis;70 the dose of methylene blue was small in the patient under study, and the patient had taken other agents capable of producing hemolysis. Patients with G-6-PD deficiency have variable activity of the enzyme and manifest different levels of disease in response to oxidant stress. For all of these reasons, the judicious use of methylene blue is warranted in most of these patients, with G-6-PD deficiency and symptomatic methemoglobinemia. If methylene blue treatment fails to significantly relieve the methemoglobinemia, a number of possibilities should be consid-

ered. The cause of the oxidant stress may not have been identified and adequately removed, allowing for continuing oxidation. In such situations, decontamination of the gut (emesis, lavage, activated charcoal, or possibly whole-bowel irrigation) and skin cleansing must be assured. Additional doses of methylene blue are also indicated. Theoretically, exchange transfusion or hyperbaric oxygen may be beneficial when methylene blue is ineffective. Both interventions are time consuming and costly, but hyperbaric oxygen offers the alternative of allowing the dissolved oxygen time to protect the patient while the body reduces methemoglobin. Ascorbic acid has no place in the management of acquired methemoglobinemia because the rate at which it reduces methemoglobin is considerably slower than that of the normal intrinsic mechanisms.9 Methylene blue has no therapeutic effect on sulfhemoglobinemia.65

DAPSONE The treatment of dapsone deserves special consideration because of the frequency in which it is seen in overdose situations and its tendency to produce prolonged methemoglobinemia. The N-hydroxylation of dapsone to its hydroxylamine metabolite by a cytochrome P450–mediated reaction is in part responsible for methemoglobin formation both in therapeutic and overdose situa-

CHAPTER 94

tions. Both the parent compound and it metabolites are oxidants. Cimetidine is an inhibitor of this metabolic pathway and reduces methemoglobin levels during therapeutic dosing.69 In overdose situations, cimetidine may exert some protective effects as well and should be given.

SULFHEMOGLOBIN Sulfhemoglobin is a darkly colored hemoglobin with a sulfur atom incorporated into the heme molecule but not attached to iron. The exact location of the sulfur atom in the porphyrin ring is unclear. Sulfhemoglobin is a darker pigment than methemoglobin, producing cyanosis when only 0.5 g/dL of blood is affected. The cyanosis produced is similar to that produced by methemoglobinemia. It is characterized in the laboratory by its spectrophotometric appearance and its lack of reaction when cyanide is added to the mixture. The methemoglobin absorption peak is eliminated by the addition of cyanide. However, this is not routinely done in clinical laboratory practice, and the diagnosis is often made by the failure to improve with methylene blue. In the laboratory, isoelectric focusing techniques further define the substance. Sulfhemoglobin is an extremely stable compound that is eliminated only when the red blood cell is removed naturally from circulation. Although the oxygen-carrying capacity of hemoglobin is reduced by sulfhemoglobinemia, unlike methemoglobinemia there is a decreased affinity for oxygen in the remaining “unaltered” hemoglobin. This makes oxygen more available to the tissues. The oxyhemoglobin dissociation curve is shifted to the right (see Fig. 20–2). This phenomenon, fortunately, reduces the clinical effect of sulfhemoglobin at the tissue level. Sulfhemoglobin can be produced experimentally in vitro by the action of hydrogen sulfide on hemoglobin and was produced in dogs fed elemental sulfur.49 A number of drugs induce sulfhemoglobin in humans, including acetanilid, phenacetin, nitrates, trinitrotoluene, and sulfur compounds. Most of the drugs that produce methemoglobinemia have been reported in various degrees to produce sulfhemoglobinemia. Sulfhemoglobinemia is also recognized in individuals with chronic constipation and those who purge.49 Table 94–4 lists some differences between methemoglobin and sulfhemoglobin. Sulfhemoglobinemia usually requires no therapy other than the withdrawal of the offending agent. It also appears that patients come to the attention of clinicians earlier because sulfhemoglobinemia produces greater cyanosis than methemoglobinemia at a lower sulfhemoglobin level. There is no antidote for sulfhemoglobinemia because it is an irreversible chemical bond that occurs within the hemoglobin molecule. Exchange transfusion would lower sulfhemoglobin levels, but this approach is usually unnecessary.

SUMMARY Oxidation of hemoglobin is a rare but treatable etiology of cyanosis. In the absence of findings of cardiopulmonary disease, cyanosis from methemoglobinemia is likely. The diagnosis is confirmed by cooximetry evaluation of blood. When treatment is clinically indicated, methylene blue is the treatment of choice. The source of oxidant stress should be sought and eliminated.

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TABLE 94–4. Differences Between Methemoglobin and Sulfhemoglobin

Definition

Clinical appearance

Methemoglobin

Sulfhemoglobin

Commonly accepted: hemoglobin with an oxidized heme moiety Cyanosis, may appear ill Peak absorption at 570 and 620 mm Yes

Less well understood: hemoglobin with sulfur attached through an oxidative reaction Cyanosis, appears less ill at a comparable degree Peak absorption at 520 and 626 mm No

Spectrophotometric characteristics Reversible by antidote Level necessary to detect cyanosis Etiologies

1.5 g/dL

0.5 g/dL

See Table 94–1

Diagnosis

Cooximetry

Effects on oxyhemoglobin dissociation curve

Decreased oxygencarrying capacity, shifts curve to left with impaired O2 delivery to tissues Very good

Similar to methemoglobin, an oxidant and a source of sulfur needed to produce sulfhemoglobin Cyanide added to blood in laboratory will completely eliminate methemoglobin, but not sulfhemoglobin; some newer cooximeters measure directly Decreased oxygencarrying capacity, shifts curve to right, improving O2 delivery to tissue Eliminated only with RBC natural turnover, no specific treatment

Response to treatment

REFERENCES 1. Bacon R: Nitrate preserved sausage meat causes an unusual food poisoning incident. Commun Dis Rep CDR Rev 1997;7:R45–R47. 2. Bakshi SP, Fahey JL, Pierce LE: Sausage cyanosis-acquired methemoglobinemic nitrite poisoning. N Engl J Med 1967;277:1072. 3. Barker SJ, Tremper KK, Hyatt J: Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology 1989;70: 112–117. 4. Beutler E: Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1991;324:169–174. 5. Beutler E: Methemoglobinemia and other causes of cyanosis. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds: William’s Hematology, 5th ed. New York, McGraw-Hill, 1995, pp. 654–663. 6. Beutler E: The hemolytic effect of primaquine and related compounds: A review. J Hematol 1959;14:103–139. 7. Birky M, Malek D, Paabo M: Study of biological samples obtained from victims of MGM Grand Hotel fire. J Anal Toxicol 1983;7: 265–271. 8. Bodansky O: Methemoglobinemia and methemoglobin producing compounds. Pharmacol Rev 1951;3:144–196. 9. Bolyai JZ, Smith RP, Gray CT: Ascorbic acid and chemically induced methemoglobinemias. Toxicol Appl Pharmacol 1972;21:176–185. 10. Bower PJ, Peterson JN: Methemoglobinemia after sodium nitroprusside therapy. N Engl J Med 1975;293:865.

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11. Brandes JC, Bufill JA, Pisciotta AV: Amyl nitrite-induced hemolytic anemia. Am J Med 1989;86:252–254. 12. Caprari P, Bozzi A, Ferroni L, et al: Membrane alterations in G6PDand PK-deficient erythrocytes exposed to oxidizing agents. Biol Med Metab Biol 1991;45:16–27. 13. Chan TY: Food-borne nitrates and nitrites as a cause of methemoglobinemia. Southeast Asian J Trop Med Public Health 1996;27: 189–192. 14. Cohen BL, Bovasso GJ: Acquired methemoglobinemia and hemolytic anemia following excessive Pyridium (phenazopyridine hydrochloride) ingestion. Clin Pediatr 1971;10:537–540. 15. Comly HH: Cyanosis in infants caused by nitrates in well water. JAMA 1945;129:112–116. 16. Craun GF, Greathouse DG, Gunderson DH: Methemoglobin levels in young children consuming high nitrate well water in the United States. Int J Epidemiol 1981;10:309–317. 17. Darling RC, Roughton FJW: The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physiol 1942; 137:56–66. 18. Dawson AH, Whyte IM: Management of dapsone poisoning complicated by methemoglobinemia. Med Toxicol Adverse Drug Exp 1989; 4:387–392. 19. Elonen E, Neuvonen PJ, Halmekoski J, Mattila MJ: Acute dapsone intoxication: A case with prolonged symptoms. Clin Toxicol 1979;14: 79–85. 20. Fibuch EE, Cecil WT, Reed WA: Methemoglobinemia associated with organic nitrate therapy. Anesth Analg 1979;58:521–523. 21. Fincher ME, Campbell HT: Methemoglobinemia and hemolytic anemia after phenazopyridine hydrochloride (Pyridium) administration in end-stage renal disease. South Med J 1989;82:372–374. 22. Fogh-Andersen N, Siggarrad-Andersen O, Lundsgaard FC, Wimberly PD: Diode-array spectrophotometry for simultaneous measurement of hemoglobin pigments. Clin Chim Acta 1987;166:283–289. 23. Fung H: Pharmacokinetic determinants of nitrate action. Am J Med 1984;76:22–27. 24. Gaetani GD, Parker JC, Kirkman HN: Intracellular restraint: A new basis for the limitation in response to oxidative stress in human erythrocytes containing low-activity variants of glucose-6-phosphate dehydrogenase. Proc Natl Acad Sci USA 1974;9:3584–3587. 25. Garrison FH: An Introduction to the History of Medicine, 4th ed. Philadelphia and London, WB Saunders, 1929, pp. 566–567. 26. Gelberg KH, Church L, Casey G, et al: Nitrate levels in drinking water in rural New York State. Environ Res 1999;80:34–40. 27. Gibson QH: The reduction of methaemoglobin in red blood cells and studies on the causes of ideopathic methemoglobin. Biochem J 1948; 42:13. 28. Goldstein BD: Exacerbation of dapsone-induced Heinz body hemolytic anemia following treatment with methylene blue. Am J Med Sci 1974;267:291–297. 29. Greenberg MS, Wong H: Methemoglobinemia and Heinz body hemolytic anemia due to phenazopyridine hydrochloride. N Engl J Med 1964;271:431–435. 30. Gupta PM, Lala DS, Arsura E: Benzocaine-induced methemoglobinemia. South Med J 2000;93:83–86. 31. Hanukoglo A, Danon PN: Endogenous methemoglobinemia associated with diarrheal disease in infancy. J Pediatr Gastroenterol Nutr 1996;23:1–7. 32. Harris JC, Rumack BH, Peterson RG, McGuire BM: Methemoglobinemia resulting from absorption of nitrates. JAMA 1979;242: 2869–2871. 33. Harrison MR: Toxic methemoglobinemia: A case of acute nitrobenzene and aniline poisoning tested with exchange transfusion. Anaesthesia 1977;32:270–272. 34. Hartman AF, Perley AM, Barnett HL: A study of some of the physiological effects of sulfanilamide. II. Methemoglobin formation and its control. J Clin Invest 1938;17:699–710.

35. Harvey JW, Keitt AS: Studies of the efficacy and potential hazards of methylene blue therapy in aniline-induced methemoglobinemia. Br J Haematol 1983;54:29–41. 36. Hegesh E, Hegesh J, Kaftory A: Congenital methemoglobinemia with a deficiency of cytochrome b5. N Engl J Med: 1985;314:757–761. 37. Hjelt K, Lund JT, Scherling B, et al: Methemoglobinemia among neonates in a neonatal intensive care unit. Acta Paediatr 1995;84: 365–370. 38. Hoffman RS, Sauter D: Methemoglobinemia resulting from smoke inhalation. Vet Hum Toxicol 1989;31:40–42. 39. Horne MK, Waterman MR, Simon LM, Garriott JC, Foerster EH: Methemoglobinemia from sniffing butyl nitrite. Ann Intern Med 1979;91:417–418. 40. Johnson CJ, Bonrud PA, Dosch TL, et al: Fatal outcome of methemoglobinemia in an infant. JAMA 1987;257:2796–2797. 41. Katsumata Y, Aoki M, Oya M, et al: Simultaneous determination of carboxyhemoglobin and methemoglobin in victims of carbon monoxide poisoning. J Forensic Sci 1980;25:546–549. 42. Kearney TE, Manoguerra AS, Dunford JV: Chemically induced methemoglobinemia from aniline poisoning. West J Med 1984;140: 282–286. 43. Kellermeyer RW, Tarlov AR, Brewer GJ, et al: Hemolytic effect of therapeutic drugs: clinical considerations of the primaquine-type hemolysis. JAMA 1962;180:128–134. 44. Khan NA, Kruse JA: Methemoglobinemia induced by topical anesthesia: a case report and review. Am J Med Sci 1999;318:415–418. 45. Kirlangitis JJ, Middaugh RE, Zablocki A, Rodriquez F: False indication of arterial oxygen desaturation and methemoglobinemia following injection of methylene blue in urological surgery. Mil Med 1990; 155:260–262. 46. Laney RF, Hoffman RS: Methemoglobinemia secondary to automobile exhaust fumes. Am J Emerg Med 1992;10:426–428. 47. Larsen VH, Freudendal-Pedersen A, Fogh-Andersen NF: The influence of patent blue V on pulse oximetry and haemoximetry. Acta Anesthesiol Scand 1995;39:53–55. 48. Lehman H, Huntsman RG, Cosey R, et al: Hemoglobinopathies associated with unstable hemoglobin. In: Williams JW, Beutler E, Erslev AJ, Lichtman MA, eds: Hematology, 4th ed. New York, McGrawHill, 1995, pp. 650–654. 49. Leroux A, Junien C, Kaplan JC, Bamberger J: Generalized deficiency of cytochrome b5 reductase in congenital methemoglobinemia with mental retardation. Nature 1975;258:619–620. 50. Lubash GD, Phillips RE, Shields JD, Bonsnes RW: Acute aniline poisoning treated by hemodialysis. Arch Intern Med 1964;114: 530–532. 51. Lukens JN: The legacy of well water methemoglobinemia. JAMA 1987;257:2793–2795. 52. Machabert R, Testud F, Descotes J: Methaemoglobinemia due to amyl nitrite inhalation: a case report. Hum Exp Toxicol 1994;13: 313–314. 53. Mansouri A, Lurie AA: Concise review: methemoglobinemia. Am J Hematol 1993;42:7–12. 54. Methemoglobinemia in an infant—Wisconsin. MMWR 1993;42: 217–219. 55. Murray KM, Meth B: Methemoglobin, medline, and hyperlipemia. Crit Care Med 1987;15:797–798. 56. Nathan DM, Siegel AJ, Bunn F: Acute methemoglobinemia and hemolytic anemia with phenazopyridine. Arch Intern Med 1977;137: 1636–1638. 57. Nathan GD, Oski FA: Hematology of Infancy and Childhood, 4th ed. Philadelphia, WB Saunders, 1993, pp. 698–731. 58. Neuvonen PJ, Elonen E, Haapanen EJ: Acute dapsone intoxication: Clinical findings and effect of oral charcoal and hemodialysis on dapsone elimination. Acta Med Scand 1983;214:215–220. 59. Nguyen SI, Cabrales RE, Bashour CA, et al: Benzocaine induced methemoglobinemia. Anesth Analg 2000;90:369–371.

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60. Nijland R, Jongsma HW, Nijhuis JG, et al: Notes on the apparent discordance of pulse oximetry and multiwavelength hemoglobin photometry. Acta Anaesthesiol Scand 1995;107:49–52. 61. Nilsson A, Engberg G, Henneberg S, et al: Inverse relationship between age-dependent erythrocyte activity of methaemoglobin reductase and prilocaine-induced methaemoglobinemia during infancy. Br J Anaesth 1990;64:72–76. 62. Nitzan M, Volovitz B, Topper E: Infantile methemoglobinemia caused by food additives. Clin Toxicol 1979;15:273–280. 63. Odonohue WJ, Moss LM, Angelillo VA: Acute methemoglobinemia induced by topical benzocaine and lidocaine. Arch Intern Med 1980; 140:1508–1509. 64. Paris PM, Kaplan RM, Steward RD, Weiss LD: Methemoglobin levels following sublingual nitoglycerin in human volunteers. Ann Emerg Med 1986;15:171–173. 65. Park CM, Nagel RL: Sulfhemoglobinemia: Clinical and molecular aspects. N Engl J Med 1984;310:1579–1584. 66. Pollack ES, Pollack CV: Incidence of subclinical methemoglobinemia in infants with diarrhea. Ann Emerg Med 1994;24:652–656. 67. Prchal JT, Borgese N, Moore MR, et al: Congenital methemoglobinemia due to methemoglobin reductase deficiency in two unrelated American black families. Am J Med 1990;89:516–522. 68. Ralston AC, Webb RK, Runchiman WB: Potential errors in pulse oximetry. Anaesthesia 1991;46:291–295. 69. Rhodes LE, Tingle MD, Park BK, et al: Cimetidine improves the therapeutic/toxic ratio of dapsone in patients on chronic dapsone therapy. Br J Dermatol 1995;132:257–262. 70. Rosen PJ, Johnson C, Mcgehee WG, Beutler E: Failure of methylene blue treatment in toxic methemoglobinemia. Ann Intern Med 1971; 76:83–86. 71. Sager S, Garyson GH, Feig SA: Methemoglobinemia associated with acidosis of probable renal origin. J Pediatr 1995;126:59–61. 72. Sass MD, Caruso CJ, Farhangi M: TPNH-methemoglobin reductase deficiency: A new red-cell enzyme defect. J Lab Clin Med 1967; 5:760–767.

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73. Schwerd W, Schulz E: Carboxyhemoglobin and methemoglobin findings in burnt bodies. Forensic Sci Int 1978;12:233–235. 74. Sharon M, Puente G, Cohen LB: Phenazopyridine (Pyridium) poisoning: possible toxicity of methylene blue administration in renal failure. Mt Sinai J Med 1986;3:280–282. 75. Sinex JE: Pulse oximetry: principles and limitations. Am J Emerg Med 1999;17:59–66. 76. Smith ER, Smiseth IK, Maryari D, et al: Mechanism of action of nitrates. Am J Med 1984;76:14–22. 77. Smith R, Olson M: Drug-induced methemoglobinemia. Semin Hematol 1973;10:253–268. 78. Spurzem JR, Bonchat HW, Shigeoka JW: Factitious methemoglobinemia caused by hyperlipemia. Chest 1984;88:84–86. 79. Totapally BR, Nolan B, Zureikat G, Inove S: An unusual case of methemoglobinemia in infancy. Am J Emerg Med 1998;16:723–724. 80. Tremper KK, Barker SJ: Using pulse oximetry when dyshemoglobin levels are high. J Crit Illness 1988;11:103–107. 81. Watcha MF, Connor MT, Hing AV: Pulse oximetry in methemoglobinemia: Am J Dis Child 1989;143:845–847. 82. Wendel WB: The control of methemoglobinemia with methylene blue. J Clin Invest 1939;18:179–185. 83. White CD, Weiss LD: Varying presentations of methemoglobinemia: two cases. J Emerg Med 1991;9:45–49. 84. Wintrobe MM, Lee GR: Wintrobe’s Clinical Hematology, 10th ed. Lee GR, ed. Baltimore, Williams & Wilkins, 1999, pp. 1046–1055. 85. Yano SS, Danish EH, Hsia YE: Transient methemoglobinemia with acidosis in infants. J Pediatr 1982;100:415–418. 86. Zijlstra WG, Buursma A, Zwart A: Performance of an automated sixwavelength photometer (Radiometer OSM3) for routine measurement of hemoglobin derivatives. Clin Chem 1988;34:149–152.

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METHEMOGLOBINEMIA

ANTIDOTES IN DEPTH

Methylene Blue Mary Ann Howland Methylene blue is an extremely effective antidote for toxininduced methemoglobinemia. Recently, other actions of methylene blue including inhibition of nitric oxide and guanylate cylase and inhibition of the generation of oxygen free radicals were discovered. These effects are being used to explain methylene blue’s beneficial effects in the hepatopulmonary syndrome, modulation of streptozocin-induced insulin deficiency, and the reduction of the development of surgery-induced peritoneal adhesions.13,14,18,34 Methylene blue was initially recommended for use as an intestinal and urinary antiseptic and subsequently recognized as a weak antimalarial agent.17 In 1933, Williams and Challis successfully used methylene blue to treat aniline-induced methemoglobinemia.43 Methylene blue is tetramethyl thionine chloride,17 which as an electron acceptor is reduced to an elector donor status in the presence of NADPH and NADPH methemoglobin reductase to leukomethylene blue (see Fig. 94–5). Leukomethylene blue then becomes available to reduce methemoglobin to hemoglobin.9,17 In the presence of methylene blue, methemoglobin reduction via this NADPH pathway is dramatically increased (four to five times in dogs), making methylene blue the treatment of choice for methemoglobinemia. Spectrophotometric assays have been used to study the pharmacokinetics of methylene blue and leukomethylene blue.9 Methylene blue has a pKa close to −1, making it completely ionized in the GI tract.10 Administration of 10 mg of methylene blue in capsule form to seven volunteers demonstrated good oral absorption, with an average urinary recovery of 74%.10 The majority of the methylene blue was excreted as a salt complex of leukomethylene blue, whereas the remainder was excreted as the parent product.10 Previous animal experiments suggest that methylene blue is poorly absorbed orally. In a canine model, intravenous administration of increasing doses of methylene blue led to two divergent pharmacokinetic interpretations: a nonlinear single-compartment model and a classic linear two-compartment open model (volume of distribution 0.22–0.87 L/kg; plasma clearance 1.98–2.65 L/kg/h).11 Reports of the apparent paradoxic ability of methylene blue to induce methemoglobinemia suggest an equilibrium between the ability of methylene blue to oxidize hemoglobin directly to methemoglobin and the ability of methylene blue (through the NADPH and NADPH methemoglobin reductase pathway and leukomethylene blue production) to reduce methemoglobin to hemoglobin.4,5 Methylene blue does not produce methemoglobin at doses of 1 to 2 mg/kg. The equilibrium seems to favor the reducing properties of methylene blue unless excessively large doses of methylene blue are given3,16,42 or the NADPH methemoglobin reductase system is abnormal. This equilibrium constant may vary substantially, as 20 mg/kg IV in dogs and 65 mg/kg intraperitoneally in rats failed to produce methemoglobinemia.37

In the earliest studies, 50 to 100 mL of a 1% concentration of methylene blue was used intravenously to evaluate volunteers27 and treat patients with aniline dye–induced methemoglobinemia.43 Methemoglobin levels measured when symptoms were most pronounced were found to be approximately 1.0 g/dL (0.4–8.3% of total hemoglobin) and unlikely to be solely responsible for the adverse effects demonstrated. Other consequential adverse effects included shortness of breath, tachypnea, chest discomfort, burning sensation of the mouth and stomach, initial bluish-tinged skin and mucous membranes, paresthesias, restlessness, apprehension, tremors, nausea and vomiting, dysuria, and excitation. Urine and vomitus had a blue color. This experience led to the recommendation to avoid doses in excess of 7 mg/kg. Methylene blue doses of 1 to 2 mg/kg IV or 65 to 130 mg orally every 4 hours reversed sulfanilamide-induced methemoglobinemia.19,41 With these regimens a very rapid fall in methemoglobin occurred with a disappearance of cyanosis. Later investigations confirmed the effectiveness and safety of IV doses of 1 to 2 mg/kg of methylene blue in reversing the methemoglobinemia produced by sulfanilamide,40 aniline dye,12 and silver nitrate, among other agents.38 In high doses, methylene blue can also induce an acute hemolytic anemia in the absence or presence of methemoglobinemia.16,25 In dose–response studies in G-6-PD–deficient homozygous African American men, daily doses with hemolytic potential were 390 to 780 mg (5.5–11 mg/kg) of methylene blue.24 This was comparable to 15 mg of primaquine base.24 Because of the sensitivity of neonates (HbF and diminished NADH reductase) to these risks, the smallest effective dose should be employed.21,25 Because oxidizing agents can independently result in chemical-induced Heinz body hemolytic anemia, the contribution of methylene blue is often difficult to elucidate.23 Methylene blue is suggested to be ineffective in reversing methemoglobinemia in patients with G-6-PD deficiency33 because the G-6-PD in the hexose monophosphate shunt is essential for the generation of NADPH. Without NADPH, methylene blue cannot act as a reducing agent in the transformation of methemoglobin to oxyhemoglobin. However, G-6-PD deficiency is an X-linked hereditary deficiency with more than 400 variants. The red cells containing the more common G-6-PD A
variant found in 11% of African Americans retain 10% residual activity, mostly in younger erythrocytes and reticulocytes. The enzyme is barely detectable in those of Mediterranean descent who have inherited the defect. Therefore, it is impossible to predict before the use of methylene blue who will or will not respond and to what extent. Currently it appears that most individuals have adequate G-6-PD and do not express deficiency states in absolute but only in relative terms. This variable expression of their deficiency allows an effective response to most oxidant stresses. A risk-to-benefit ratio must be determined when methylene blue is administered to achieve methemoglobin reversal. However, when therapeutic doses of methylene blue fail to have an impact on the methemoglobin level, the possibility of G-6-PD deficiency should be considered. Further doses of methylene blue should not

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be administered in these cases because the risk of methylene blueinduced hemolysis exists in the absence of any potential benefit. In these cases, exchange transfusion and hyperbaric oxygen are potential alternatives (Chap. 94). Theoretically normal cells might convert methylene blue to leukomethylene blue, and the leukomethylene blue might diffuse into G-6-PD–deficient cells and achieve methemoglobin reduction to hemoglobin.2 Before it is assumed that G-6-PD deficiency is responsible for continued methemoglobin levels in spite of the administration of methyelene blue, continued toxin absorption and/or continued methemoglobin production must always be excluded. Methylene blue is a dye. It will alter pulse oximeter readings.6 Large doses may interfere with a clinician’s ability to detect a decrease in cyanosis, and therefore, repeat cooximeter readings and arterial blood gas analysis should be used in conjunction with clinical findings. Methylene blue will cause the urine to turn a bluishgreen and may cause dysuria, although it may also be prescibed for dysuria.30 Methylene blue is quite irritating and exceedingly painful; even without extravasation it may cause local tissue damage.31 Subcutaneous and intrathecal administration are contraindicated.31 After IV access was unobtainable, intraosseous administration of 0.3 mL of a 1% solution (1 mg/kg) over 3 to 5 minutes into the anterior tibia of a 6-week-old infant was well tolerated.20,29 Intraamniotic injection of methylene blue may result in a number of different adverse effects, including infants born with skin dyed blue, leading to inaccurate pulse oximetry readings, methemoglobin, hemolysis, phototoxic skin reactions, or intestinal obstruction.6,20,22,25,28,31 One infant exposed in utero at 51⁄2 weeks was born normal.22 When there is continued absorption or slow elimination of the xenobiotic producing the methemoglobinemia, repetitive dosing of methylene blue may be required in conjunction with efforts to decontaminate the GI tract and perhaps stop the formation of the methemoglobin-inducing metabolite with the use of inhibitors of drug metabolism such as cimetidine.7,32 A continuous IV infusion of methylene blue at 0.1 mg/kg/h or 3 to 7 mg/h in a concentration of 0.05% in normal saline has been used.1,36 However, this method of administration has not yet been adequately studied. Methylene blue is indicated when patients are symptomatic from methemoglobinemia. This usually occurs at methemoglobin levels greater than 20% but may occur at lower levels in anemic patients or those with cardiovascular, pulmonary, or central nervous system compromise. Judicious use of methylene blue is warranted in patients with questionable levels of G-6-PD deficiency. Very large doses of methylene blue may produce methemoglobinemia or a hemolytic anemia in the absence of a G-6-PD deficiency, but this is extremely rare at doses of 1 to 2 mg/kg IV. Methylene blue is ineffective in treating other entities such as sulfhemoglobinemia (Chap. 94). In summary, methylene blue is a very effective reducer of xenobiotic-induced methemoglobinemia. When used in the proper dose, adverse reactions are limited, and the onset of action is rapid. Repeat doses are often required when methemoglobin-producing drugs such as dapsone with a long duration of effect are ingested. In most cases, doses of 1 to 2 mg/kg IV given over 5 minutes, followed immediately by a 15- to 30-mL fluid flush to minimize local pain is both effective and relatively safe. In neonates doses of 0.3–1 mg/kg are often effective.21 The onset of action is quite rapid, with effects usually seen within 30 minutes. Methylene blue is available in 10-mL 1% ampules containing 10 mg/mL.

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REFERENCES 1. Berlin G, Brodin B, Hilden J, Martensson J: Acute dapsone intoxication. A case treated with continuous infusion of methylene blue, forced diuresis and plasma exchange. J Toxicol Clin Toxicol 1984–1985; 22:537–548. 2. Beutler E, Baluda M: Methemoglobin reduction: studies of the interaction between cell populations and of the role of methylene blue. Blood 1963;22:323–333. 3. Blass N, Fung D: Dyed but not dead—methylene blue overdose. Anesthesiology 1976;45:458–459. 4. Bodansky O: Methemoglobinemia and methemoglobin-producing compounds. Pharmacol Rev 1951;3:144–196. 5. Bodansky O: Mechanism of action of methylene blue in treatment of methemoglobinemia. JAMA 1950;142:923. 6. Coleman MD, Coleman NA: Drug-induced methaemoglobinemia. Drug Safety 1996;14:394–405. 7. Coleman MD, Rhodes LA, Scott AK, et al: The use of cimetidine to reduce dapsone-dependent methemoglobinemia in dermatitis herpetiformis patients. Br J Clin Pharmacol 1992;34:244–249. 8. Crooks J: Haemolytic jaundice in a neonate after intra-amniotic injection of methylene blue. Arch Dis Child 1982;57:872–886. 9. DiSanto AR, Wagner JG: Pharmacokinetics of highly ionized drugs. I: Methylene blue—whole blood, urine and tissue assays. J Pharm Sci 1972;61:598–602. 10. DiSanto AR, Wagner JG: Pharmacokinetics of highly ionized drugs. II: Methylene blue—absorption, metabolism and excretion in man and dog after oral absorption. J Pharm Sci 1972;61:1086–1090. 11. DiSanto AR, Wagner JG: Pharmacokinetics of highly ionized drugs. III: Methylene blue—blood levels in the dog and tissue levels in the rat following intravenous administration. J Pharm Sci 1972;61: 1090–1094. 12. Etteldorf JN: Methylene blue in the treatment of methemoglobinemia in premature infants caused by marking ink. J Pediatr 1951;38:24–27. 13. Fallon MB: Methylene blue and cirrhosis: pathophysiologic insights, therapeutic dilemmas. Ann Intern Med 2000;133:738–740. 14. Galili Y, Ben-Abraham R, Rabau M, et al: Reduction of surgeryinduced peritoneal adhesions by methylene blue. Am J Surg 1998;175: 30–32. 15. Geiger JC: Cyanide poisoning in San Francisco. JAMA 1932;99: 1944–1945. 16. Goluboff N, Wheaton R: Methylene blue-induced cyanosis and acute hemolytic anemia complicating the treatment of methemoglobinemia. J Pediatr 1961;58:86–89. 17. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan, 1941, p. 869. 18. Haluzik M, Neduidkova J, Skrha J: Endocrine Research 1999;25: 163–171. 19. Harman A, Perley A, Barnett H: A study of some of the physiological effects of sulfanilamide. II: Methemoglobin formation and its control. J Clin Invest 1938;17:699–710. 20. Herman M, Chyka P, Butler A, Rieger S: Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med 1999; 33:111–113. 21. Hjelt K, Lund JT, Scherling B, et al: Methemoglobinemia among neonates in a neonatal intensive care unit. Acta Pediatr 1995;84: 365–370. 22. Katz Z, Lancet M: Inadvertent intrauterine injection of methylene blue in early pregnancy. N Engl J Med 1981;304:1427. 23. Kearney T, Manoguerra A, Dunford JV: Chemically induced methemoglobinemia from aniline poisoning. West J Med 1984;140: 282–286. 24. Kellermeyer RW, Tarlov A, Brewer G, et al: Hemolytic effect of therapeutic drugs. JAMA 1962;180:128–134. 25. Kirsch I, Cohen M: Heinz body hemolytic anemia from the use of methylene blue in neonates. J Pediatr 1980;96:276–278.

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26. McEnerney JK, McEnerney LN: Unfavorable neonatal outcome after intra-amniotic injection of methylene blue. Obstet Gynecol 1983;61: 35S–37S. 27. Nadler JE, Green M, Rosenbaum A: Intravenous injection of methylene blue in man with reference to its toxic symptoms and effect on the electrocardiogram. Am J Med Sci 1934;188:15–21. 28. Nicolini U, Monni G: Intestinal obstruction in babies exposed in utero to methylene blue. Lancet 1990;336:1258–1259. 29. Orlowski JP, Porembka DT, Gallagher JM, et al: Comparison study of intraosseous, central intravenous, and perpheral intravenous infusions of emergency drugs. Am J Dis Child 1990;144:112–117. 30. Prischl F, Hofinger I, Kramar R: Fever, shivering . . . and blue urine. Nephrol Dial Transplant 1999;14:2245–2246. 31. Raimer S, Quevedo E, Johnston R: Dye rashes. Cutis 1999;63: 103–106. 32. Rhodes LE, Tingle MD, Park BK, et al: Cimetidine improves the therapeutic/toxic ratio of dapsone in patients on chronic dapsone therapy. Br J Dermatol 1995;132:257–262. 33. Rosen PJ, Johnson C, McGehee WG, Beutler E: Failure of methylene blue treatment in toxic methemoglobinemia. Ann Intern Med 1971; 76:83–86. 34. Schenk P, Madl C, Rezaie-Majd S, et al: Methylene blue improves hepatopulmonary syndrome. Ann Intern Med 2000;133:701–706. 35. Serota FT, Bernbaum JC, Schwartz E: The methylene blue baby. Lancet 1979;2:1142–1143.

36. Southgate HJ, Masterson R: Lessons to be learned: A case study approach. Prolonged methemoglobinemia due to inadvertent dapsone poisoning; treatment with methylene blue and exchange transfusion. J Royal Soc Promotion Health 1999;119:52–55. 37. Stossel TP, Jennings RB: Failure of methylene blue to produce methemoglobinemia in vivo. Am J Clin Pathol 1966;45:600–604. 38. Strauch B, Buch W, Grey W, et al: Successful treatment of methemoglobinemia secondary to silver nitrate therapy. N Engl J Med 1969; 281:257–258. 39. Troche BI: The methylene blue baby. N Engl J Med 1989;320: 1756–1757. 40. Wendel WB: The control of methemoglobinemia with methylene blue. J Clin Invest 1939;18:179–185. 41. Wendel WB: Use of methylene blue in methemoglobinemia from sulfanilamide poisoning. JAMA 1937;109:1216. 42. Whitwam JG, Taylor AR, White JM: Potential hazard of methylene blue. Anesthesiology 1979;34:181–182. 43. Williams JR, Challis FE: Methylene blue as an antidote for aniline dye poisoning. J Lab Clin Med 1933;19:166–171. 44. Yiu P, Robin J, Pattison CW: Reversal of refractory hypotension with single dose methylene blue after coronary artery bypass surgery. J Thorac Cardiovasc Surg 1999;118:195–196.

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95

SIMPLE ASPHYXIANTS AND PULMONARY IRRITANTS Lewis S. Nelson

On a daily basis our bodies are exposed to a variety of potentially damaging external influences. Although most organs remain relatively protected from such influence, the skin and respiratory tract, by their nature, maintain constant contact with the external environment. At rest, the respiratory tract encounters nearly 3000 L of air during a typical 8-hour workday, and even mild exertion can triple the volume inhaled. Several critical mechanisms exist within the respiratory system to prevent or minimize toxicity from without and allow humans to breathe safely in what potentially is a hostile environment. Although these efficient mechanisms provide substantial protection under normal circumstances, they may be overburdened occasionally. Additionally, the lungs are also a common portal of entry for systemic toxins that have no pulmonary effects; the best examples of these are lead (Chap. 80), carbon monoxide (Chap. 97), and cyanide (Chap. 98). The respiratory tract, as discussed in Chapter 20, performs several important physiologic functions. Its most important role involves the transfer of oxygen to hemoglobin across the pulmonary endothelium. This facilitates oxygen distribution throughout the body to permit effective cellular respiration. Diverse toxins may act at unique points in this distribution pathway to produce tissue hypoxia. For example, toxins such as opioids or paralytic agents may induce hypoventilation, whereas carbon monoxide or methemoglobin inducers may prevent binding of oxygen to hemoglobin. Certain toxins prevent adequate oxygenation of hemoglobin at the level of pulmonary gas exchange. Two mechanistically distinct groups of agents are capable of interfering with gas exchange: simple asphyxiants and pulmonary irritants. Impairment of transpulmonary oxygen diffusion, regardless of the etiology, reduces the oxygen content of the blood and can result in tissue hypoxia.

SIMPLE ASPHYXIANTS Case 1 A 50-year-old medical researcher was discovered dead in a small refrigerated room that contained 15 new 10-cubic-inch blocks of dry ice. The dry ice was stored in the refrigerator (4°C, 39.2°F) at approximately 9 AM on the day of the scientist’s death. The researcher was last seen at approximately noon, suggesting that at least 3 hours had elapsed between the initial dry ice storage and his first exposure. Scene analysis suggested that at the time of his death the decedent was crouching several inches from the ground to store samples in a container. There were no signs of struggle, and the decedent had no history of psychiatric disorders, recent personal crises, or medical illnesses.

Postmortem examination of the decedent was unrevealing, as was the toxicologic evaluation. A blood PCO2 was not performed because of its well–described rapid postmortem rise. In order to confirm the cause of death, the conditions at the time of the event were reproduced using the same cold room. Air was sampled serially at several heights; the O2 concentration fell and the CO2 concentration rose within 20 minutes and peaked by 3 hours. The FIO2, 3 hours after dry ice storage, was 13.6%, and the CO2 concentration was 27.6%, both at a height of 9 inches. Concentrations of 20 to 30% (200,000–300,000 ppm) CO2 are associated with the rapid development of unconsciousness and death. Additionally, the temperature of the room had fallen to
15°C (5°F). Thus, it appears that even at the cold temperatures of the cold room, sublimation of dry ice progresses rapidly.

Pathophysiology Simple asphyxiants displace oxygen from ambient air, thereby reducing the fraction of oxygen in air, or FIO2, below 21%, resulting in a fall of the partial pressure of oxygen. The partial pressure is a measure of the oxygen contribution to the total inspired air and is based on both the FIO2 and the barometric pressure. For example, because the ambient pressure at sea level (less water vapor, 47 mm Hg) is 713 mm Hg, and the percentage of oxygen is 21%, the partial pressure of oxygen is 150 mm Hg. Under these typical conditions, the FIO2 is a suitable surrogate for the partial pressure of oxygen. However, this relationship is not applicable at other barometric pressures. For example, at the summit of a mountain, the reduced barometric pressure results in a fall in the partial pressure of oxygen despite a near normal FIO2. This reduced partial pressure may be insufficient to allow an adequate oxygen saturation, and supplemental oxygen becomes necessary. As barometric pressure falls, exposure to simple asphyxiant gases may further reduce the oxygen partial pressure to life-threatening levels. Conversely, underwater divers could, in theory, reduce their FIO2 to less than 21% by adding simple asphyxiant gases, such as helium, to their breathing mixture and still maintain adequate oxygenation. This is because the elevated barometric pressure raises the partial pressure of oxygen to normal levels despite the addition of an asphyxiant gas. However, systemically poisonous gases that entered the breathing mixture would have a magnified effect, given their increased partial pressure at depth. In general, simple asphyxiants have no pharmacologic activity. For this reason, exceedingly high ambient concentrations of these gases are necessary to produce asphyxia. Asphyxiation occurs when one is working in confined spaces or with extremely concen-

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trated forms of the simple asphyxiants. The widespread use of liquefied gas, which expands several hundred-fold on depressurization or warming, accounts for a substantial number of workplace injuries. 105,152

cryogenic liquids, which expand rapidly to their gas phase on decompression. The liberation of these agents in closed spaces may result in asphyxiation or freezing injuries. Xenon has unique anesthetic properties because of its high lipid solubility; the other noble gases have no direct toxicity.

Clinical Manifestations A patient exposed to any simple asphyxiant gas will develop characteristic symptoms of hypoxia (Table 95–1), which are directly related to the partial pressure of the gas in the air or, more correctly, to the reduction in ambient oxygen partial pressure.105 Cardiovascular and central nervous system complications of simple asphyxiants predominate, as they are the organ systems with the greatest oxygen requirements, but as hypoxemia becomes severe, multi-system organ failure and death may occur.32 Under most circumstances, however, carbon dioxide exchange is not impaired, and hypercapnia does not occur. Because dyspnea develops more rapidly from hypercapnia than hypoxemia, the breathlessness associated with physical asphyxiation does not develop until severe hypoxemia intervenes.68,96 Thus, as likely occurred in the above case, victims may succumb to hypoxemia without the development of the expected warning symptoms.

Specific Agents Noble Gases: Helium, Neon, Argon, Xenon. Noble gases, stored almost exclusively in the compressed form, are employed in numerous industrial and medical roles. Argon is predominantly used as a shielding gas during welding operations, and neon is utilized in lighting manufacture. Xenon, in its radioactive gaseous form, finds diagnostic medical applications in ventilation–perfusion scans. Helium has the lowest molecular weight and is the smallest member of the noble gas family of elements. Because of its lower lipid solubility, helium is used by underwater divers to replace nitrogen to prevent nitrogen narcosis at depth (see Nitrogen). Even at diving gas mixtures of 50% helium, divers suffer no adverse effects as long as a normal partial pressure of oxygen is maintained in the mixture.The fact that helium has a lower density than nitrogen results in a lower viscosity, or a marked decrease in flow resistance. This property of helium is the basis for its use in patients with increased airway resistance, such as asthmatics, and also facililtates breathing by divers at depth, where the volume of air inspired per breath is severalfold greater than that at sea level. Similarly, helium’s low viscosity has led to its utilization as an inflation gas for an intraaortic balloon, where rapid inflation and deflation is critical. All noble gases, when compressed, form

TABLE 95–1. Clinical Findings Associated with a Reduction of Inspired Oxygen FIO2ab (%)

Symptoms/Signs

16–12

Tachypnea, hyperpnea (resultant hypocapnia), tachycardia, reduced attention and alertness, euphoria, headache, mild incoordination Altered judgment, incoordination, muscular fatigue, cyanosis Nausea, vomiting, lethargy, air hunger, severe incoordination, coma Gasping respiration, seizure, coma, death

14–10 10–6 10% TLV–TWA = 50 ppm Values greater than or equal to the action level usually necessitate clinical intervention. Values less than this level may necessitate intervention based on the clinical condition of the patient.

A 35-year-old woman was found sitting outside of a warehouse. Her boss stated that she had been operating a forklift in an enclosed building all morning. She came stumbling out complaining of dizziness and headaches. Coworkers in an adjoining building also complained of mild headache. After collapsing outside, she regained consciousness immediately but still appeared confused to coworkers. Prehospital personnel started an IV of 0.9% sodium chloride and placed her on 100% oxygen at the scene before transport. On arrival at the ED, the patient was still somewhat drowsy, oriented only to person and place, and complaining of a severe headache. Initial vital signs were: blood pressure 92/58 mm Hg, pulse 112 beats/min, respirations 26 breaths/min, and rectal temperature 100°F (38°C). Examination of the head revealed midsize reactive pupils with a supple neck. Chest examination revealed clear lungs with a regular tachycardia. Neurologic examination revealed good strength and sensation bilaterally with normal reflexes. The patient refused to stand because of weakness and dizziness. The boss arrived and stated that the patient was probably suffering from the flu or food poisoning. Several other employees had been complaining of similar symptoms all week. This was not surprising because the local health department had reported record cases of influenza A that season. The patient was placed on a cardiac monitor and 100% oxygen by nonrebreather face mask. A fingerstick bedside blood glucose was 80 mg/dL. As the physician obtained a blood specimen for carboxyhemoglobin determination, the patient then related that she had been having palpitations and mild chest pain. An ECG was ordered. Laboratory results finally returned. The ECG revealed normal sinus rhythm without ischemic changes. Arterial blood gas results were: pH 7.32, PCO2 32 mm Hg, PO2 124 mm Hg. Later a carboxyhemoglobin level of 18% returned. Further questioning of EMS personnel revealed that patient transport was delayed, and the patient was on 100% oxygen for at least 30 minutes before the blood drawing in the emergency department. After 2 hours on 100% oxygen, the patient remained somewhat drowsy and still complained of a severe headache. On brief mental status examination the patient was still amnestic for the events that occurred and was oriented only to person and place. She could apparently remember only two out of three objects at 5 minutes. In addition, when standing she still had problems walking a straight

line heel to toe. The health care worker decided to consult a local poison center to see if further neurologic evaluation was warranted. After discussing the case with the poison center, the health care worker felt that she should transfer the patient to the nearest hyperbaric facility for further treatment. The patient was transferred by helicopter, requiring less than one hour to reach the hyperbaric center. On arrival she was fully alert and mentioned her concern for HBO treatment when in fact she might be pregnant. A urine pregnancy test was promptly done, testing positive. After being explained the risks and benefits of the procedure, she decided to proceed with HBO treatment. After one dive, her symptoms improved, but 4 hours later she still complained of a mild headache. A second HBO treatment was recommended by the hyperbaric staff 6 hours after her initial treatment. She refused, stating that she was severely claustrophobic and refused to reenter the confines of the monoplace unit. On the subsequent day the patient felt much better. A bedside mini–mental status examination revealed good attention and memory. A more formal neuropsychological battery revealed no deficiencies. She returned to work in 3 days. At 3-week followup, she reported no untoward symptoms. Seven months later she gave birth to an apparently normal infant boy. The onset of headache and dizziness, especially with involvement of coworkers, strongly suggested an airborne toxin. With poor air circulation, there could be a buildup of various air pollutants, microbial agents, and allergens that could result in sick building syndrome. Although patients suffering from sick building syndrome often have a headache, this is usually accompanied by irritation of the airways and mucous membranes, which would occur with CO poisoning.18 The forklift was a likely culprit for an exposure in this case. Propane, the typical fuel of indoor forklifts, is an asphyxiant and at low doses can cause euphoria232 (Chap. 95). However, the accompanying mercaptans would have alerted workers to a dangerous leak. Nitrogen dioxide, an occasional combustion product of propane, can cause delayed respiratory symptoms but does not typically cause headache.89 The most likely gas exposure responsible for these symptoms is CO. For optimal performance propane-powered forklifts are typically adjusted to produce no less than 10,000 ppm CO in exhaust and in fact average more than 30,000 ppm.60 In an enclosed warehouse,

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with poor ventilation, CO levels could exceed toxic levels within an hour at this rate of production. Workers, as in the case example, would succumb to its toxic effects without warning because CO is a clear, odorless, nonirritating gas.

INTRODUCTION Carbon monoxide (CO) is the leading cause of poisoning morbidity and mortality in the United States. A comprehensive review of death certificate data compiled by the National Center for Health Statistics shows an average of 5613 deaths each year (1979–1988) from CO poisoning.34 More recent estimates show at least 2100 unintentional poisonings each year in the United States.236 A more significant problem may be the morbidity associated with this poisoning. One source has estimated that approximately 10,000 people seek medical attention or lose at least 1 day of normal activity because of CO toxicity each year.178 The most serious complication of this poisoning is persistent or delayed neurologic dysfunction in 14 to 40% of discharged patients.144,190 These numbers may underestimate the real problem because many more patients may be treated and released for a myriad of complaints when in reality they have unrecognized CO poisoning.

EPIDEMIOLOGY Although CO is found naturally in the body as a by-product of hemoglobin degradation, it reaches toxic concentrations following inhalation or by absorption and metabolism following exposure to methylene chloride.35 External sources of CO include incomplete combustion of any carbonaceous fossil fuel. In a 10-year review of CO-related deaths, over half of unintentional deaths were caused by motor vehicle exhaust.34 Occupants of motor vehicles are not the only victims of exhaust gases. Carbon monoxide poisoning is also reported in children riding in the back of pickup trucks.83 Workers also become symptomatic from use of propane-powered equipment indoors such as forklifts57,61 and ice skating rink resurfacers.102 Even occupants of boats are not immune to this insidious toxin.187 In the past 10 years, unintentional CO exposures from nonvehicular sources have resulted in an average of 500 deaths per year in the United States.34 Predominantly, these have involved the burning of charcoal, wood, or natural gas for heating and cooking.41,62,64,82 Furnaces for heating are often the culprits, especially when the flue is blocked.15,76,88 Gas kitchen stoves are an important source of CO in indigent populations with marginal heating systems.193 In fact, the use of gas stoves for supplemental heat is predictive of high COHb levels in patients with headache and dizziness.86 Fires are another important source of CO exposure. In the past 10 years, CO was listed as the cause of or major contributor to 15,523 fire deaths.34 Carbon monoxide is considered to be the most common hazard to smoke inhalation victims.15,46,185,220 Exposure to smoke that may include cyanide, another by-product of fire combustion, can result in morbidity and mortality greater than that predicted by the amount of CO exposure alone13 (Chaps. 96 and 98).

PHARMACOLOGY CO has a molecular mass of 28.01 daltons. It has a gas density 0.968 relative to air. CO is found naturally in the body as a byproduct of heme degradation.35 As a gas, CO appears to be a neu-

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ronal messenger by virtue of the fact that as a gas it can diffuse and signal adjacent cells.9 Heme oxygenase, the responsible enzyme, is primarily found in the liver and spleen, to break down old blood. But a second form is in the brain, where once CO is produced it can behave like nitric oxide (NO), binding to guanylate cyclase and thereby increasing cGMP levels.128 Although low endogenous levels are physiologic, excessive concentrations of CO from exogenous sources may be problematic because CO persists much longer than NO.73

PHARMACOKINETICS AND TOXICOKINETICS Carbon monoxide is readily absorbed after inhalation. The Coburn-Forster-Kane (CFK) model allows the prediction of COHb levels based on exposure history.37 This model has been simplified to allow estimation of the equilibrium based on the ambient concentration of CO in ppm: COHb (%) = 100/[1 + (643.3/ppm CO)].216 This assumes that the individual weighs 70 kg and is not anemic. With exponential uptake, it may take more than 4 hours for equilibrium to be attained. Meanwhile, endogenous production of CO is not factored in because its contribution to COHb is only 2%. Once absorbed, CO is carried in the blood, primarily bound to hemoglobin. The Haldane ratio states that CO has approximately a 200 to 250 times greater affinity than oxygen for hemoglobin.25 Therefore, CO is primarily confined to the blood compartment, but eventually up to 15% of total CO body stores are taken up by tissue, primarily bound to myoglobin.36 The dissolved CO concentration in the serum, therefore, may better reflect the ultimate potential for poisoning, as it is available for diffusion into all tissue compartments, including the brain.123 Elimination of CO, like absorption, from the blood can be modeled mathematically, using the CFK model. The equation predicts a half-life of 252 minutes.37 In actual volunteer studies, means of 249 and 320 minutes have been found.155,161 With 100% oxygen, these half-lives can be reduced significantly to means of 47, 78, and 80 minutes in studies of volunteers who attain COHb levels of 10 to 12%.155,161,199 Two series of patients poisoned with CO showed actual mean half-lives of 74 and 131 minutes when treated with 100% oxygen.19,230 Methylene chloride, a paint-stripping agent, is another source of CO. It is readily absorbed through the skin or by inhalation and is metabolized in the liver to CO.196 After a delay of 8 hours or longer, peak levels of COHb can range from 10 to 50%.59,115,122,171 Because of ongoing production of CO, the apparent COHb halflife is prolonged to 13 hours.169 COHb levels after methylene chloride exposure appear to be proportional to the concentration and duration of exposure.185

PATHOPHYSIOLOGY CO’s most obvious effect is binding to hemoglobin, rendering it incapable of delivering oxygen to the cells, because as previously stated, the affinity for hemoglobin is 200 to 250 times greater than that of oxygen.54 Therefore, in spite of adequate partial pressures of oxygen in blood (PO2 ), there is decreased arterial oxygen content. Further insult occurs because CO causes a leftward shift of the oxyhemoglobin dissociation curve, thus decreasing the of-

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floading of oxygen from hemoglobin to tissue.174 This may result in part from a decrease in erythrocyte 2,3-diphosphoglycerate concentration.7,215 The net effect of all these processes is the decreased ability of oxygen to be carried by the bloodstream and released to cells. Carbon monoxide toxicity cannot be attributed solely to COHb-mediated hypoxia.170 Neither clinical effects nor the phenomena of delayed neurologic deficits can be completely predicted by the extent of binding between hemoglobin and CO.140,149,191,210 Furthermore, it does not explain why negligible levels of COHb (4–5%) can result in cognitive impairment.119 An early study showed that dogs breathing 13% CO died within an hour with COHb levels 54 to 90%; however, exchange transfusion of this same blood into healthy dogs caused no untoward effects.71 Comparable levels of anemia also lacked adverse effects. The conclusion was that inherent to CO toxicity is its delivery to target organs such as the brain and heart.70,71 The delivery of CO intracellularly and its binding to heme proteins other than hemoglobin may also account for its toxicity. Ten to 15% of the total body store of CO is extravascular.36 Some of this CO may be interfering with cellular respiration by binding to mitochondrial cytochrome oxidase, as occurs in vitro.8,26 Initial studies show that this binding is especially exaggerated under conditions of hypoxia and hypotension.20 Inactivation of cytochrome oxidase may be only an initial part of the cascade of events resulting in an ischemic reperfusion injury to the brain after CO poisoning. During recovery from the initial poisoning, white blood cells are attracted to and adhere to the damaged brain microvasculature.212 This attraction may be partly attributable to endothelial changes from initial cytochrome oxidase dysfunction, mediated primarily through the free radical nitric oxide.98,204 Carbon monoxide displaces nitric oxide from platelets that in turn form peroxynitrites, even stronger inactivators of cytochrome oxidase.212 Multiple animal studies show that nitric oxide is ultimately responsible for much of the endothelial damage from CO, which can be blocked by nitric oxide synthase inhibitors.208,211,214 After the leukocytes attach to the damaged endothelium, they release proteases that convert xanthine dehydrogenase to xanthine oxidase, an enzyme that promotes formation of oxygen free radicals.202 The end result of this process is delayed lipid peroxidation of the brain, as demonstrated in a rat model.201 CO neuronal damage may not be a simple matter of cytochrome oxidase inactivation accompanied by ischemic-reperfusion injury. In addition, glutamate increases in rat brains after CO poisoning.239 Glutamate is an excitatory amino acid that can bind at N-methyl-D-aspartate (NMDA) receptors and cause intracellular calcium release, resulting in delayed neuronal cell death.16 Blockade of NMDA receptors can prevent the neuronal death and learning deficits that accompany serious CO poisoning in a mouse.99 Newer data suggest that ultimately CO neuronal cell death may be a form of apoptosis.221 Rises in the glutamate in rat brain in the first hour after severe CO poisoning are followed by a later rise in hydroxyl radicals.162 Ultimately, at 1 to 3 weeks the animals show histologic evidence of both neuronal necrosis and apoptosis in the frontal cortex, globus pallidus, and cerebellum that are accompanied by deficits in learning and memory in a radial maze. The role of apoptosis has been confirmed in bovine pulmonary artery cells, where CO exposure is accompanied by activation of caspase-1, a protease implicated in delayed cell death.207 Confirmatory evidence was provided in the same study in that both caspase-1 and nitric oxide synthase inhibitors blocked apoptosis. The end result

of all these cellular processes is brain injury within the basal ganglia and hippocampus, resulting in impaired learning.205 Thus, animal models correlate well with what ultimately occurs in victims of serious CO poisoning, namely, the learning and memory deficits so common in persistent or delayed neurologic sequelae. Myoglobin is another heme-protein that binds CO with an affinity about 60 times greater than that of oxygen.38 A dog model demonstrates that this binding is enhanced under hypoxic conditions.38 This binding may partially explain the myocardial impairment that occurs in both animal studies43 and low-level exposures in patients with ischemic heart disease.6 Isolated rat heart studies demonstrate that this toxic effect on the heart exists regardless of COHb formation.27 The combination of COHb formation, which decreases oxygen-carrying capacity, and the production of reduced myoglobin in the heart, which decreases oxygen extraction, may explain the preterminal dysrhythmias seen in animal studies.66 Volunteers, especially those with preexisting heart disease, develop an increase in life-threatening dysrhythmias and ischemic changes with low-level exposures (resulting in COHb levels up to 6%) during stress testing.2,183 Several recent studies suggest that CO effects on the cardiovascular system are necessary for ischemic reperfusion injury of the brain. Hypotension, essential for ischemic reperfusion injury, results from a combination of myocardial depression from carboxymyoglobin formation and vasodilation from cellular effects of CO. Carbon monoxide is a presumed neural messenger that activates guanylate cyclase, which in turn relaxes vascular smooth muscle.224,226 Also, CO can act on platelets to displace nitric oxide, which in turn is also a potent vasodilator.111,206 These factors contribute to the hypotension that occurs in animal experiments with high doses of CO toxicity.69,78 Such an episode of hypotension may be represented clinically by the syncope or loss of consciousness that accompanies serious CO poisoning and portends a worse clinical outcome.31,63,134 In the rhesus monkey, cerebral white matter lesions correlate better with decreases in blood pressure than with COHb level.69,150 Lipid peroxidation of the brain in rats develops an hour after a CO exposure that has terminated in syncope and hypotension.201 This delay is comparable to that necessary to produce mitochondrial destruction from oxidative stress in rats exposed to CO.238 In a feline model, central nervous system damage comparable to that associated with CO can be reproduced only when hypoxia is accompanied by one interval of ischemia, confirming the ischemic-reperfusion model for central nervous system insult after CO poisoning.151

CLINICAL MANIFESTATIONS Effects of Acute Exposure The earliest symptoms associated with CO poisoning are often nonspecific and readily confused with other illnesses, typically viral syndromes23 (Table 97–1). The initial symptom reported by volunteers within 4 hours of exposure to 200 ppm COHb levels (15–20%) is headache; shorter exposures at 500 ppm lead to nausea as well.197,198 The incidence of CO poisoning in symptomatic patients presenting with flulike symptoms to emergency departments in the winter ranges from 3 to 24% in some series.29,53,85,86 Because the typical presenting complaints are headache, dizziness, and nausea, and the most frequent exposures occur during winter, it is not surprising that influenza is the most common misdiagnosis.53,76 Carbon monoxide poisoning is also frequently misdiag-

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TABLE 97–1. Clinical Manifestations of Carbon Monoxide Poisoning Severity

Symptoms

Signs

Mild

Headache Nausea Dizziness Confusion Chest pain Dyspnea Weakness Blurred vision Chest pain Palpitations Disorientation

Vomiting

Moderate

Severe

Tachypnea Tachycardia Cognitive deficits Ataxia Myonecrosis Coma Seizures Ventricular dysrhythmias Hypotension Myocardial ischemia

nosed as food poisoning,11 gastroenteritis,64,93 and even colic in infants.163 Children tend to show nonspecific symptoms, eg, nausea, headache, and vomiting, with CO poisoning, making the diagnosis equally difficult.44 Continued exposure to CO can lead to symptoms attributable to another extremely oxygen-dependent organ, the heart. Lowlevel exposures (COHb 2–4%) in volunteers with stable angina result in decreased exercise tolerance as well as signs and symptoms of myocardial ischemia.2,3,5 At higher levels (COHb 6%) there is a greater frequency of premature ventricular contractions during exercise.183 Myocardial infarction, life-threatening dysrhythmias, and cardiac arrest are commonly described in victims of CO poisoning.4,127,179,188 In fact, acute mortality from CO is usually a result of ventricular dysrhythmias, probably predominantly caused by the accompanying hypoxia.2,4,43,179 The central nervous system is the most sensitive area to CO poisoning. Acutely, otherwise healthy patients may manifest headache, dizziness, and ataxia at COHb levels as low as 15 to 20%; with longer exposures, syncope, seizures, or coma can result.23,90 Patients may present with symptoms of an acute stroke.11,105 The EEG can show diffuse frontal slow-wave activity.63,148 Within a day of exposures that result in coma, the CT scan can show decreased density in the central white matter and globus pallidus (Fig. 97–1).186,217 Autopsies show involvement of other areas including the cerebral cortex, hippocampus, cerebellum, and substantia nigra.116 Metabolic changes may reflect CO’s toxic effects better than any particular COHb level. Mild CO cases may be accompanied by respiratory alkalosis to compensate for the reduction in oxygen-carrying capacity and delivery.130 Longer exposures with decreased levels of consciousness result in metabolic acidosis, from the lactate production that accompanies tissue hypoxia.191 In fact, a series of 48 CO poisoned cases showed retrospectively that hydrogen ion concentration, rather than COHb level, was a better predictor of poor recovery during initial hospitalization.223 Although the brain and heart are the most sensitive, other organs may also manifest the effects of CO poisoning. One-fifth to one-third of severe CO cases, ie, those that required intubation, go on to develop cardiogenic pulmonary edema.75,192 This does not appear to be a direct effect of CO. Studies of sheep with prolonged exposure to CO, resulting in COHb levels greater than 50%, showed no anatomic or physiologic change in lung function.184 Al-

Figure 97–1. Computerized tomography of the brain showing bilateral lesions of the globus pallidus (lucent areas) in a patient with poor recovery from severe CO poisoning. (Courtesy of New York City Poison Center Fellowship in Medical Toxicology.)

though myonecrosis and even compartment syndromes occur, patients rarely develop renal failure.14,182 Retinal hemorrhages can develop with exposures greater than 12 hours.48,105 Cherry-red skin coloration occurs only after excessive exposure (2–3% of cases referred to one hyperbaric center) and may represent a combination of CO-induced vasodilation with concomitant tissue ischemia.144,172 Another classic but uncommon phenomenon is the development of cutaneous bullae following severe exposures.144 These bullae are thought to be caused by a combination of pressure necrosis and possibly direct CO effects in the epidermis.95,120

Delayed Effects The persistent or delayed effects of CO poisoning are varied and include dementia, amnestic syndromes, psychosis, parkinsonism, paralysis, chorea, cortical blindness, apraxia and agnosias, peripheral neuropathy, and incontinence.65,121 The neurologic deterioration can be preceded by a lucid period of 2 to 40 days after the initial CO poisoning.31 In patients admitted to an intensive care unit for severe CO toxicity and treated with 100% oxygen, 14% of survivors had permanent neurologic impairment.111 In a Korean series of 2360 CO-poisoned patients, almost 3% continued to show memory failure or parkinsonian features 1 year postexposure.31 In contrast, another series of 63 seriously poisoned patients showed memory impairment in 43% and deterioration of personality in 33% at 3-year followup.190 Children have shown behavioral and educational difficulties after severe poisoning.114 However, older patients (more than 30 years old) appear to be much more susceptible to developing delayed sequelae.31 Most cases of delayed neurologic sequelae are associated with loss of consciousness in the acute phase of intoxication.31,63,190 Delayed neurologic sequelae probably involve lesions of the cerebral white matter and basal ganglia.65 Weeks postexposure,

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autopsies show necrosis of the white matter, globus pallidus, cerebellum, and hippocampus.63 Computerized tomography and MRI confirm the damage to the white matter and hippocampus.94,150,186,217 Animal studies show that marked COHb alone cannot cause similar white-matter lesions; there must be an episode of hypotension.69,151 The fact that the areas permanently damaged in serious CO poisoning cases are the areas with the poorest vascular supply in the brain is consistent with these animal findings.

Effects of Chronic Exposure Often, patients will complain of persistent headaches and cognitive problems after long-term exposure to low levels of carbon monoxide. Unfortunately, to date, there are no controlled studies showing that such exposures, in the absence of a severe acute poisoning episode, result in any long-term sequelae. With continued exposure to low levels of CO, highway toll workers have trouble performing on parallel processing tasks.101 Warehouse workers, chronically exposed to CO from propane combustion, have intermittent problems with headache, nausea, and lightheadedness.57 However, unless there has been an episode of severe poisoning with acute deterioration, most workers go on to have resolution of their symptoms.60 Without baseline testing before exposure, it is hard to definitely attribute one woman’s permanent verbal memory, learning, and visual recall problems to long-term CO exposure. She had had ongoing headache, depression, and confusion from a 3-year exposure to CO at 180 ppm from a faulty furnace.176 Although it is unclear that chronic exposure to low levels of CO can do any damage, healthcare providers still should be vigilant for symptomatic individuals in order to prevent continued or catastrophic outcomes.

DIAGNOSTIC TESTING The most useful diagnostic test obtainable in a suspected CO poisoning is a COHb level. Normal levels of COHb range from 0 to 5%, with levels at the high range in neonates and patients with hemolytic anemia,234 as carbon monoxide is a natural by-product of the breakdown of protoporphyrin to bilirubin.35 Carboxyhemoglobin levels average 6% in one-pack-per-day smokers but can range as high as 10%.195 Although high COHb levels confirm exposure to CO, particular levels are not necessarily predictive of symptoms or outcome. In fact, COHb can return to normal or be zero if the patient has been treated with oxygen before obtaining the blood test.140,149,191 The usual method for measuring COHb is with a CO-oximeter, which spectrophotometrically reads the percentage of total hemoglobin saturated with CO.12,39 Traditionally, arterial blood is used for this determination; however, venous blood levels from a heparinized (lithium heparin tube) specimen are just as accurate.219 Of note, refrigerated heparinized samples yield accurate carboxyhemoglobin levels for several weeks, making retrospective evaluations possible.52 Bedside tests with ammonia or sodium hydroxide are unable to differentiate reliably various levels of COHb versus controls.153 Breath-sampling methods may be used for screening patients; however, ethanol, a common cointoxicant, can falsely elevate breath levels unless an activated charcoal filter is used.113,161,222 Because of the similarities in extinction coefficients, COHb is misinterpreted as oxyhemoglobin on pulse oximetry (Chap. 20).10 The pulse oximetry reading overestimates oxyhemo-

globin by the approximate amount of carboxyhemoglobin present.22,80 Recently, some clinicians have begun to measure CO directly in blood samples, rather than carboxyhemoglobin.123 This technique involves assaying CO directly with infrared spectrophotometry after it is extracted from the blood sample with a manometer.138 Based on calculations, rather than true experimental data, the assumption has been made that for a patient with a normal hemoglobin, a CO concentration of 1 mmol/L corresponds to 11% COHb.154 A simpler method to measure plasma CO content is to add a known solution of hemoglobin followed by sodium dithionite to form COHb.30 The resulting COHb is measured spectrophotometrically, with the assumption that 1 mole of hemoglobin binds 4 moles of CO. Interestingly, in one study, plasma CO ranged 0.14 to 0.6 mg/L but was the same in smokers (average 4.6%COHb) and nonsmokers (average 1%).30 At this time, further research is required to determine the clinical import of plasma CO content. Additional laboratory tests may be useful in severe poisoning cases. An arterial blood gas will confirm the presence of metabolic acidosis, a complication of CO poisoning associated with neurologic sequelae and death.117 This acidosis is presumably a reflection of high lactate, an index more reliable than COHb in determining severity of toxicity.191 Unfortunately, arterial pH does not correlate with either COHb level or initial neurologic examination, making it a poor criterion for deciding the need for HBO treatment.140 Mild elevations of CPK are common (ranging 20 to 1315 IU/L in one series of 65 cases), but severe rhabdomyolysis and its complications are also reported.182 Cardiac monitoring and a 12-lead ECG are essential to document ischemia or dysrhythmias in symptomatic patients with preexisting coronary artery disease or severe exposure. Recently, it has been found that rats have early increases in glutathione released from erythrocytes, a potential marker for CO oxidative stress that could ultimately lead to brain injury.209 The problem with using COHb levels to base treatment is that there is a wide variation in clinical manifestations with identical COHb levels.139,146 Furthermore, particular COHb levels are not predictive of symptoms or final outcome.130,140,149,191 In a large prospective study of CO poisoning, COHb levels did not correlate with loss of consciousness and were not predictive of delayed neurologic sequelae.168 Part of the problem is that admission COHb levels are inaccurate predictors of peak levels.140 The use of nomograms to extrapolate to earlier levels has not been validated. Their credibility is also suspect because of the great variability in COHb half-lives and differences in treatment with oxygen.

Neuropsychological Testing The extent of neurologic insult from CO can be assessed with a variety of tests. The most basic is documentation of a normal neurologic examination with a quick mini–mental status examination. A more sensitive indicator of the acute effects of CO on cortical function is a detailed neuropsychiatric test battery developed specifically for CO patients.143 The advantages of such testing, which usually takes about 30 minutes, are that (1) it can reliably distinguish 79% of the time between CO-poisoned patients and controls, and (2) it shows improvement with appropriate HBO treatment.132 Unfortunately, such testing shows a sensitivity of only 77% and specificity of 80% for CO poisoning.173 There may be practice effects as well, if repeated testing is performed. The

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biggest problem with such neuropsychiatric testing is that it is unclear if deficits in the test during the acute CO poisoning are at all predictive of which patients will develop neurologic sequelae and therefore require HBO treatment.

Neuroimaging Acute changes on CT scan of the brain have been seen within 12 hours of CO exposure that resulted in loss of consciousness.103,135,147 Symmetric low-density areas in the region of the globus pallidus, putamen, and caudate nuclei frequently occur.96,107,147 Although a normal initial CT usually predicts a favorable outcome, changes in the globus pallidus and subcortical white matter early within the first day after poisoning are associated with poor outcomes135,165 (Fig. 97–1). In one series of 18 patients, a negative CT within a week of admission was associated with favorable outcome.217 The use of contrast may enhance early isodense changes that may not be visible on initial CT scan.237 MRI appears to be superior in detecting basal ganglia lesions.94,104 Neuroimaging usually does not influence patient management and can be reserved for patients who show poor response or have an equivocal diagnosis. The most promising area of neuroimaging after CO poisoning is in the area of assessment of regional cerebral perfusion. Singlephoton emission computed tomography (SPECT) gauges regional blood flow noninvasively using an iodine or technetium tracer.49 In one series of 13 patients with delayed neurologic sequelae, all cases showed patchy hypoperfusion throughout the cerebral cortex initially within 11 days of poisoning.32 These changes in perfusion can occur as early as 1 day and primarily involve watershed regions such as the temporoparietooccipital area.49 Xenon-enhanced computed tomography, which may be more readily available, appears to parallel perfusion changes seen on SPECT scanning.181 Deficits on SPECT scanning appear to be associated with delayed neurologic sequelae.33 Unfortunately, because of the scant availability of the procedure and the lack of comprehensive studies, SPECT scanning is not the definitive tool at this time for determining prognosis or need for HBO. Positron emission tomography (PET) can be also be used for looking at regional blood flow as well as oxygen metabolism in the brain. In one series of severely CO-poisoned patients, PET examination after HBO treatment showed increased oxygen extraction and decreased blood flow in the frontal and temporal cortices.50 Of note, patients with permanent deficits persisted in showing these abnormalities on PET scanning.51 Although PET scanning cannot be used to predict outcome, abnormalities that persist on the scan usually indicate those patients with permanent neurologic sequelae. To complement perfusion studies, EEG mapping was performed on CO-poisoned patients. Although initial studies show that many patients have regional EEG abnormalities after poisoning, it is undetermined if these are predictive of persistent or delayed neurologic problems.49,55 EEG mapping may be discrepant relative to SPECT scanning because EEG preferentially shows subcortical lesions.49

MANAGEMENT The mainstay of treatment is initial attention to the airway. One hundred percent oxygen should be provided as soon as possible by either nonrebreather face mask or endotracheal tube. The immediate effect of oxygen will be to enhance the dissociation of

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COHb.174 In volunteers this reduces the half-life of COHb from a mean of 5 hours (range 2–7 hours) in room air to approximately 1 hour in 100% oxygen at normal atmospheric pressure.155,161 Actual poisonings show a range in half-lives of 30 to 150 minutes when breathing 100% oxygen; the longer elimination half-lives appear to be most often associated with long, low-level exposures.142 With oxygenation and intensive care treatment, hospital mortality rates for serious exposures range from 1 to 30%.63,111 Cardiac monitoring and intravenous access are necessary in any patient with consequential carbon monoxide poisoning. Hypotension can initially be treated with intravenous fluids; inotropic agents may also be necessary to treat any myocardial depression.126 Standard ACLS protocols can be followed for the treatment of life-threatening dysrhythmias. Patients with depressed mental status should have a rapid blood glucose check. This should precede the administration of intravenous dextrose because of the theoretical potential for hyperglycemia-induced exacerbation of cerebral damage (see Antidotes in Depth: Dextrose).159,166,167 However, animal studies of CO poisoning suggest that hypoglycemia can be deleterious as well.156,158,160 Correction of any acidemia with bicarbonate is controversial and could result in further cell hypoxia secondary to a left shift of the oxyhemoglobin dissociation curve.

Hyperbaric Oxygen Hyperbaric oxygen therapy appears to be the treatment of choice for patients with significant CO exposures.81,149 One hundred percent oxygen at ambient pressure reduces the half-life of COHb to 40 minutes; at 2.5 atmospheres absolute, it is reduced to 20 minutes.155,161,177 Actual CO-poisoned victims treated with HBO show half-lives ranging from 4 to 86 minutes.142 Hyperbaric oxygen also increases the amount of dissolved oxygen by about 10 times, which is sufficient alone to supply cerebral needs.16 But this is not the most important clinical issue because most patients have already been stabilized and have appreciably decreased carboxyhemoglobin levels just with ambient oxygen, even before using the chamber. More importantly, in rats following loss of consciousness from CO exposure, hyperbaric, but not normobaric, oxygen therapy prevents brain lipid peroxidation.200 This is because HBO appears to prevent ischemic reperfusion injury by a variety of mechanisms. First, in animal models HBO accelerates regeneration of inactivated cytochrome oxidase, which may be the initiating site for CO neuronal damage.21 Second, HBO also prevents the subsequent leukocyte adherence to brain microvascular endothelium, a process essential for amplification of central nervous system damage from CO.28,203 This may explain why HBO, but not 100% oxygen at atmospheric pressure, prevented delayed deficits in a learning and memory maze model.218 Clinical studies of the effectiveness of HBO in preventing neurologic damage from CO are not as convincing as basic science studies would suggest. In uncontrolled human clinical series, the incidence of persistent neuropsychiatric symptoms, including memory impairment, ranged from 12 to 43% in patients treated with 100% oxygen, and has been as low as 0 to 4% in patients treated with HBO.75,130,145,149,190 The first randomized study of CO poisoning had over 300 patients and failed to show a benefit from HBO in patients who had no initial loss of consciousness.168 Unfortunately, seriously ill patients were not randomized to surface

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pressure oxygen; they received either one or three treatments of HBO. Flaws in that study included significant delays to treatment and use of suboptimal pressure. A smaller (n = 60), more recent controlled study avoided some of these flaws and showed that HBO was able to decrease delayed neurologic sequelae from 23% to 0% in CO-poisoned patients without loss of consciousness.213 However, all patients with syncope, a marker of serious poisoning, were excluded. A very small study (n = 26) of patients presenting with GCS > 12 after CO poisoning included almost half with loss of consciousness.55 Randomization to HBO versus 100% normobaric oxygen resulted in decreased EEG abnormalities and less reduction in blood flow reactivity to acetazolamide at 3 weeks. Unfortunately, all of these studies failed to definitively study all CO poisoned patients, including those with syncope or coma. The first randomized trial to really address the issue of HBO efficacy in seriously CO-poisoned patients was recently completed with 191 patients.180 All CO-poisoned patients referred for HBO treatment were randomized to a minimum of three daily treatments of HBO (2.8 ATA for 60 minutes, 100 minutes total) or 100% oxygen (1.0 ATA for 100 minutes). Although the HBO group had a higher incidence of persistent neurologic sequelae at 1 month, there was no significant difference between the two groups; over two-thirds of each group had persistent problems. This study, although the largest controlled, randomized study to date, suffered from several flaws.137 Fewer than half of the patients had followup at 1 month. Disproportionate numbers of suicide cases (about two-thirds) and drug toxicity (44%), with accompanying neuropsychological defects, could have confounded any beneficial effect from HBO. Finally, HBO treatment was delayed over 6 hours, making it much less likely to be effective.75,168 In light of prior clinical and animal studies, it would be premature to reject HBO as an early viable treatment for serious CO poisoning. This is even truer because of the low risk of using HBO in CO poisoning.188

Indications for Hyperbaric Oxygen Therapy Specific indications for HBO after acute CO poisoning are listed (Table 97–2), but these have not been prospectively evaluated. The patients most likely to benefit are those most at risk for persistent or delayed neurologic sequelae, such as patients presenting in coma.75,108,189,235,240 Other potential markers for delayed neurologic sequelae include a history of syncope.31,63,134,190 This may represent the episode of hypotension that is necessary for causing neuronal damage from CO-induced ischemic-reperfusion injury in animal models.69,150 Patients with long exposures, or “soaking” periods, are also at greater risk for neurologic sequelae.17,229 The TABLE 97–2. Indications for Hyperbaric Oxygen Treatment in Carbon Monoxide Poisoning Definite Loss of consciousness Seizures Coma Altered mental status Relative Persistent neurologic symptoms after several hours of oxygen treatment Pregnancy Persistent cardiac ischemia Increased carboxyhemoglobin levels

presence of a significant metabolic acidosis may be a reliable marker for this.117,191,223 Some authors advocate ongoing myocardial ischemia as an indication for HBO; however, in our experience, these patients usually already meet neurologic criteria for treatment (eg, loss of consciousness, ongoing mental status changes). Isolated cardiac ischemia, more importantly, deserves immediate proven myocardial salvaging therapy rather than delayed treatment with an unproven therapy such as HBO. Some authors advocate treating all patients with COHb levels of 40% or greater with HBO.97,141 Many HBO centers arbitrarily use a more conservative level of 25% as an indication for HBO. More important than actual level are patient history and examination. If the patient had loss of consciousness or significant neurologic symptoms (eg, coma, seizures, focal neurologic deficits, GCS < 15), he or she should be treated with HBO regardless of COHb levels. It is still unclear if mild neurologic symptoms (eg, confusion, headache, dizziness, visual blurring) or abnormal mental status testing on initial presentation is prognostic of delayed sequelae. These symptoms simply represent CO poisoning, which, at COHb levels approaching 20% in volunteers, can cause some temporary mental impairment.118,197 Patients with these mild signs and symptoms deserve several hours of oxygen by nonrebreather face mask; then, if symptoms do not resolve, HBO can be considered. However, any delay in HBO may decrease its efficacy.75 Beyond good supportive care, all CO-poisoned patients require 100% oxygen as soon as possible. Hyperbaric oxygen may provide additional benefits, as outlined above. This might be especially useful in smoke-inhalation victims, to treat concomitant cyanide poisoning, chemical pneumonitis, and thermal burns.84 Some authors recommend selective use of HBO because of cost and difficulties in transport if the primary facility lacks a chamber.152 However, complications that may make such transfers and treatment unsafe are rare.188 Although HBO cannot be recommended for every patient with CO poisoning, it is a relatively safe treatment that should be considered in all serious exposures. Fortunately, three-quarters of cases with delayed neurologic sequelae will resolve, albeit after several months.31 It is our hope that completion of well-designed and scientifically controlled clinical studies will allow clarification of the indications for HBO.

Delayed Administration of Hyperbaric Oxygen. The optimal timing and number of HBO treatments for CO poisoning is unclear at this time. Patients treated later than 6 hours tend to fare worse in terms of delayed sequelae (30% vs 19%) and mortality (30% vs 14%).75 One reason that this large randomized study may have failed to show any benefit from HBO is that patients were treated more than 6 hours after poisoning. 180 However, others suggest that late treatment may still be useful. Patients who have experienced unconsciousness from CO may benefit from an initial treatment of HBO as late as 6 hours postexposure, with no resulting neurologic sequelae.146,240 In addition, patients who did not receive HBO initially and have already developed neuropsychological sequelae may have benefitted from HBO as late as 21 days postexposure.145 The problem with studies showing HBO benefits days after an acute poisoning, or after chronic poisoning, is that these cases are all anecdotal and lack controls. In fact, almost all cases of delayed neurologic sequelae resolve within 2 months in mild poisoning213 and ~75% within 1 year in severe poisoning.31 In fact, benefits in these delayed or chronic cases may simply represent the salutary

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effects of HBO. A preliminary study shows that HBO improves memory scores temporarily by over 50% in normal volunteers.100 Repeat Treatment With Hyperbaric Oxygen. There are no studies to date that show that more than one HBO treatment is helpful in CO poisoning. However, this has still been advocated for patients who have persistent symptoms, particularly coma, after initial treatment.47 In a nonrandomized retrospective study, CO-poisoned patients who received a second HBO treatment had a reduction in delayed neurologic sequelae from 55%, seen in comparable controls, to 18%.74 However, prospective studies have failed to confirm any benefit from a repeated HBO treatment, and therefore, it cannot be recommended at this time.168 Treatment of Carbon Monoxide–Poisoned Pregnant Patients. The management of CO exposure in the pregnant patient is difficult because of the potential adverse effects of both the toxin and its treatment. A literature review of all CO exposures during pregnancy revealed a high incidence of fetal central nervous system damage and stillbirth after severe maternal poisonings.225 A series of three severely symptomatic patients who did not receive HBO had adverse fetal outcomes: two stillbirths and one case of cerebral palsy.110 There have even been cases of limb malformations, cranial deformities, and a variety of mental disabilities in children poisoned in utero.24,124 Although neurologic sequelae have been noted after severe acute exposures, a retrospective case-control study showed no association of CO exposure in the last trimester with low birth weight.1 Maternal COHb levels do not accurately reflect fetal hemoglobin or tissue levels.40,45,72,129 In primate studies, a single CO exposure insufficient to cause clinical disease in a rhesus mother led to intrauterine hypoxia, fetal brain injury, and increased rates of fetal death.67,68 In humans, minor exposures without loss of consciousness in the mother have resulted in poor fetal outcomes.24,110 In one fetal loss case, the fetus had much higher levels than the peak COHb of 24% measured in the mother.42 The problem is that CO absorption and elimination are slower in the fetal circulation than in the maternal circulation.68,125 A mathematical model predicts that elimination of CO from the fetus takes 3.5 times longer than maternal CO elimination.91 Treatment of pregnant patients with HBO is not without theoretical risk. Animal studies show conflicting results on the effects of HBO on fetal development.225 Some studies have shown that HBO causes developmental abnormalities in the central nervous, cardiovascular, and pulmonary systems of the fetus.133 This is in marked contrast to the extensive Russian experience, where hundreds of pregnant women were treated with HBO, apparently without significant perinatal complications and with improvement in fetal/maternal status for their underlying conditions (eg, toxemia, anemia, diabetes).136 Cases in this country where HBO was used for CO poisoning have resulted in normal infants at birth.56,92,110,225 There currently is no scientific validation for an absolute level at which to dive a pregnant patient for CO exposure. Arbitrarily, COHb levels greater than 20% are defined as an indication to dive a pregnant patient regardless of symptoms.225 Pregnant patients should not be treated any differently if they meet criteria for HBO that have already been mentioned (see Table 97–2). Additional criteria would include any signs of fetal distress, such as abnormal fetal heart rate. Elevated levels of COHb (>15%), especially with a symptomatic mother, warrant HBO if locally available. This will

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facilitate more efficient treatment of the mother because of the necessity for prolonged oxygen therapy in pregnant patients, in the face of uncertain fetal COHb levels. Treatment of CO Poisoning in Children. It has been suggested that children are most sensitive to the effects of carbon monoxide because of their increased metabolic rate.44 Epidemiologic studies suggest that pediatric patients can become symptomatic at COHb levels less that 10%, lower than is commonly expected in adults.109 The other problem is that these cases may have unusual presentations. Most pediatric patients manifest nausea, headache, or lethargy.44 An isolated seizure or vomiting may be the only manifestation of CO toxicity in an infant or child.90 In drawing COHb levels in infants, clinicians must be aware of two confounding factors. First, many CO-oximeters can give falsely elevated COHb levels, in proportion to the amount of fetal hemoglobin present.227 Second, carbon monoxide is produced during breakdown of protoporphyrin to bilirubin. Therefore, infants can normally have high levels of COHb, >3%, and even higher in the presence of kernicterus.194,228 Thus, before it is assumed that an elevated COHb level implies CO poisoning in an infant, the contribution of jaundice and fetal hemoglobin must be considered in the final analysis. Although children may be more susceptible to acute toxicity with CO, their long-term outcomes appear to be more favorable than adults. In a series of 2360 serious CO cases, all incidences of delayed neurologic sequelae were in adults aged over 30 years.31 Two pediatric series of CO poisoning show an incidence of delayed neurologic sequelae of approximately 10% after severe CO poisoning.106,131 This low incidence, in patients treated only with 100% normal-pressure oxygen treatment, has been used as an argument to avoid HBO.131 However, there still is a real risk of such sequelae, and HBO has been used successfully to prevent such sequelae.175 If the use of surface-pressure oxygen is selected to treat a pediatric case, it is comforting to know that the COHb half-life is approximately 44 minutes, which is comparable to that in adults.109

Other Neuroprotective Treatments A variety of neuroprotective agents have been tested in animal models. They are targeted primarily at preventing the delayed neurologic sequelae associated with serious CO poisoning. One of the simplest treatments tested is insulin. Hyperglycemia has been shown to exacerbate neuronal injury from stroke as well as in arrest situations, and in CO poisoning of rodents, it is associated with worse neurologic outcome.159 However, insulin, independent of its glucose-lowering effect, appears to be protective after ischemia.79 In rodent studies, improved neurologic outcome, as measured by locomotor activity, occurs after CO poisoning treated with insulin.233 In light of these findings, it is reasonable to aggressively treat documented hyperglycemia with insulin in serious CO poisoning cases. Many neuroprotective agents involve blockage of excitatory amino acids, such as glutamate, that are implicated in neuronal cell death after CO poisoning. Pretreatment of mice with dizocilpine (MK-801), which blocks the action of glutamate at N-methyl-D-aspartate receptors, ameliorates learning, memory, and hippocampal deficits with CO poisoning.99 Ketamine, a glutamate antagonist as well, decreases mortality of rats poisoned with CO after carotid ligation.157 Use of related drugs, although promising, awaits further animal testing because of potential adverse effects.

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Other modalities have been tested in preventing neuronal damage from CO without much success. Hypothermia, rather than being beneficial, actually increases mortality in animals.160,164 Allopurinol has been tested to prevent formation of free radicals through xanthine oxidase. This drug, when given as pretreatment, prevents lipid peroxidation mediated by xanthine oxidase in CO poisoning.202 This strategy has not been promising because of the necessity for pretreatment.

Prevention of Carbon Monoxide Exposures Early diagnosis will prevent much of the associated morbidity and mortality associated with CO poisoning, especially in unintentional exposures. The increased quality of home carbon monoxide–detecting devices will allow personal intervention in the prevention of exposure.112 Routine laboratory screening of emergency department patients during the winter is not very efficacious in diagnosing unsuspected CO poisoning; the yield is less than 1% when patients are tested in whom the diagnosis of CO exposure was already excluded by history.87,222 Instead, selecting patients with CO-related complaints, such as headache, dizziness, or nausea, increases the yield to 5 to 11%.77,222 During winter, risk factors such as gas heating or symptomatic cohabitants in patients with influenza symptoms (eg, headache, dizziness, nausea) will be the most useful method for deciding when to obtain COHb levels on potential cases.85,86,88 The issue of symptomatic cohabitants is especially important from a preventive standpoint. Alerting other cohabitants to this danger and effecting evacuation may prevent needless deaths.231 Most communities have multiple resources for on-site evaluation. Usually the local fire department or utility company can either check home appliances or measure ambient CO levels with portable monitoring equipment. Current workplace standards for ambient CO exposures are 35 ppm for a 1-hour limit and 9 ppm for an 8-hour limit.58 There is a ceiling limit of 200 ppm (measured over a 15-minute period). Just a 4-hour exposure to 100 ppm of CO can result in COHb greater than 10% with symptoms.161 Until rescue personnel arrive, natural-gas-fueled appliances should be turned off and the area evacuated, leaving all windows and doors open.

SUMMARY Unintentional exposures to CO can easily be misdiagnosed. Carbon monoxide should also be suspected in any patient with coma, acidosis, or signs of cardiac ischemia that may be attributable to suicide. Fire victims, in addition to airway problems and potential cyanide toxicity, may succumb to CO toxicity.13 The mainstay of treatment in all these cases is good supportive care with early oxygenation to increase the elimination of CO. Because of the overwhelming clinical successes with HBO and its limited risks, early use of this treatment modality in severe exposures is encouraged. Discussion with a poison control center or hyperbaric facility will help in identifying those patients most likely to benefit from such treatment.

REFERENCES 1. Alderman BW, Baron AE, Savitz DA: Maternal exposure to neighborhood carbon monoxide and risk of low birth weight. Public Health Rep 1987;102:410–414.

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178. Schaplowsky AF, Oglesbay FB, Morrison JH, et al: Carbon monoxide contamination of the living environment: a national survey of home air and children’s blood. J Environ Health 1974;36: 569–573. 179. Scharf SM, Thames MD, Sasrgent RK: Transmural myocardial infarction after exposure to carbon monoxide in coronary-artery disease. N Engl J Med 1974;291:85–86. 180. Scheinkestel CD, Bailey M, Myles PS, et al: Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomized controlled clinical trial. Med J Aust 1999;170:203–210. 181. Sesay M, Bidabe AM, Guyot M, et al: Regional cerebral blood flow measurements with Xenon-Ct in the prediction of delayed encephalopathy after carbon monoxide intoxication. Acta Neurol Scand [Suppl] 1996;166:22–27. 182. Shapiro AB, Maturen A, Herman G, et al: Carbon monoxide and myonecrosis: a prospective study. Vet Hum Toxicol 1989;31: 136–137. 183. Sheps DS, Herbst MC, Hinderliter AL, et al: Production of arrhythmias by elevated carboxyhemoglobin in patients with coronary artery disease. Ann Intern Med 1990;113:343–351. 184. Shimazeu T, Ikeuchi H, Hubbard GB, et al: Smoke inhalation injury and the effect of carbon monoxide in the sheep model. J Trauma 1990;30:170–175. 185. Shusterman D, Alexeeff G, Hargis C, et al: Predictors of carbon monoxide and hydrogen cyanide exposure in smoke inhalation patients. J Toxicol Clin Toxicol 1996;34:61–71. 186. Silver DAT, Cross M, Fox B, Paxton RM: Computed tomography of the brain in acute carbon monoxide poisoning. Clin Radiol 1996; 51:480–483. 187. Silvers SM, Hampson NB: Carbon monoxide poisoning among recreational boaters. JAMA 1995;274:1614–1616. 188. Sloan EP, Murphy DG, Hart R, et al: Complications and protocol considerations in carbon monoxide-poisoned patients who require hyperbaric oxygen therapy: report from a ten-year experience. Ann Emerg Med 1989;18:629–634. 189. Smith GI, Sharp GR: Treatment of carbon monoxide poisoning with oxygen under pressure. Lancet 1960;2:905–906. 190. Smith JS, Brandon S: Morbidity from acute carbon monoxide poisoning at 3 years following. Br Med J 1973;1:318–321. 191. Sokal JA, Kralkowska E: The relationship between exposure duration, carboxyhemoglobin, blood glucose, pyruvate and lactate and the severity of intoxication in 39 cases of acute carbon monoxide poisoning in man. Arch Toxicol 1985;57:196–199. 192. Sone S, Higashihara T, Kotake T, et al: Pulmonary manifestations in acute carbon monoxide poisoning. Am J Roentgenol 1974;120: 865–871. 193. Sterling TD, Sterling E: Carbon monoxide levels in kitchens and homes with gas cookers. J Air Pollut Control Assoc 1979;29: 238–241. 194. Stevenson DK, Vreman HJ: Carbon monoxide and bilirubin production in neonates. Pediatrics 1997;100:252–254. 195. Stewart R, Baretta ED, Platte LR, et al: Carboxyhemoglobin levels in American blood donors. JAMA 1974;229:1187–1195. 196. Stewart RD: Paint remover hazard. JAMA 1976;235:398–401. 197. Stewart RD, Peterson JE, Baretta ED, et al: Experimental human exposure to carbon monoxide. Arch Environ Health 1970;21:154–164. 198. Stewart RD, Peterson JE, Fisher TN, et al: Experimental human exposure to high concentrations of carbon monoxide. Arch Environ Health 1973;26:1–7. 199. Takeuchi A, Vesely A, Rucker J, et al: A simple “new” method to accelerate clearance of carbon monoxide. Am J Respir Crit Care Med 2000;161:1816–1819. 200. Thom SR: Antagonism of carbon monoxide-mediated brain lipid peroxidation by hyperbaric oxygen. Toxicol Appl Pharmacol 1990; 105:340–344. 201. Thom SR: Carbon monoxide–mediated brain lipid peroxidation in the rat. J Appl Physiol 1990;68:997–1003.

202. Thom SR: Dehydrogenase conversion to oxidase and lipid peroxidation in brain after carbon monoxide poisoning. J Appl Physiol 1992; 73:1584–1589. 203. Thom SR: Functional inhibition of leukocyte B2 integrins by hyperbaric oxygen in carbon monoxide-mediated brain injury in rats. Toxicol Appl Pharmacol 1993b;123:248–256. 204. Thom SR: Leukocytes in carbon monoxide-mediated brain oxidative injury. Toxicol Appl Pharmacol 1993a;123:234–247. 205. Thom SR: Learning dysfunction and metabolic defects in globus pallidus and hippocampus after CO poisoning in a rat model [abstract]. Undersea Hyperbaric Med 1997;23(suppl):20. 206. Thom SR, Fisher D, Xu YA, et al: Role of nitric oxide-derived oxidants in vascular injury from carbon monoxide in the rat. Am J Physiol 1999;276:H984–H992. 207. Thom SR, Fisher D, Xu YA, et al: Adaptive responses and apoptosis in endothelial cells exposed to carbon monoxide. Proc Natl Acad Sci 2000;97:1305–1310. 208. Thom SR, Ischiropoulos H: Mechanism of oxidative stress from low levels of carbon monoxide. Res Rep Health Effects Inst 1997;80: 1–19. 209. Thom SR, Kang M, Fisher D, Ischiropoulos H: Release of glutathione from erythrocytes and other markers of oxidative stress in carbon monoxide poisoning. J Appl Physiol 1997;82:1424–1432. 210. Thom SR, Keim LW: Carbon monoxide poisoning: a review of epidemiology, pathophysiology, clinical findings, and treatment options including hyperbaric oxygen therapy. J Toxicol Clin Toxicol 1989; 27:141–156. 211. Thom SR, Ohnishi ST, Fisher D, et al: Pulmonary vascular stress from carbon monoxide. Toxicol Appl Pharmacol 1999;154:12–19. 212. Thom SR, Ohnishi ST, Ischiropoulos H: Nitric oxide release by platelets inhibits neutrophil B2 integrin function following acute carbon monoxide poisoning. Toxicol Appl Pharmacol 1994;128: 105–110. 213. Thom SR, Taber RL, Mendiguren I, Clark JM, Hardy KR, Fisher AB: Delayed neuropsychological sequelae after carbon monoxide CO poisoning: prevention by treatment with hyperbaric oxygen. Ann Emerg Med 1995;25:474–480. 214. Thom SR, Xu YA, Ischiropoulos H: Vascular endothelial cells generate peroxynitrite in response to carbon monoxide exposure. Chem Res Toxicol 1997;10:1023–1031. 215. Thomas MF, Penney DG: Hematologic responses to carbon monoxide and altitude: a comparative study. J Appl Physiol 1977;43:365 216. Tikuisis P: Modeling the uptake and elimination of carbon monoxide. In: Penney DG, ed: Carbon Monoxide. Boca Raton, CRC Press, 1996, pp. 69–86. 217. Tom T, Abedon S, Clark RI, Wong W: Neuroimaging characteristics in carbon monoxide toxicity. J Neuroimag 1996;6:161–166. 218. Tomaszewski C, Rosenberg N, Wathen J, et al: Prevention of neurological sequelae from carbon monoxide by hyperbaric oxygen in rats [abstract]. Neurology 1992;42(Suppl 3):196. 219. Touger M, Gallagher EJ, Tyrell J: Relationship between venous and arterial carboxyhemoglobin levels in patients with suspected carbon monoxide poisoning. Ann Emerg Med 1995;25:481–483. 220. Treitman RD, Burgess WA, Gold A: Air contaminants encountered by firefighters. Am Ind Hyg Assoc J 1980;41:796–802. 221. Turcanu V, Dhouib M, Gendrault JL, et al: Carbon monoxide induces murine thymocyte apoptosis by a free radical-mediated mechanism. Cell Biol Toxicol 1998;14:47–54. 222. Turnbull TL, Hart RG, Strange GR, et al: Emergency department screening for unsuspected carbon monoxide exposure. Ann Emerg Med 1988;17:478–483. 223. Turner M, Esaw M, Clark RJ: Carbon monoxide poisoning treated with hyperbaric oxygen: metabolic acidosis as a predictor of treatment requirements [abstract]. J Accid Emerg Med 1999;16:96–98. 224. Utz J, Ullrich V: Carbon monoxide relaxes ileal smooth muscle through activation of guanylate cyclase. Biochem Pharmacol 1991; 41:1195–1201.

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225. Van Hoesen KB, Camporesi EM, Moon RE, et al: Should hyperbaric oxygen be used to treat the pregnant patient for acute carbon monoxide poisoning? A case report and literature review. JAMA 1989; 261:1039–1043. 226. Verma A, Hirsch DJ, Glatt CE, et al: Carbon monoxide: a putative neural messenger. Science 1993;259:381–384. 227. Vreman HJ, Ronquillo RB, Ariagno RL, et al: Interference of fetal hemoglobin with the spectrophotometric measurement of carboxyhemoglobin. Clin Chem 1988;34:975–977. 228. Vreman HJ, Stevenson DK: Carboxyhemoglobin determined in neonatal blood with a co-oximeter unaffected by fetal oxyhemoglobin. Clin Chem 1994;40:1522–1527. 229. Wasowaski J, Myslack Z, Graczyk M, et al: An attempt at comparing the results of carboxyhemoglobin level in blood and gasometric determination in capillary blood in cases of carbon monoxide poisoning when treatment began at the place of accident. Anaesth Resusc Intens Ther 1976;4:245–249. 230. Weaver LK, Larson-Lohr V, Howe S, et al: Carboxyhemoglobin (COHb) half-life (t1/2) in carbon monoxide poisoned patients treated with normobaric oxygen or HBO—an interim report. Undersea Hyperbaric Med 1994;21:13 231. Wharton M, Bistowish JM, Hutcheson RH: Fatal carbon monoxide poisoning at a motel. JAMA 2001;261:1177–1178. 232. Wheeler MG, Rozycki AA, Smith RP: Recreational propane inhalation in an adolescent male. J Toxicol Clin Toxicol 1992;30:135–139.

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233. White SR, Penney DG: Initial study: Effects of insulin and glucose treatment on nuerologic outcome after CO poisoning. Ann Emerg Med 1994;23:606–607. 234. Wright GR, Shephard RJ: Physiological effects of carbon monoxide. Int Rev Physiol 1979;20:311–368. 235. Yee LM, Brandon GK: Successful reversal of presumed carbon monoxide-induced semicoma. Aviat Space Environ Med 1983;54: 641–643. 236. Yoon SS, MacDonald SC, Parrish RG: Deaths from unintentional carbon monoxide poisoning and potential for prevention with carbon monoxide detectors. JAMA 1998;279:685–687. 237. Zeiss J, Brinker R: Role of contrast enhancement in cerebral CT of carbon monoxide poisoning. J Comput Assist Tomogr 1988;12: 341–343. 238. Zhang J, Piantadosi CA: Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J Clin Invest 1992;90:1193–1199. 239. Zhang J, Piantadosi CA: Nitric oxide mediates excitotoxicity induced by carbon monoxide poisining in rat brain [abstract]. Undersea Hyperbaric Med 1995;22:16–16. 240. Ziser A, Shupak A, Halpern P, et al: Delayed hyperbaric oxygen treatment for acute carbon monoxide poisoning. BMJ 1984; 289:960.

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Hyperbaric Oxygen Stephen R. Thom Hyperbaric oxygen (HBO) therapy is a treatment modality in which a person breathes 100% O2 while exposed to increased atmospheric pressure in a specialized chamber. Treatments are typically conducted at pressures 2 to 3 times higher than normal atmospheric pressure (1 atmosphere = 14.7 psi), or 2 to 3 atmospheres absolute (ATA). The hyperbaric chamber, per se, is not the therapeutic agent. Oxygen is the therapeutic drug, and the chamber serves as a dosing device. Hyperbaric oxygen treatment can be delivered in either a mono- or multiplace hyperbaric chamber. Monoplace chambers, which accommodate only a single patient, are pressurized with pure oxygen. Larger walk-in, or multiplace, chambers accommodate two or more patients as well as support staff for hands-on patient care. These chambers are pressurized with air while patients breathe pure oxygen via mask, head tent, or endotracheal tube. Portable “chambers” made of synthetic textile materials capable of withstanding pressures of 2 ATA can also be inflated with gas, typically air. The current use of these portable chambers has been for emergency treatment of high-altitude sickness, although they have been investigated for HBO use in remote or wilderness situations.47,52,88,101 In 1967, an international scientific organization, the Undersea and Hyperbaric Medical Society (UHMS), was founded to foster the exchange of data on the physiology of diving and hyperbaric medicine. The UHMS publishes a biannual report, “Hyperbaric Oxygen Therapy: A Committee Report,” which outlines current knowledge and lists those conditions for which HBO is considered to be an effective treatment.43 In toxicology, HBO is most commonly used for treatment of carbon monoxide (CO) poisoning. Hyperbaric oxygen therapy can also be considered for managing life-threatening poisonings from cyanide (CN
), hydrogen sulfide (H2S), or carbon tetrachloride (CCl4) and in patients with methemoglobinemia. Management of patients with diverse poisonings of greater rarity have been investigated experimentally.110 Therapeutic mechanisms of action for HBO are based on elevation of both hydrostatic pressure and the partial pressure of oxygen. All perfused tissues are subjected to elevated partial pressures of oxygen in association with HBO exposure. Because, under normal environmental conditions, hemoglobin is virtually saturated with oxygen on passage through the pulmonary microvasculature, the primary effect of HBO is to increase dissolved oxygen content of plasma. Application of each additional atmosphere of oxygen increases the dissolved oxygen concentration in the plasma by 2.2 mL O2/dL (vol%) (Chap. 20). Elevation of the hydrostatic pressure causes a reduction in the volume of gas according to Boyle’s law. This action has direct relevance to pathologic conditions where gas bubbles are present in the body, such as arterial gas embolism and decompression sickness. In fact, HBO therapy was recently used successfully in an unusual case of cerebral gas embolism resulting from unintentional ingestion of a large amount of hydrogen peroxide.71

There is now ample evidence that reactive species of oxygen and nitrogen are second messengers in vivo and that they serve to signal a variety of cellular response (Fig. 97–2). Pharmacologic actions linked to reactive species and the resulting cellular signaling cascades are an active focus of investigation with regard to mechanisms of action of HBO. In animal studies, HBO is beneficial in the treatment of various forms of reperfusion injury.11,36,37,40,54,75,86,91,95,103,107,113,122,124 These results initially appear paradoxical given the fact that HBO is expected to accelerate production of reactive oxygen species, which commonly contribute to reperfusion injuries. Interactions between circulating neutrophils and endothelial cells in the reperfused vascular bed are a major part of the reperfusion pathologic cascade. Methods to impede adherence between neutrophils and reperfused endothelium are frequently beneficial in experimental models of reperfusion injury.115 For example, inhibition of the membranebound neutrophil 2 integrin adhesion molecules and their intercellular adhesion molecule (ICAM) endothelial counterreceptors is typically achieved by infusing monoclonal antibodies. Hyperbaric oxygen can diminish injuries associated with a number of pathologic processes characterized by oxidative stress because HBO inhibits 2 integrin-dependent neutrophil adhesion.103,109,113,124 In fact, HBO exhibits efficacy over a broader period of time pre- and postinjury than monoclonal antibody infusions, and HBO is not associated with immunocompromise, as noted following the use of anti–2 integrin infusions.67,77,103 The affinity of CO for heme proteins is well known, and formation of carboxyhemoglobin (COHb) is a recognized effect of CO exposure. An elevated COHb can precipitate tissue hypoxia, and this stress appears to be responsible for fatalities, cardiac injuries, and the acute neurologic abnormalities that develop in approximately 14 % of survivors of serious CO poisoning.2,29,33 However, both clinical and animal studies have failed to establish a correlation between elevated COHb levels and delayed neurologic injuries.23,44,72,103 In experimental CO poisoning, endothelial changes mediated by the free radical nitric oxide are a prerequisite for neutrophil adherence to the cerebral microvasculature.44 Activated leukocytes incite a cascade of biochemical and cellular processes that lead to oxidative injury. Brain injury is demonstrated as impaired glucose metabolism in the basal ganglia and hippocampus and as impaired learning.106,110 Hyperbaric oxygen inhibits experimental brain injury by inhibiting β2 integrin-dependent leukocyte adhesion.103 Neutrophils from humans exposed to hyperbaric oxygen exhibit the same diminished adherence as those in animals.104 Use of supplemental oxygen is a cornerstone to the treatment of CO poisoning.51 Since 1960, hyperbaric oxygen has been used with increasing frequency for severe CO poisoning, as clinical recovery appeared to be improved beyond that expected with ambient-pressure oxygen therapy.34,64,72 However, no definition is established for staging the severity of CO poisoning. Therefore, it remains difficult to evaluate patients in a prospective manner or compare the efficacy of different treatments. Some centers propose using psychometric screening tests to identify patients with subtle neurologic compromise and as a method to stratify patients

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Figure 97–2. Cascade of events as identified in rat model of CO poisoning.44,103,106,110 COHb = carboxyhemoglobin; COMb = carboxymyoglobin; XD = xanthine dehydrogenase; XO = xanthine oxidase; NO• = free radical nitric oxide.

for treatment. However, when examined in a prospective study, abnormalities during the initial screening did not correlate with development of delayed sequelae.105 The first prospective clinical trial involving HBO therapy failed to find it superior to ambient-pressure treatment.81 This study has been criticized because the authors used a low oxygen partial pressure (2 ATA) versus the more usual protocols with 2.5 to 3 ATA and because nearly half of all patients received hyperbaric treatments more than 6 hours after they were discovered.15 In 1969, a retrospective study indicated that HBO reduced mortality and morbidity only if administered within 6 hours after CO poisoning.35 HBO has been found effective in several prospective investigations: In one trial involving mildly to moderately poisoned patients, 23 % of patients (7 of 30) treated with ambientpressure oxygen developed neurologic sequelae, whereas no patients (0 of 30; p < .05) treated with HBO (2.8 ATA) developed

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sequelae.105 In another prospective, randomized trial, 26 patients were hospitalized within 2 hours of discovery and were equally divided between two treatment groups: ambient-pressure oxygen, or 2.5-ATA O2.30 Three weeks later patients treated with HBO had significantly fewer abnormalities on electroencephalogram, and SPECT scans showed that cerebral vessels had nearly normal reactivity to carbon dioxide, in contrast to diminished reactivity in patients treated with ambient-pressure oxygen. The fourth prospective trial investigating hyperbaric oxygen therapy for CO poisoning involved 191 patients and reported no benefit from relatively unorthodox administration of hyperbaric versus ambient-pressure oxygen therapy that extended over 3 days.85 Concerns with this study include a mean delay to treatment of 7.5 hours, and only 46% of patients who entered the study were assessed to evaluate delayed neurologic sequelae. An adequate fraction of the population was studied to make comparisons with regard to the incidence of acute neurologic abnormalities, and no significant difference was found between treatment groups. Controversy exists, however, over the validity of the conclusion because 67% of the study population had attempted suicide, and the evaluation was performed with an arbitrary set of psychometric tests influenced by depression. Therefore, it is unclear whether abnormalities ascribed to CO may have been secondary to underlying, preexisting pathology. Furthermore, comatose patients accounted for 53% of the study group, and 44% of patients had taken additional poisons, but no specific information on these cases was provided to assess whether central nervous system insults may have been caused by factors other than CO. A recent reevaluation of the subset of patients in this study who were presumed to be suffering from mild CO poisoning once again presents the dilemma of patient selection criteria. These reconstructed data were examined to assess the difference in incidence of acute or persistent neurologic sequelae between the two treatment groups.50 Those treated with HBO had a significantly lower incidence of sequelae than did those treated with ambientpressure oxygen. Finally, in as yet the largest prospective, randomized trial, which involved 575 patients, the incidence of delayed neurologic sequelae was lower among noncomatose patients who had suffered transient unconsciousness when treated with hyperbaric oxygen versus ambient-pressure oxygen therapy.65 Because most patients with sequelae resolved their symptoms spontaneously over a period of 6 months, the benefit of HBO treatment has been discussed in terms of reducing the incidence and duration of functional disabilities caused by CO poisoning. This study65 and a recent double blind randomized trial119a have demonstrated that HBO therapy reduces cognitive sequelae after acute CO poisoning. The most recent study119a was performed with 152 patients treated three times at 6–12 hour intervals with HBO or normobaric O2 inside a hyperbaric chamber. Interim analysis was conducted at 50, 100, and 150 patients, with a goal of 200 patients. The trial was stopped after the third interim analysis because HBO was found to be efficacious (p = 0.007 for the difference in cognitive sequelae between groups). There were 144 patients who had complete neuropsychological data at all follow up time points. Among these patients, 24% of the group treated with HBO had cognitive sequelae compared to 43.1% of the normobaric O2-treated group (p = 0.014). Post hoc subgroup analysis showed that HBO reduced cognitive sequelae in patients with any of the following: loss of consciousness, COHb ≥25%, age ≥50 years, or a base excess 90%).94 Absorption is impaired by antacids and H2 blockers. Itraconazole is metabolized in the liver to inactive metabolites. It is widely distributed in the body, with therapeutic tissue levels at sites of fungal infection.94 The standard dosage is 100 to 400 mg/d. The toxic profile is similar to that of ketoconazole. Itraconazole interferes weakly with the cytochrome P450 (CYP3A4) enzyme system, so it will decrease the metabolism of cyclosporine, digoxin, astemizole, and terfenadine. Rifampin, phenytoin, and carbamazepine increase the elimination of itraconazole and may result in treatment failures.

Antimycobacterial Therapy Rifabutin. Rifabutin (Mycobutin), a rifamycin S derivative, inhibits DNA-dependent RNA polymerase and is approved for prophylactic therapy for Mycobacterium avium complex (MAC) and is also used in combination therapy for MAC. Rifabutin is well absorbed from the GI tract, with peak serum levels of 0.49 µg/mL occurring 4 hours after administration.74 The serum half-life is 16 hours; the intracellular half-life is 10 times

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higher.74 Rifabutin is principally eliminated in the bile, where enterohepatic circulation results in progressive deacetylation. One of the metabolites (25-deacetylrifabutin) retains the same biologic activity as the parent drug.74 Rifabutin is adsorbed to activated charcoal and is dialyzable. The recommended dosage of rifabutin is 300 mg/d. Rifabutin has a relatively mild toxicity profile. Gastrointestinal upset with nausea, vomiting, and diarrhea are common. Clinically insignificant hepatotoxicity is manifest by elevated aminotransferases, bilirubin, and alkaline phosphatase. Neutropenia and thrombocytopenia may occur. Various hypersensitivity reactions (rash and fever) are reported. Rifabutin stimulates cytochrome P450 microsomal enzymes, which may increase metabolism of certain drugs, especially drugs like AZT. Conversely, ritonavir causes elevation of rifabutin levels, resulting in toxicity19 (see Table 108–5). A patient who overdoses with rifabutin should be treated supportively. Induction of emesis is usually not necessary and may be contraindicated because of the frequency of vomiting associated with overdose. Intravenous hydration and activated charcoal are the standard of care. Hemodialysis and charcoal hemoperfusion might be useful in severe overdose where supportive therapy is not adequate. Clarithromycin. Clarithromycin (Biaxin) is a macrolide analogue of erythromycin with broad-spectrum antimicrobial activity against MAC. It is used both for prophylaxis and in combination with other drugs in treatment of MAC. It is acid stable with an oral bioavailability of 85%.47 The majority of the drug is metabolized by the liver to an active 14-hydroxyl metabolite. Approximately 20 to 30% of the drug is renally excreted unchanged. The parent compound and metabolite have serum half-lives of 2 to 6 hours and 2 to 9 hours, respectively.47 The usual dose for MAC disease is 500 to 1000 mg twice a day. Clarithromycin is better tolerated than erythromycin, with less GI upset. Headache and dizziness occur rarely. Reversible dose-related hearing loss has occurred in patients treated for MAC infection. Clarithromycin, like all macrolide antibiotics except for azithromycin, inhibits cytochrome P450 hepatic metabolism and consequently decreases elimination of theophylline, carbamazepine, cyclosporine, warfarin, corticosteroids, and ergotamine. Combination with ergots may precipitate signs of ergotism (Chap. 45). Azithromycin. Azithromycin (Zithromax) is another macrolide with a spectrum similar to that of clarithromycin. The oral bioavailability is 37%.47 It has wide tissue distribution with very low serum concentrations and is extensively metabolized by the liver, with only 5% excreted unchanged by the kidneys.47 The toxicity profile and drug interactions are unlike those of clarithromycin because it does not inhibit CYP3A4.

SUMMARY As the HIV pandemic continues, new drugs are being formulated and used, mostly in combination. With the multiple-organ-system disease that HIV creates and with its effect on drug metabolism, many adverse and potentially fatal reactions have been reported. With recognition of various toxidromes and understanding management strategies, it is the hope that a decrease in morbidity and mortality will occur.

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23. Cohn J, Shapiro C, Keyes C, Smothers K: Neurologic disease associated with zidovudine [AZT (ZDV)] [abstract]. Presented at the 27th ICAAC, Washington, DC, 1987, p. 381. 24. Collaborative DHPG Treatment Study Group: Treatment of serious cytomegalovirus infections with 9-(1,3-dihydroxy-2-propoxymethyl) guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1986;314:801–805. 25. Connolly GM, Gazzard BG, Hawkins DA: Fixed drug eruption due to foscarnet. Genitour Med 1990;66:97–98. 26. Coopman SA, Johnson RA, Platt R: Cutaneous disease and drug reactions in HIV infection. N Engl J Med 1993;328:1670–1674. 27. Cote TR, Biggar RJ, Dannenberg AL: Risk of suicide among persons with AIDS. JAMA 1992;268:2066–2068. 28. Crumpacker KS, Bubley G, Hussey S, Connor J: Ribavirin enters cerebral spinal fluid. Lancet 1986;2:45–46. 29. Crumpacker KS, Heagy W, Bubley G, et al: Ribavirin treatment of the acquired immunodeficiency syndrome (AIDS) and acquired immunodeficiency syndrome–related complex (ARC). Ann Intern Med 1987;107:664–674. 30. Dalakas MC, Illa I, Pezeshkpour GH, et al: Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990; 322:1098–1105. 31. Dannenberg AL, McNeil JG, Brundage JF, et al: Suicide and HIV infection mortality follow-up of 4147 HIV-seropositive military service applicants. JAMA 1996;276:1743–1746. 32. DeClerq E: Perspectives for the chemotherapy of AIDS. Anticancer 1987;7:1023–1038. 33. Deeks SG, Volberding PA: Antiretroviral therapy: In: Sande MA, Volberding PA, eds: The Medical Management of AIDS, 6th ed. Philadelphia, WB Saunders, 1999, pp. 97–115. 34. DeMiranda P, Blum MR: Pharmacokinetics of acyclovir after intravenous and oral administration. J Antimicrob Chemother 1983;12 (Suppl B):29–37. 35. DeRay G, Diquet B, Martinez F, et al: Pharmacokinetics of zidovudine in a patient on maintenance hemodialysis. N Engl J Med 1988; 319:1606–1607. 36. Deyton LR, Walker RE, Kovacs JA, et al: Reversible cardiac dysfunction associated with interferon alfa therapy in AIDS patients with Kaposi’s sarcoma. N Engl J Med 1989;321:1246–1249. 37. Drew WL: Antiviral therapy of CMV infection. AIDS Reader 1993; 3:99–104. 38. Farese RV, Schambelan M, Hollander H, et al: Nephrogenic diabetes insipidus associated with foscarnet treatment of cytomegalovirus retinitis. Ann Intern Med 1990;112:955–956. 39. Fischl M, Galpin JE, Levine JD, et al: Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med 1990;322:1488–1493. 40. Fischl MA, Parker CB, Pettinelli C, et al: A randomized controlled trial of a reduced dose of zidovudine in patients with acquired immunodeficiency syndrome. N Engl J Med 1990;323:1009–1014. 41. Flexner C: HIV-protease inhibitors. N Engl J Med 1998;338: 1281–1292. 42. Furman PA, Fyfe JA, St Clair MH, et al: Phosphorylation of 3′azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA 1986;83:8333–8337. 43. Gilquin J, Weiss L, Kazatchkine MD: Genital and oral erosions induced by foscarnet [letter]. Lancet 1990;1:287. 44. Gold JWM: The diagnosis and management of HIV infection. In: Gold JWM, Telzak EE, White DA, eds: The Diagnosis and Management of the HIV-Infected Patient, Part 1. Med Clin North Am 1996; 80:1283–1307. 45. Greene WC: The molecular biology of human immunodeficiency virus type I infection. N Engl J Med 1991;324:308–317. 46. Grella M, Ofosu JR, Klein BL: Prolonged oral acyclovir administration associated with neutropenia and thrombocytopenia. Am J Emerg Med 1998;16:396–398.

47. Guay DRP: Pharmacokinetic of new macrolides. Infect Med 1992;9 (Suppl A):9–13. 48. Harb GE, Jacobson MA: Human immunodeficiency virus (HIV) infection: Does it increase susceptibility to adverse drug reactions? Drug Saf 1993;9:1–8. 49. Hardy WD: The human immunodeficiency virus. In: Gold JWM, Telzak EE, White DA, eds: The diagnosis and management of the HIV-infected patient, part I. Med Clin North Am 1996;80: 1239–1263. 50. Hargreaves M, Fuller G, Costello C, Gazzard B: Zidovudine overdose [letter]. Lancet 1988;2:509. 51. Henry JA, Hill IR: Fatal interaction between ritonavir and MDMA. Lancet 1998;352:1751–1752. 52. Hersh EM: Dithiocarb sodium (diethyldithiocarbamate) therapy in patients with symptomatic HIV infection and AIDS. JAMA 1991; 265:1538–1544. 53. Hughes W, Leoung G, Kramer F: Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 1993;328: 1521–1527. 54. Jaffuel D, Lebel B, Hillaire-Buys D, et al: Drug points: Eosinophilic pneumonia induced by dapsone. BMJ 1998;317:181. 55. Jones LJ, DeCock KM, Jaffe HW: Current trends in the epidemiology of HIV/AIDS. In: Sande MA, Volberding PA, eds: The Medical Management of AIDS, 6th ed. Philadelphia, WB Saunders, 1999, pp. 3–22. 56. Kahn J, Kaplan L, Gambertoglio J, et al: A phase I study of GLQ223 in subjects with AIDS and ARC. Paper presented at the VI International Conference on AIDS, San Francisco, June, 1990. 57. Klecker RW, Collins JM, Yarchoan R, et al: Plasma and cerebrospinal fluid pharmacokinetics of 3′-azido-3′-deoxythymidine: A novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther 1987;41:407–412. 58. Kovacs JA: Efficacy of atovaquone in treatment of toxoplasmosis in patients with AIDS. Lancet 1992;2:637–638. 59. Lambert JS, Seidlin M, Reichman RC, et al: 2′,3′-dideoxyinosine (ddI) in patients with acquired immunodeficiency syndrome or AIDS-related complex: A phase I trial. N Engl J Med 1990;322: 1333–1340. 60. Lane HC, Kovacs JA, Feinberg J: Anti-retroviral effects of interferon-
in AIDS-associated Kaposi’s sarcoma. Lancet 1988;2: 1218–1222. 61. Laskin OL, Longstreth JA, Hart CC, et al: Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome. Clin Pharmacol Ther 1987;41:546–555. 62. Lee BL, Moore L, Wilson M, et al: Increased prevalence of slow acetylator status in patients with the acquired immunodeficiency syndrome. Abstract presented at the 93rd annual meeting of the American Society of Clinical Pharmacology and Therapeutics, Orlando, March 1992, p. 183. 63. Masur H: Drug therapy: Prevention and treatment of Pneumocystis pneumonia. N Engl J Med 1992;327:1853–1860. 64. Mayer RA, Sergios PA, Coonan K, O’Brien L: Trichosanthin treatment of HIV-induced immune dysregulation. Eur J Clin Invest 1992;22:113–122. 65. McGrath MA, Hwang KM, Caldwell SE, et al: GLQ223: An inhibitor of human immunodeficiency virus replication in acutely and chronically infected cells of lymphocyte and mononuclear phagocytes lineage. Proc Natl Acad Sci USA 1989;86:2844–2848. 66. Mcphedran P: Using hematopoietic hormones in HIV disease. AIDS Clin Care 1992;4:43–44. 67. Meng TC, Fischl MA, Boota AH, et al: Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. Ann Intern Med 1992;116:13–20. 68. Meruelo D, Lavie G, Lavie G: Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic

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75. 76.

77. 78.

79. 80.

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83.

84. 85.

86. 87.

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polycyclic diones hypericin and pseudohypericin. Proc Natl Acad Sci USA 1988;85:5230–5234. Miles SA, Mitsuya RT, Lee K, et al: Recombinant human granulocyte colony-stimulating factor increases circulating burst forming unit: Erythron and red blood cell production in patients with severe human immunodeficiency virus infection. Blood 1990;75: 2137–2142. Moore EC, Cohen F, Kauffman RE, Aravind MK: Zidovudine overdose in a child. N Engl J Med 1990;322:408–409. Moore RD, Fortyana I, Keruly J, et al: Adverse events from drug therapy for human immunologic virus disease. Am J Med 1996; 101:34–40. Moyle GJ, Sadler M: Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf 1998; 19:481–494. Navin TR, Miller KD, Satriale RF, Lobel HO: Adverse reactions associated with pyrimethamine-sulfadoxine prophylaxis for Pneumocystis carinii infections in AIDS. Lancet 1985;1:1332. Obrien RJ, Lyle MA, Snider DE Jr: Rifabutin (ansamycin LM 427): A new rifamycin-S derivative for the treatment of mycobacterial disease. Rev Infect Dis 1987;9:519–530. Pickus OB: Overdose of zidovudine [letter]. N Engl J Med 1988; 318:1206. Pluda JM, Yarchoan R, Smith PD, et al: Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with zidovudine in leukopenic patients with severe human immunodeficiency virus infection. Blood 1990;76:463–472. Rao TK: Renal complications in HIV disease. Med Clin North Am 1996;80:1427–1451. Raviglione MC, Dinan WA, Pablos-Mendez A, et al: Fatal toxic epidermal necrolysis during prophylaxis with pyrimethamine and sulfadoxine in a human immunodeficiency virus infected person. Arch Intern Med 1988;148:2683–2685. Reines ED, Gross PA: Antiviral agents. Med Clin North Am 1988; 72:691–715. Reiter WM, Cimoch PJ: Dapsone-induced methemoglobinemia in a patient with P. carinii pneumonia and AIDS. N Engl J Med 1987; 317:1741–1742. Roberts RB, Jurica K, Meyer WA, et al: Phase I study of ribavirin in human immunodeficiency virus infected patients. J Infect Dis 1990; 162:638–642. Robinson PA, Knirsch AK, Joseph JA: Fluconazole for lifethreatening fungal infections in patients who cannot be treated with conventional antifungal agents. Rev Infect Dis 1990;12(Suppl 3): S349–S363. Roederer M, Ela SW, Staal FJ, et al: N-Acetylcysteine: A new approach to anti-HIV therapy. AIDS Res Hum Retroviruses 1992; 8:209–217. Routy JP, Prajs E, Blanc AP, et al: Seizure after zidovudine overdose. Lancet 1989;1:184–185. Schinazi RF, Chu CK, Babu JR, et al: Anthraquinones as a new class of antiviral agents against human immunodeficiency virus. Antiviral Res 1990;13:265–272. Schoenfeld P: HIV infection and renal disease. AIDS Clin Care 1991;3:9–11. Selwyn PA, Alcabes P, Hartel D, et al: Clinical manifestations and predictors of disease progression in drug users with human immunodeficiency virus infection. N Engl J Med 1992;327:1607–1703. Sin DD: Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals. J Acquir Immune Defic Syndr Hum Retroviral 1996; 12:477–481.

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89. Sjovall J, Bergdahl S, Movin G, et al: Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1989;33:1023–1031. 90. Sjovall J, Karlson A, Ogenstad S, et al: Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus. Clin Pharmacol Ther 1988;44:65–73. 91. Smith PD: Gastrointestinal infections in AIDS. Ann Intern Med 1992;116:63–177. 92. Spear JB, Kessler HA, Lehrman SN, de Miranda P: Zidovudine overdosage. Ann Intern Med 1988;109:76–77. 93. Staal FJT, Ela SW, Roederer M, et al: Glutathione deficiency and human immunodeficiency virus infection. Lancet 1992;1:909–912. 94. Sugar AM, Stern JJ, Dupont B: Overview: Treatment of cryptococcal meningitis. Rev Infect Dis 1990;2(Suppl 3):S338–S348. 95. Sundar K, Suarez M, Banogon PE, et al: Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome: Report of two patients and review of the literature. Crit Care Med 1997;25:1425. 96. Tanowitz HB, Simon D, Weiss L, et al: Gastrointestinal manifestations. In: Gold JWM, Telzak EE, White DA, eds: The Diagnosis and Management of the HIV-Infected Patient, part 1. Med Clin North Am 1996;80:1395–1414. 97. Tay-Kearney ML, Jabs DA: Ophthalmic complications of HIV infection. In: Gold JWM, Telzak EE, White DA, eds: The Diagnosis and Management of the HIV-Infected Patient, part 1. Med Clin North Am 1996;80:1471–1492. 98. Threlkeld SC, Hirsch MS: Antiviral therapy: The epidemiology of HIV and AIDS: Current trends. In: Gold JWM, Telzak EE, White DA, eds: The Diagnosis and Management of the HIV-Infected Patient, part 1. Med Clin North Am 1996;80:1263–1283. 99. Waites L, Levin AS, Starrett BA, et al: Trichosanthin treatment of HIV disease. Paper presented at the sixth international conference on AIDS, San Francisco, June 1990. 100. Walker RE, Parker RI, Kovacs JA, et al: Anemia and erythropoiesis in patients with acquired immunodeficiency syndrome (AIDS) and Kaposi sarcoma treated with zidovudine. Ann Intern Med 1988;108: 372–376. 101. Watts RG, Conte SE, Zuilinden E, et al: Effect of charcoal hemoperfusion on clearance of pentamidine after accidental overdose. J Toxicol Clin Toxicol 1997;35:89–92. 102. Wharton JM, Demopulos PA, Goldschlager N: Torsades des pointes during administration of pentamidine isothionate. Am J Med 1986; 83:571–576. 103. Whitley RJ, Gnann JW Jr: Acyclovir: A decade later. N Engl J Med 1992;327:782–789. 104. Wolf Y, Haddad R, Jossopov J, et al: Alpha interferon induced severe pneumonitis. J Toxicol Clin Toxicol 1997;35:113–114. 105. Yarchoan R, Klecker RW, Weinhold KJ, et al: Administration of 3′azido-3′-deoxythymidine, an inhibitor of HTLV III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet 1986;1: 575–580. 106. Yarchoan R, Thomas RV, Allain JP, et al: Phase I studies of 2′,3′dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988;1:76–81.

CHAPTER

109 SUBSTANCE USERS James E. Cisek

This chapter focuses on the assessment and management of complications arising in substance users, unrelated to the direct effects of the drugs involved. Optimal medical and psychiatric care and the initiation of preventive strategies require the healthcare provider to have a thorough understanding of all aspects of the substance user’s life. The following discussion focuses on the epidemiology of substance use and aims to provide a further understanding of the infectious, traumatic, psychiatric, and sociologic issues unique to the substance-using population.

DIAGNOSING SUBSTANCE DEPENDENCE/ABUSE DISORDERS There are many substance users, and a certain percentage of them are drug dependent. In the most recent Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), a diagnosis of substance dependence is based on the presence of at least three symptoms (from a list of seven) occurring at any time in a 12-month period (Table 109–1).5 This modified concept of dependence stresses the impaired control of substance use and applies to a variety of substances that do not normally produce signs of physiologic dependence (eg, anticholinergics, nonsteroidal antiinflammatory agents). Substance abuse implies a dangerous pattern of substance use and includes the inability to fulfill important roles (eg, neglect of children, absence from work), frequent use in physically hazardous environments (driving an automobile, operating a machine), recurrent substance-related legal problems, and continued use despite social problems caused or worsened by the effects of the substance.5 Despite these rather clear definitions, there is still a great deal of controversy as to what constitutes drug use, dependence, and abuse. The risk analysis for the single use of a drug is extensive and includes infection, injury, and end-organ toxicity such as stroke or myocardial ischemia. Individuals who use drugs multiple times have added risks that include such entities as dependence, prostitution, criminal activities such as theft and drug sales, violence, homelessness, and lost productivity. The societal implications of these behaviors are significant; it is estimated that 21% of tax dollars in New York City are spent on problems related to substance abuse.16

may be approached differently than that of an infectious disease or hypertension. The application of traditional epidemiologic concepts to the study of substance use should be done with great caution. The use of drugs may be prolonged, short-term, or episodic and may be associated with unique aspects of life style. Data collection can be difficult because there is no universally accepted point that separates “use” from “abuse.” Reports of drug availability and the aggressiveness of law enforcement may vary greatly and give false impressions of the prevalence of substance use. For example, a brief visit by a clandestine chemist to a community may be followed by a sharp rise in the synthesis and use of a “designer drug.”30 The limitations of epidemiologic data can be appreciated by an understanding of the methods and sources of data collection. Many different methods exist to define the epidemiology of substance abuse. The Drug Abuse Warning Network (DAWN), part of the federal agency SAMHSA, collects data on persons presenting to emergency departments aged 6 years and older.90 In 1999, 488 hospitals participated in data collection. Data are collected by designated members of the emergency department or medical records staff based on the emergency department record and analytic drug detection. At each facility reporting data, a drug-related episode must meet all four of the following criteria:

EPIDEMIOLOGY It has been proposed that the proper theoretical construct should consider drug use as a communicable disease.47,49 This is controversial, as the study of the frequency and distribution of drug use

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1. The patient was treated in the hospital emergency department. 2. The presenting problem was directly related to drug use. 3. The case involved the use of an illegal drug or the use of a legal drug contrary to directions. 4. The patient’s reason for taking the substance includes dependence, suicide attempt, and/or mind-altering effects. The DAWN data provide useful information on trends in morbidity and mortality associated with illicit drugs, but the data must be interpreted with caution because only episodes in which a drug is part of the presenting problem are reported. For example, an increased reporting of cocaine could mean that more cocaine users with HIV-related infections are seeking medical care rather than that more persons are using cocaine. The analysis does not indicate the nature of the relationship between drug use and the presenting problem; which of the various drugs, if any, caused the episode; or if the patient was a naive or experienced substance user. Finally, there is concern that DAWN data may underreport drug-related episodes.12 Critically ill patients may not provide a history of drug use in the emergency department, and analytic results are often not available until the patient has left the emergency department. Records generated outside of the emergency department are excluded from review. In summary, DAWN data are

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TABLE 109–1. Substance Dependence Defined by at Least Three of the Following in a 12-Month Period • Tolerance • Withdrawal • Administration in larger doses or over longer periods than originally intended • Decreased control over usage • Increased time investment in acquisition, use, or recovery from the substance • Decreased participation in occupational, recreational, or social events • Continued use despite social, psychological, or physical problems caused by the substance Reprinted, with permission, from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, APA, 1994.

valuable, but the healthcare provider must understand their significant limitations (see Chap. 116 for further discussions). The 1999 National Household Survey on Drug Abuse (NHSDA) surveyed 66,706 individuals aged 12 and older in households, noninstitutional group quarters (eg, shelters, rooming houses, dormitories), and civilians living on military bases.91 This survey collected data on the time of last drug use and frequency of illicit drug use, opinions about drugs, problems associated with drug use, and drug abuse treatment experience. Demographic data were also collected including employment, education, income, general and mental health status, and access to health care. In 1999, a new sample design was initiated using an interactive, bilingual, computer-based questionnaire that allowed the sample size to be expanded almost fourfold from previous years and included both national and state assessments of substance use prevalence. Other sources of data include information obtained from local and federal law enforcement agencies detailing trends in drug preferences, purity, and prices. Prescription audits establish the changes in prescribing patterns for a specific drug. Many communities perform independent local surveys to define attributes of the region that contribute to the area’s incidence and prevalence of substance use. The most recent data from the National Household Survey on Drug Abuse revealed that an estimated 14.8 million Americans (6.7% of the population 12 years of age and older) were current (in the month before the interview) illicit drug users. This is an approximately 40% decrease from 1979, which was the year with the highest recorded rate. Four percent of the 12-year-olds reported current drug use, with inhalants and nonmedical use of psychotherapeutics being most common. By age 14, the rate of current drug use increased to 9.2%, with marijuana being the dominant drug. In 1999, 10.9% of adolescents (12 to 17 years) were current users of illicit substances. Of the adolescents, 7.7% had used marijuana, and 5.3% had used some other illicit drug. The highest rates of drug use were among those individuals aged 18 to 20, with rare individuals using illicit drugs after age 50 years. Fifty-six percent of youth reported that obtaining marijuana was fairly or very easy, and 16% had been approached during the past 30 days by someone offering to sell them drugs. Men have a higher rate of current illicit drug use than women (8.7 vs 4.9%). Among pregnant women, 3.4% reported the current use of illicit drugs, which was significantly lower than in agematched nonpregnant women (8.1%). The rate of illicit drug use in metropolitan areas (7.1%) was higher than in rural areas (4.2%).

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The rate of current illicit drug use for blacks (7.7%) remained higher than for whites (6.6%) and Hispanics (6.8%) in 1999. The rate was highest among the Native American/Inuit population (10.6%) and lowest among Asians (3.2%). Illicit drug use correlates with educational status, with those who had not completed high school having the highest rate of use (7.1%), while college graduates have the lowest rate of use (4.8%). In addition to education, current employment status predicts illicit drug use. In 1999, 16.5% of unemployed adults versus 6.5% of full-time employed adults used illicit drugs. The cause-and-effect relationship of all these data is unclear. Approximately 30.2% of all Americans are currently smoking tobacco. Of the users, 25.8% smoked cigarettes, 5.5% smoked cigars, 3.4% used smokeless tobacco, and 1.1% smoked pipes. Up to age 20, current cigarette smoking rates increase by year of age from 2.2% at age 12 to 43.5% at age 20. After age 25, rates decline, reaching 22.5% in the 50 to 64 age group and 10.7% of people aged 65 and older. Native Americans and Inuits have the highest rate of tobacco usage, with 43.1% reporting the current use of at least one form of tobacco. The lowest current tobacco use rates were observed for Asians (18.6%). Current cigarette use is highly correlated with illicit drug use, and this association is strongest for adolescents. Men were more likely to report use of tobacco products. In general, the prevalence of cigarette smoking decreases with increasing levels of education. In 1999, 47.3% of the population older than 12 years were current ethanol users, with 20.2% involved in binge drinking (five or more drinks at one occasion in the past month) and 5.6% classified as heavy users (five or more drinks per occasion on five or more days in the past month). About 29.4% of persons 12 to 20 years of age reported current use of alcohol. Of this underage group, 20.2% were binge drinkers, and 6% were heavy drinkers. Individuals between the ages of 18 and 25 years had the highest prevalence of binge and heavy drinking, with the peak rate occurring at age 21. Whites have the highest rate of current ethanol use, and Asians have the lowest. Men have greater representation in all categories of ethanol consumption. The level of alcohol use was strongly associated with illicit drug use. The rates of alcohol consumption also increased with increasing educational attainment and for fulltime employment. An evaluation of trends in the NHSDA data indicates that rates of marijuana use are currently increased relative to the 1980s and are approximately equal to rates seen in mid- to late 1970s. Of great concern is the doubling of the rate of heroin initiation in the age group 12 to 17. The annual number of new users of any form of cocaine increased by 45% between 1994 and 1999 with an over threefold increase in the age 12 to 17 group. The rate of new hallucinogen use has remained constant over the past several years but is markedly elevated from the 1980s. The rate of new inhalant use has more than doubled over the past 8 years. The rate of first use of methamphetamine among youths aged 12 to 17 rose significantly from 1990 to 1998, from 2.2 to 7.4 per 1000 potential new users. DAWN data indicate that the four drugs mentioned most commonly in emergency department reports—alcohol-in-combination (35%), cocaine (30%), marijuana (16%), and heroin/morphine (15%)—were unchanged from the previous year. The majority of individuals indicated that smoking and sniffing heroin were the most common routes of administration, with only 37% ever having injected heroin by 1999. Compared to 1998, total drug-related emergency department episodes were stable for gender, race/eth-

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nicity, and most age subgroups. Dependence and suicide were the most frequently cited motives for taking the drugs among the group of emergency department patients. Illicit drug mentions increased from 1990 to 1999 as follows: marijuana (455%), methamphetamine (100%), heroin (149%), and cocaine (110%). Among patients aged 35 and older, drug-related episodes increased 124% from 1990 to 1999, while the episodes in the other age groups increased less than 20%. Inhalants were not ranked in the 15 most-mentioned drugs for any age group.

MEDICAL PROBLEMS RELATED TO ADULTERANTS, CONTAMINANTS, DILUENTS, AND ROUTES OF ADMINISTRATION In the clinical evaluation of patients who are using “street drugs,” the presence of a variety of unknown chemicals should be presumed. Contaminants are by-products of the synthetic or preparatory process. Diluents are bulk-enhancing inactive substances that have similar physical properties (color, physical state, taste, odor) to the illicit drug and serve to decrease the quantity of active drug. Common diluents include any of the sugars (mannitol, inositol), cornstarch, flour, talc (magnesium silicate), and sodium bicarbonate. Adulterants are intentionally added pharmacologically active agents, and are chosen to provide either synergistic or antagonistic effects. An example of a synergistic adulterant would be the addition of phenobarbital to low-grade heroin to enhance the central nervous system (CNS) depression. Antagonistic adulteration would be illustrated by the addition of caffeine to heroin as an analeptic agent to diminish the depressant effects of heroin and enable more drug to be used.87 Common adulterants found in cocaine, heroin, and hallucinogens include any of the local anesthetics (lidocaine most commonly), caffeine, amphetamines, phencyclidine, lysergic acid diethylamide, and phenylpropanolamine.32 Occasionally, substances are added for the purpose of inflicting physical harm (eg, strychnine, thallium). Data from crime laboratories indicates that many street drug sales involve illicit material with no mind-altering potential, sold for large sums of money to the unwary substance user. Of 614 alleged cocaine samples collected in Los Angeles County, cocaine was found to be totally absent in 19%, combined with stimulant substitutes in 23%, and found by itself in 58%. Fifty percent of the amphetamine samples lacked any of the alleged drug.53 A more recent illustration of street drug impurities involves the adulteration of heroin with scopolamine.41 Of the 241 patients who were available for this analysis, 55% presented with signs and symptoms of heroin intoxication. Interestingly, these patients became severely agitated with anticholinergic symptoms when naloxone was administered. Clandestine drug laboratories may produce an undesired chemical as a result of a sloppy synthesis. In the early 1980s, “designer” chemists produced a formulation contaminated with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) while attempting to synthesize an analogue of meperidine. This contaminant caused a rapidly developing, severe form of parkinsonism characterized by hypokinesia, rigidity, tremor, and fixed posture (see Chap. 62).15,55 The illegal synthesis of drugs can also be associated with potential exposures to metals, caustics, and solvents. These unintentional exposures occur during the synthetic process or by the

injection of contaminated product. Methcathinone (CAT) is a synthetic amphetamine produced from ephedrine. In the synthesis, ephedrine is oxidized using sodium dichromate in an acid environment and then extracted using solvents. “Green cat” was sold at a reduced price and was contaminated with residual chromium salts, with the potential for chromium-induced multisystem organ failure.30 Methamphetamine abuse was associated with an epidemic of lead poisoning when lead acetate was used in the synthetic process.3,57 Law enforcement personnel consider all clandestine laboratories as harboring hazardous materials and proceed with great caution in their investigations. Unique medical problems also occur in substance users related to the route of drug administration. Barotrauma occurs in individuals while smoking cocaine and nasally insufflating cocaine and other drugs. Patients will present with cough, chest pain, and dyspnea secondary to a pneumothorax, pneumomediastinum, or pneumopericardium. Barotrauma occurs secondary to an increased intraalveolar pressure generated by the deep inhalation followed by a Valsalva maneuver and the cough provoked by the drug and heated gases. Carbonaceous sputum is quite common in individuals smoking cocaine and is probably related to the inhalation of residue from the butane and alcohol used to ignite the drug.40 Heroin overdose can also be associated with acute lung injury (ALI/ARDS) accompanied by fever and leukocytosis. ALI is most likely related to hypoxia and usually becomes clinically apparent within 6 hours of the toxicity but may be delayed up to 24 hours (see Chap. 95). Chronic exposure to starch, cotton fibers, and talc causes pulmonary granulomas when injected.75 The chronic nasal application of cocaine commonly leads to epistaxis and septal perforation.

MEDICAL ILLNESS IN THE SUBSTANCE USER The poisoned patient’s clinical manifestations are often nonspecific and could represent acute medical, surgical, psychiatric, or combined processes.20,21,72,73,86 A thorough history and physical examination are essential because the differential diagnosis is often extensive. Medical causes must be meticulously sought before a primary psychiatric disease can be diagnosed. A psychiatric diagnosis in a substance user must often be a diagnosis of exclusion. Drug-induced agitation or coma has an extensive differential diagnosis and involves many substances that may not be reported on routine urine and serum drug screens. Without a history, it is often impossible to distinguish between a primary medical event and a drug-induced event. Even then, the primary and secondary characteristics can simulate each other. It is best to admit the patient to a medical facility and provide close observation for either clinical resolution or worsening symptomatology. The healthcare provider must always assume the presence of concomitant trauma and thoroughly examine the patient for subtle injuries.

INFECTIOUS COMPLICATIONS The diagnosis and management of the infected substance user can be complicated by the presence of multiple medical problems and the unique psychosocial aspects of the individual’s life. Common difficulties are the lack of a clear history, malnutrition, poverty, homelessness, concomitant HIV-1 infection, noncompliance, and

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associated mental illness. Parenteral drug users often purchase “street” antibiotics at the time they obtain their drugs. One study demonstrated that 18% of intravenous drug users (IVDUs) had purchased antibiotics compared to only 5% of nonparenteral drug users.59 The self-administration of antibiotics before hospital arrival can make the diagnosis of an infectious process very difficult. Frequent parenteral injections, colonization with resistant Staphylococcus aureus, and the self-administration of antibiotics are important considerations in the evaluation of infectious processes. The drug itself is usually not contaminated with the causative organism.70 Immunologic dysfunction is probably of minor importance in the pathogenesis of infection in drug users who are not infected with HIV. There is no evidence for an impaired humoral immunity in parenteral drug users. In fact, there is evidence of a polyclonal B-cell activation with IgM, the immunoglobulin most frequently elevated in IVDUs. Clinical examples of enhanced humoral response include a false-positive rheumatoid factor and Venereal Disease Research Laboratory (VDRL) test. Depressed cell-mediated immunity is, however, common in IVDUs. In vitro lymphocyte response to mitogens is diminished by the addition of methadone, and the delayed hypersensitivity skin test is commonly absent in heroin addicts. Altered populations and functioning of helper, suppressor, and natural killer cells are demonstrated in patients receiving methadone, but the clinical significance is uncertain. Clinical infections typical of T-cell dysfunction were uncommon in drug abusers before the advent of the HIV virus.13,56 The influence of cocaine on the immune response is an area of active research, with data thus far suggesting an immunosuppressive effect of cocaine and its metabolites. Cocaine increases the risk of HIV infection in humans even when there is control for parenteral drug use. It is postulated that this increased susceptibility may be a result of decreased immune function in these patients.22,23,54,77,79,98 Interestingly, cocaine has an antiviral effect in vitro by enhancing the secretion of interferon.36 Infection is the most common cause of death in hospitalized parenteral drug users. Infectious complications account for 60% of hospital admissions among IVDUs, and endocarditis is associated with 5 to 8% of these episodes.59 It is estimated that two cases of endocarditis will occur per 1000 IVDUs per year.59 Infective endocarditis implies infection of the endocardial surface of the heart and the physical presence of microorganisms in the lesion. Endocarditis is of great importance, given its high frequency of serious complications and significant mortality. The initial history and physical examination are of limited value in diagnosing endocarditis in the febrile IVDU. Fever is nonspecific because it may be associated with bacterial, viral, fungal, or protozoan infections; reactions to injected drugs, adulterants, or contaminants; or of unknown origin. The presence of embolic phenomena and echocardiographically demonstrated vegetations are the most important predictors of endocarditis in febrile IVDUs. All IVDUs with a fever should be admitted for the evaluation of bacteremia and possible endocarditis.95 The diagnosis of viral syndromes and other trivial illnesses cannot be established on the initial evaluation. Of all parenterally abused drugs, cocaine injection has the highest incidence of endocarditis.18 Table 109–2 lists the common criteria adopted for the diagnosis of endocarditis in the IVDU.95 Endocarditis in the IVDU presents in a similar fashion to non–substance-using patients with a few exceptions. Important differences include a high incidence of right-sided endocarditis

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TABLE 109–2. Criteria for Diagnosis of Endocarditis in Parenteral Drug Users 1. Temperature greater than or equal to 38.0°C (100.4°F) with two positive blood cultures and vegetations on 2-D echocardiography. 2. Temperature greater than or equal to 38.0°C (100.4°F) with new vegetations seen on 2-D echocardiography with negative blood cultures (culture-negative endocarditis). 3. Positive blood cultures with new vegetations seen on 2-D echocardiography in absence of fever. 4. Temperature greater than 38.0°C (100.4°F), positive blood cultures, evidence of systemic embolization or valve regurgitation, but absence of vegetations on echocardiography. Reprinted, with permission, from Weisse AB, Heller DR, Schimenti RJ, et al: The febrile parenteral drug abuser: A prospective study in 121 patients. Am J Med 1993;94: 274–280.

(tricuspid valve) and the absence of underlying structural heart disease in two-thirds of IVDUs with endocarditis.94 Cardiac murmurs are noted in only 35% of IVDUs with proven endocarditis.59 The distribution of valvular involvement in IVDUs with endocarditis is illustrated in Table 109–3.60 A study of 74 intravenous opioid abusers with endocarditis found the following bacterial agents: Staphylococcus aureus, 61%17; streptococci, 16%; Pseudomonas aeruginosa, 14%; polymicrobial, 8%; and Corynebacterium, 1%.59 S. aureus is of endogenous origin in the majority of cases, as it is infrequently isolated from street heroin or paraphernalia. Biventricular and multiple-valve disease occur more frequently with Pseudomonas infections. Left-sided endocarditis secondary to P. aeruginosa is often refractory to antibiotic therapy and has a mortality rate of 60%. Regional and transient variations occur (eg, P. cepacia for a few years in New York City), making it important that clinicians have knowledge of current epidemiologic trends unique to their institutions. HIV infection predisposes the IVDU to unusual pathogens including Corynebacterium species, Neisseria species, Salmonella species, and fungal infections of the endocardium.27,67,83 Parenteral drug abuse is the most common risk factor for recurrent nativevalve endocarditis. Patients frequently survive the initial infection, with subsequent infections causing more significant cardiac complications (valvular dysfunction, myocardial abscess, and conduction blocks). A study of IVDUs with endocarditis and HIV infection demonstrated that HIV infection was not associated with a lower maximum temperature but was associated with a decreased white blood cell count.84 A prospective cohort study of 292 consecutive IVDUs with endocarditis found that clinical outcome was generally similar according to HIV status but that a CD4 count less than 200 was a strong risk factor for mortality.82 All IVDUs who present with fever (>38°C, >100.4°F) should be admitted and have at least two blood samples obtained from different sites for aerobic, anaerobic, and fungal cultures (Fig.

TABLE 109–3. Distribution of Valvular Involvement in Intravenous Drug Users with Endocarditis Tricuspid valve alone or in combination Aortic valve alone Mitral valve alone Aortic and mitral valves together

52% 19% 11% 13%

Reprinted, with permission, from Levine D, Sobel J: Infections in Intravenous Drug Abusers. New York, Oxford University Press, 1991.

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109–1).68,95 Empiric antibiotic therapy should consider the most common organisms and their antibiotic sensitivities in the geographic location. Initial coverage is usually directed against S. aureus using either nafcillin or vancomycin if methicillin-resistant organisms are common. The addition of an aminoglycoside provides synergy against S. aureus and may shorten the duration of therapy to 2 weeks in patients with right-sided endocarditis. Leftsided involvement mandates 6 weeks of intravenous antibiotic therapy. The typical aminoglycoside dosing used for synergy with S. aureus provides little effect against Pseudomonas, which requires large doses (8 mg/kg) for satisfactory activity. The initial use of an aminoglycoside to provide protection against gram-negative organisms is controversial. Enterococcal endocarditis is typically treated with a combination of vancomycin and gentamicin. Enterococci that develop gentamycin resistance are commonly treated with streptomycin, and resistance to vancomycin is treated with early surgical intervention, as there is no established antibiotic therapy. It is essential that antibiotic therapy is based on susceptibility data and that pharmacokinetic information is followed closely. Septic emboli are frequent after the initiation of antibiotic therapy. Vegetation size does not correlate with embolization; however, vegetations greater than 2 cm are associated with a 33% mortality versus a 1.3% mortality with vegetations less than than 2 cm.21,60 Skin and soft tissue infections represent the most common infectious etiologies requiring hospital admission (Fig. 109–2). Approximately one-third of IVDUs, particularly those who inject subcutaneously or intramuscularly, have soft tissue abscesses or cellulitis at any give time. Microbiologic contamination can occur at one of any steps, including production, mixing, dilution, or

Figure 109–1 Algorithm for the evaluation of the febrile intravenous drug user.

Figure 109–2 Markedly swollen hands with ulcerated cellulitic forearms in a chronic heroin user. The dorsum of each hand demonstrates nonpitting edema.

preparation of the drugs or at the time of injection through contaminated paraphernalia or skin. The infection may involve only a limited region of the epidermis and superficial dermis, as in “skin popping,” or may extend into a more typical abscess, cellulitis, or necrotizing fasciitis. The infection may progress to involve the mediastinum, great vessels, muscle, or fascia and can lead to sepsis and death. Necrotizing fasciitis may present subtly with pain and hemodynamic instability disproportionate to the apparent diameter of the infected area. Great care must be maintained, as bullae, crepitance, and skin necrosis are late physical findings in necrotizing fasciitis. Imaging procedures such as ultrasound or computed tomography can help identify abscesses in the neck and groin if the diagnosis is uncertain. Vascular imaging before surgery is sometimes necessary if a pseudoaneurysm is suspected at the infected site (Fig. 109–3). Early antibiotic therapy and surgical drainage are essential.9,21,60 Suppurative thrombophlebitis is an inflammation of the vein wall caused by the presence of bacteria and is frequently associated with thrombosis. Fever, warmth, tenderness, swelling, and lymphadenopathy are common. Superficial and deep venous involvement may occur, depending on the injection site (Fig. 109–4). Recurrent injections can lead to deep venous thrombosis with the potential for pulmonary emboli. Antibiotic therapy should include a semisynthetic penicillin or vancomycin. Surgery is usually required. Anticoagulants are usually contraindicated because a clear benefit has not been established, and the IVDU is at great risk from complications related to anticoagulation.21,60 Mycotic aneurysms may occur as an isolated entity or accompany endocarditis. The femoral (most common) and neck vessels are the sites of mycotic aneurysms that occur directly during the injection of drugs. Frequent intravascular injections cause the formation of a perivascular hematoma that subsequently becomes infected by direct spread of cutaneous bacteria or overlying infections. These usually represent pseudoaneurysms, as only the vascular adventitia is involved. Involvement of the cerebral or abdominal vessels most commonly occurs during an episode of bacteremia with infection of the arterial vasa vasorum. Common clinical findings include fever, a painful pulsatile mass associated with a bruit or thrill, and ischemia distal to the mass. Early diagnosis before rupture is essential and commonly involves the use of

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A

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B

Figure 109–3 A. Chest radiograph of a young drug abuser who used the supraclavicular approach for heroin injection. The large mass in the left chest was thought to be a pseudoaneurysm. B. An arch aortogram performed on the patient revealed a large pseudoaneurysm and hematoma subsequent to an arterial tear during attempted injection. Surgical repair was performed. (Courtesy of Richard Lefleur, Department of Radiology, Bellevue Hospital.)

ultrasound or angiography. Needle aspiration and incisions must be avoided in inguinal or neck masses before imaging procedures, as clinical examination may be unreliable in detecting the presence of an aneurysm. Early surgical excision is usually required, as expansion and rupture are common.21,60 Viral hepatitis is very common in substance users and is acquired by parenteral drug administration and by sexual transmission. Virtually every form of viral hepatitis can be found in substance users with high prevalence and incidence rates. IVDUs account for 15% of acute hepatitis B infections. Data from the United States and Europe indicate that 25 to 50% of IVDUs have antibodies against hepatitis B surface antigen.46,78,85 Approximately 5 to 12% of infected patients become hepatitis B surface antigen carriers with higher percentages among those who are also HIV infected. Ethanol abuse in combination with hepatitis B infection is associated with a more severe injury to the liver. Hepatitis B polymerase chain reaction testing of 681 syringes returned to a needle exchange program revealed a decline from 7.8% at the programs outset to 2.6% and an overall rate of 12.1% for Hepatitis C antibodies. The hepatitis D virus is a co-virus that requires the presence of hepatitis B for its replication. This virus occurs in 80% of chronic carriers of hepatitis B but is present in less than 10% of IVDUs who have serum antibodies to hepatitis B surface antigen. Patients are most commonly infected with hepatitis B before they acquire of hepatitis D. Simultaneous infection with both hepatitis B and D is uniquely common in IVDUs and will more likely result in fulminant hepatic failure.58 Hepatitis C (HCV) is the next emerging infectious disease (after HIV) to strike persons who inject drugs. HCV infection fre-

quently occurs early in the time course of drug use, usually before the patient seeks help for drug problems. Of additional concern is the fact that approximately 80% of persons infected become chronic carriers. There is currently no vaccine for HCV, and the rapid mutation rate of the virus will make development difficult.97 A recent study in the United States found 1.8% of unselected patients to have antibodies to hepatitis C, with people using illegal drugs or engaging in high-risk sexual behavior accounting for the majority of cases.4 The incidence of hepatitis C among IVDUs is in excess of 70% in Amsterdam and Spain.43 A study of 362 IVDUs in a Spanish prison found the prevalence of concomitant HBV-HCV to be 42.5%, and the HIV-HBV-HCV coninfection rate was 37.3%. The overall rate of a single virus infection was 13%. A case-control study of 2316 HCV-seropositive blood donors revealed intravenous drug abuse (odds ratio 50) and sex with an IVDU (odds ratio 6.3) to be strong risk factors for HCV among United States blood donors. In the United States, intravenous drug use currently accounts for 60% of HCV transmission, while sexual exposures account for 20%, and other known exposures (occupational, hemodialysis, household, perinatal) account for 10%. Blood transfusion rarely accounts for recently acquired HCV infections. July 1992 is when multiantigen anti-HCV tests to screen blood donors came into general use. Even among IVDUs who do not share needles, 54% of HCV infections may be attributed to cooker/cotton sharing.39 Because 25% of patients infected with HCV will develop end-stage liver disease, it is a statistical certainty that a large number of drug users will develop cirrhosis. Even with antiviral therapy, the need for liver transplants will exceed the number of organs available in the very near future.1,64

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY sites include the sternoclavicular, manubriosternal (Fig. 109–5), costochondral (almost pathognomonic for substance use), and sacroiliac joints. Vertebral osteomyelitis commonly involves the cervical and lumbosacral spine (see Fig. 8–12B) and may lead to epidural abscess formation with possible spinal cord compression. Patients with vertebral body infections often have an early subtle presentation, and a prompt diagnosis is based on a heightened awareness in a substance user with spine pain, fevers, and/or focal neurologic deficits. A diagnostic aspiration is essential in assessing skeletal infections, as there is commonly a discrepancy between organisms causing bone and joint infections and those isolated from the blood. Specific antimicrobial therapy for 4 to 6 weeks is essential, along with frequent arthrocentesis and debridement of necrotic bone as needed.19 The rheumatologic manifestations of hepatitis B or hepatitis C and chronic amyloidosis associated with frequent parenteral drug use should also be considered in substance users with bone or joint pain.48 The evaluation of a substance user with neurologic findings is quite challenging and must involve both infectious and noninfectious etiologies. In the non–HIV-infected patient, endocarditis is the most common cause of CNS infection, which includes brain abscesses, meningitis, and subarachnoid hemorrhage from ruptured mycotic aneurysms. Mycotic aneurysms present with focal neurologic dysfunction as a result of the expanding aneurysm, or subarachnoid/intracerebral hemorrhage (see Fig. 8–24). Cerebral

Figure 109–4 Venogram of a 50-year-old patient who routinely injected heroin into his groin. Occlusion of the femoral vein (large arrow) with diffuse aneurysmal dilation (small arrow) and extensive collaterals are shown. Incidental radiopaque materials are noted in the right buttock (double arrow). By history, this represents either bismuth or arsenicals he received as antisyphilitic therapy. (Courtesy of Richard Lefleur, Department of Radiology, New York University.)

Splenic abscesses are common and may be multiple and small or singular and large. Common symptoms include fever, abdominal pain, left shoulder pain, and pleuritic chest pain. Physical examination may reveal splenomegaly, left upper quadrant tenderness, and left pleural effusion. Antibiotics with percutaneous drainage or splenectomy are the mainstays of therapy.24 Most lung infections result from the common respiratory pathogens that occur in community-acquired pneumonias. Opportunistic infections must be considered if the patient is HIV infected. Primary pulmonary infections must be distinguished from septic pulmonary emboli arising from endocarditis or extremity deep venous thrombosis. Lung abscesses are common and occur through aspiration, necrotizing pneumonia, or septic emboli. Tuberculosis is common even in the non-HIV-infected patient as a result of alcoholism, malnutrition, crowding, poor compliance with medical care, and coughing induced during the smoking and nasal insufflation of drug. Pneumonia is one of the most common infections in febrile substance users. The initial antibiotic therapy must be broad based before definitive cultures, and the healthcare provider must always consider the possibility of multiple processes affecting the lung simultaneously.60 Bone and joint infections are also common in parenteral drug users. The infection most commonly occurs during an episode of bacteremia but may also develop via the spread from contiguous foci. Most joint infections involve the knee, but other common

Figure 109–5 A patient with a manubriosternal osteomyelitis complicating IV drug use. He presented with chest pain and fever that developed over 2 weeks. The patient was treated with long-term antistaphylococcal penicillinase-resistant antibiotics. The manubriosternal region is also a characteristic site for osteomyelitis in parenteral drug users. (Courtesy of the New York City Poison Center Toxicology Fellowship).

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abscesses usually result from emboli arising from the mitral or aortic valves. Cerebritis may have a viral etiology or be caused by excessive bacteremia associated with endocarditis.60 Currently, the incidence of sexually transmitted diseases (STDs) in substance users is increasing dramatically. Prostitution and sexual promiscuity are strongly related to drug use. The most important organisms include HIV, penicillinase-producing strains of Neisseria gonorrhoeae, Treponema pallidum, Haemophilus ducreyi, and Chlamydia trachomatis.35 Approximately one-third of female IVDUs have a history of prostitution, and 60% of IVDUs report a history of an STD.21,60 The common practice of exchanging sex (usually unprotected) for crack cocaine has dramatically increased the incidence of all sexually transmitted diseases. The risk of transmission of HIV infection in parenteral drug users via the sexual route is tremendous. A 1993 Centers for Disease Control study of male IVDUs with known HIV infection revealed that 28% reported having vaginal or anal sex without a condom during the preceding 30 days, and 23% admitted to trading sex for money. Thirty-two percent had not revealed their HIV status to all partners.25 A study of an indigent group of emergency department patients who admitted to using cocaine once each week found a syphilis rate of 28%.31 A study of 311 lower-risk patients entering residential drug treatment found the prevalence of sexually transmitted diseases to be as follows: Chlamydia trachomatis 2.3%; Neisseria gonorrhoeae 1.6%; trichomoniasis 43%; syphilis 6%.6 The healthcare provider must always consider the possibility of uncommon infections in the substance abuser. In the early 1970s, a group of patients acquired Plasmodium vivax in California by the sharing of needles.33 Substance users risked quinine toxicity in the 1930s as the drug was added to heroin to help control malaria. The ease of travel to areas endemic with malaria makes this disease a consideration even in the United States. Historically, tetanus is the oldest infectious complication afflicting patients who use parenterally administered drugs. Tetanus and botulism must be considered in substance users, as Clostridium spp can grow well in facial sinuses (as with cocaine insufflation) or in extremities as a result of “skin popping” or compromised extremity perfusion.7,96 Bleach distribution and needle/syringe exchange programs were developed in an attempt to minimize the spread of infectious diseases and have been a subject of great controversy. The last 15 years have provided data demonstrating that these programs are generally effective in limiting the transmission of infectious diseases. The number of new programs has been increasing by about 20% per year. Approximately one-half of new HIV infections are a result of reuse and sharing of contaminated syringes. Results from several programs demonstrate a reduction in the transmission of hepatitis B, hepatitis C, and HIV.11,14,28,38,43,51,63,89,93 The healthcare provider must understand the limitations of these programs and educate each IVDU, as drug sharing can play an important role in the social organization of the drug-using culture.37 The HCV epidemic will provide society with a chance to learn from the HIV experience and institute appropriate preventive measures. Additional research is needed to maximize the availability of these resources and to integrate them into other needed health and social services for substance users. The HIV epidemic remains a significant problem for injecting drug users. CDC data indicate that 22% of the new cases of HIV between July 1999 and June 2000 were in patients injecting drugs.45 An encouraging recent study evaluated the HIV incidence

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rate among IVDUs living in New York City between 1992 and 1997 and found the incidence to be low (0.7 per 100 person-years at risk) for a high-seropositivity population of patients.29 The significant epidemic of HIV infection among IVDUs in New York City appears to be declining as demonstrated by this low incidence and declining prevalence. Data from the Centers for Disease Control indicate that the recent marked declines in AIDS incidence and deaths began in 1996 and continued into 1998. This is associated with the widespread use of combination antiretroviral therapies. These dramatic declines have slowed during the latter part of 1998 and 1999. In 1999, the incidence and death rates each quarter have stabilized. AIDS prevalence continued to rise in 1999, although the rate of increase has slowed.

TRAUMATIC COMPLICATIONS Deaths in substance users may occur unrelated to the drug, as a result of an overdose of the drug, as a result of medical complications associated with the drug, or from drug-induced psychological responses that lead to trauma. Drug use increases both the incidence of trauma and the severity of each event. Numerous drugs such as alcohol, marijuana, cocaine, and benzodiazepines are all demonstrated to impair driving tasks.52 Benzoylecgonine was detected in 27% of all New York City residents sustaining fatal injuries, and cocaine was detected in 18%. This study found that two-thirds of the deaths were not from acute toxicity but resulted from homicides, suicides, automobile collisions, and falls.10,69 A study involving six regional trauma centers demonstrated that 40% of adult trauma patients had a positive blood alcohol content on admission.88 A recent CDC report indicates that in 1997 and 1998, 38% of traffic fatalities were alcohol related.2 A prospective study of patients at a level I trauma center found that 71% screened positive for alcohol or drugs and that cocaine and opioids represented 91% of positive drug screens.26 Of 1118 patients admitted to a level I trauma center, 24% were currently alcohol dependent, and 18% were currently dependent on another drug. In a study of 450 trauma patients, 70% had positive blood ethanol and/or urine toxicology results, and victims of intentional trauma showed an even higher percentage of positive screens (80%).65 In a study of 231 injured patients aged 12 to 18 years, alcohol use was identified in 39%.62,66 Toxicologic testing results from 1356 trauma patients aged 10 to 14 years revealed that 9% were positive for alcohol and/or other psychoactive drugs.61 Even though the elderly have a lower incidence of drug-related trauma, 14% of drivers over age 60 were found to have the presence of ethanol in their blood.44 Numerous studies from burn centers demonstrate that substance use is commonly associated with thermal injury and that substance users have a greater percentage of burned body surface area, inhalation injury, and mortality.42 Substance use is one of the most substantial risk factors for traumatic brain injury. Similar relationships exist between substance use and hypothermia fatalities, drownings, and spinal cord injuries. A study of 634 patients admitted to a Chicago level I trauma center following trauma demonstrated that 45% were considered impaired with either alcohol or drugs.74 Of the impaired group, only 17% were cited by police for driving under the influence. These data indicate the importance of close working relationships and dialogue between the healthcare provider and law enforce-

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ment to communicate possible mechanisms involved in the traumatic event. The clinical evaluation of poisoned patients is difficult, and thus, more diagnostic testing is required to determine occult internal organ injury. Common examples include the need for a computed tomography evaluation of the brain and abdomen, as physical diagnosis is less reliable if the patient is intoxicated. Sympathomimetic agents may cause a tachycardia unrelated to blood loss, and the relative hypertension may mask hypovolemic shock. Long bone, pelvic, and cervical spine fractures may not be perceived as painful events, mandating a low threshold for obtaining radiographs. Routine drug testing may be important to allow for an early diagnosis of substance use and the initiation of chemical dependence treatment. One study suggested that surgical services identified alcoholism in fewer than 25% of affected patients and addressed the problem in fewer than one-half of the patients detected. Chemical dependence consultation and referral for rehabilitation are critical to the management of these patients if prevention of further events is to be achieved. A number of authors suggest that patients are more amenable to a “critical intervention” and referral for rehabilitation in the posttraumatic period. Long-term survival may depend more on substance use rehabilitation than on initial trauma management.34,76

PSYCHIATRIC ILLNESS Comorbidity implies the presence of two or more psychiatric disorders in the same patient. The National Institute of Mental Health’s Epidemiologic Catchment Area Study remains a landmark study demonstrating the large percentage of substance users with a dual diagnosis. This study was conducted in the early 1980s and involved the interviews of more than 20,000 people in five communities in the United States. In this study, 76% of men and 65% of women demonstrated comorbidity (Table 109–4).50,81 The consequences of substance use for patients include symptom exacerbation, increased hospitalization, medication noncompliance, disruptive behaviors, decreased social functioning, and higher rates of utilization of acute services leading to more costly care.

TABLE 109–4. Prevalence of Other Psychiatric Disorders among Men and Women Diagnosed as Having Drug Use Dependence Disorders Prevalence of Other Disorders Specific Additional Diagnoses

Men (%)

Women (%)

Alcohol use dependence Antisocial personality disorder Phobic disorders Major depression Dysthymia Obsessive-compulsive disorder Mania Schizophrenia Panic disorder

60 22 19 14 9 6 5 5 3

30 10 29 28 12 9 7 8 6

Reprinted, with permission, from Kandal DB: Epidemiological trends and implications for understanding the nature of addiction. In: O’Brien CP, Jaffe JH, eds: Addictive States. New York, Raven Press, 1992, pp. 23–40.

There is evidence to suggest that the integration of mental health and drug and alcohol services will result in improved detection, assessment, and management of comorbidity.80 Studies thus far describe the incidence of comorbidity, but they do not explain the reasons for the associations. It is uncertain whether the use of substances with mind-altering properties is an attempt at self-medication or whether mentally ill patients are less able to contend with the effects of substance use and thus are more likely to become dependent. The causal relationship between these disorders is complex, and further studies are necessary to determine whether substance use and abuse contribute to the risk of developing other psychiatric disorders or vice versa. A reliable psychiatric diagnosis in substance users requires a 2-week period of abstinence to eliminate the potential for concurrent intoxication or withdrawal. Several important principles must be remembered when performing a psychiatric evaluation of a substance user. The medical assessment must always precede the psychiatric evaluation. In most patients with a presumed dual diagnosis, inpatient care is probably the best setting, and psychotropic medications are initiated only when spontaneous remission is not possible. Care must be given to identifying medical and drug-induced disease that may masquerade as psychiatric illnesses. Substance abusers are often unable to give reliable clinical information, and emphasis must be placed on analytic drug data from biologic specimens, physical examinations, laboratory testing, history from family and friends, past medical histories, and family psychiatric histories. In prescribing medication, avoid addictive agents once detoxification is accomplished, as these drugs may stimulate the cycle of euphoria and craving and thus jeopardize the recovery. Psychiatric and rehabilitative approaches are often conflicting in philosophy and must be carefully coordinated to optimize care.

SUMMARY The optimal care of substance users is quite challenging and demands a thorough understanding of all aspects of their life style. The healthcare provider must approach these patients in a compassionate and nonjudgmental manner so as to gain their confidence and enhance the care rendered. It is essential to maintain knowledge of the current patterns of substance use and to understand the many medical, surgical, and psychiatric issues these patients face as a result of their drug use. Physicians are an integral part of a team of professionals that includes psychologists, home care nurses, social workers, substance abuse counselors, law enforcement personnel, clergy, and volunteers at shelters. In an era of cost containment, it is essential that each provider of healthcare maintain a focus on this important group of individuals and not allow financial pressures to alter appropriate decisions.

REFERENCES 1. Abraham HD, Degli-Esposti S, Marino L: Seroprevalence of hepatitis C in a sample of middle class substance abusers. J Addict Dis 1999; 18:77–87. 2. Alcohol involvement in fatal motor-vehicle crashes—United States, 1997–1998. MMWR 1999;38:1086–1087. 3. Allcott JV, Barnhart RA, Mooney LA: Acute lead poisoning in two users of illicit methamphetamine. JAMA 1987;258:510–511.

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4. Alter MJ, Kruszon-Moran D, Nainan O, et al: The prevalence of hepatitis C virus infection in the United States, 1988–1994. N Engl J Med 1999;341:556–562. 5. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, American Psychiatric Association, 1994. 6. Bachmann LH, Lewis I, Allen R, et al: Risk and prevalence of treatable sexually transmitted diseases at a Birmingham substance abuse treatment facility. Am J Public Health 2000;90:1615–1618. 7. Bardenheier B, Prevots D, Khetsuriani N, Wharton M: Tetanus surveillance—United States, 1995–1997. MMWR CDC Surveill Summ 1998;47:1–13. 8. Bayer BM, Mulroney SE, Hernandez MC, et al: Acute infusions of cocaine result in time- and dose-dependent effects on lymphocyte responses and corticosterone secretion in rats. Immunopharmacology 1995;29:19–28. 9. Binswanger IA, Kral AH, Bluthenthal RN, et al: High prevalence of abscesses and cellulitis among community-recruited injection drug users in San Francisco. Clin Infect Dis 2000;30:579–581. 10. Blanc PD, Saxena M, Olson KR: Drug detection and trauma cause— A case control study of fatal injuries. J Toxicol Clin Toxicol 1994; 32:137–145. 11. Bluthenthal RN, Kral A, Gee L, et al: The effect of syringe exchange use on high-risk injection drug users: a cohort study. AIDS 2000; 14:605–611. 12. Brookoff D, Campbell EA, Shaw LM: The underreporting of cocainerelated trauma: Drug abuse warning network reports versus hospital toxicology tests. Am J Public Health 1993;83:369–371. 13. Brown SM, Stimmel B, Taub R, et al: Immunologic dysfunction in heroin addicts. Arch Intern Med 1974;134:1001–1006. 14. Bruneau J, Lamothe F, Franco E, et al: High rates of HIV infection among injection drug users participating in needle exchange programs in Montreal: results of a cohort study. Am J Epidemiol 1997;146: 994–1002. 15. Burns RS, Lewitt PA, Ebert MH, et al: The clinical syndrome of striatial dopamine deficiency: Parkinsonism induced by MPTP. N Engl J Med 1985;312:1418–1421. 16. Center on Addiction and Substance Abuse at Columbia University: Substance abuse and urban America: Its impact on an American city. New York, 1996. 17. Chambers HF, Korzeniowski OM, Sande MA: Staphylococcus aureus endocarditis: Clinical manifestations in addicts and nonaddicts. Medicine 1983;62:170–177. 18. Chambers HF, Morris DL, Tauber MG, Modin G: Cocaine use and the risk for endocarditis in intravenous drug abusers. Ann Intern Med 1987;106:833–836. 19. Chandrasekar PH, Narula A: Bone and joint infections in intravenous drug abusers. Rev Infect Dis 1986;8:904–910. 20. Cherubin CE: The medical sequelae of narcotic addiction. Ann Intern Med 1967;67:23–33. 21. Cherubin CE, Sapira JD: The medical complications of drug addiction and the medical assessment of the intravenous drug abuser: 25 years later. Ann Intern Med 1993;119:1017–1028. 22. Chiappelli F, Frost P, Manfrini E, et al: Cocaine blunts human CD4+ cell activation. Immunopharmacology 1994;3:233–240. 23. Chiappelli F, Kung MA, Villanueva P, et al: Immunotoxicology of cocaethylene. Immunopharmacol Immunotoxicol 1995;2:399–417. 24. Chun C, Raff M, Varghese R, et al: Splenic abscess. Medicine 1980; 59:50–65. 25. Continued sexual risk behavior among HIV-seropositive, drug-using men—1993. MMWR 1996;45:151–154. 26. Cornwell EE 3rd, Belzberg H, Velmahos G, et al: The prevalence and effects of alcohol and drug abuse on cohort-matched critically injured patients. Am Surg 1998;64:461–465. 27. Currie PF, Sutherland GR, Jacob AJ, et al: A review of endocarditis in acquired immunodeficiency syndrome and human immunodeficiency virus infection. Eur Heart J 1995;16:15–18.

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28. Des Jarlais DC, Paone D, Friedman SR, et al: Regulating controversial programs for unpopular people: Methadone maintenance and syringe exchange programs. Am J Public Health 1995;85:1577–1584. 29. Des Jarlais DC, Marmor M, Friedman P, et al: HIV incidence among drug users in New York City, 1992–1997: evidence for a declining epidemic. Am J Public Health 2000;90:352–359. 30. Emerson TS, Cisek JE: Methcathinone: A Russian designer amphetamine infiltrates the rural midwest. Ann Emerg Med 1993;22: 1897–1903. 31. Ernst AA, Martin DH: High syphilis rates among cocaine abusers identified in an emergency department. Sex Transm Dis 1992;20: 66–69. 32. Fucci N, DeGiovanni N: Adulterants encountered in the illicit cocaine market. Forensic Sci Int 1998;95:247–252. 33. Friedman CT, Dover AS, Roberto RR, Kerns OA: A malaria epidemic among heroin addicts. Am J Trop Med Hyg 1973;22:302–307. 34. Fuller MG, Diamond DL, Jordan ML, Walters MC: The role of a substance abuse consultation team in a trauma center. J Stud Alcohol 1995;56:267–271. 35. Goldsmith M: Sex tied to drugs = STD spread. JAMA 1988;260: 2009–2011. 36. Grattendick K, Jansen DB, Lefkowity DL, Lefkowitz SS: Cocaine causes increased type I interferon secretion by both L929 cells and murine macrophages. Clin Diagn Lab Immunol 2000;7:245–250. 37. Grund JP, Friedman SR, Stern LS, et al: Syringe-mediated drug sharing among injecting drug users: Patterns, social context, and implications for transmission of blood-borne pathogens. Soc Sci Med 1996; 42:691–703. 38. Hagan H, Jarlais DC, Friedman SR, et al: Reduced risk of hepatitis B and hepatitis C among injection drug users in the Tacoma syringe exchange program. Am J Public Health 1995;85:1531–1537. 39. Hagan H, Thiede T, Weiss N, et al: Sharing of drug preparation equipment as a risk factor for hepatitis C. Am J Public Health 2001;91: 42–46. 40. Haim DY, Lippman ML, Goldberg SK, Walkenstein MD: The pulmonary complications of crack cocaine: A comprehensive review. Chest 1995;107:233–240. 41. Hamilton RJ, Perrone J, Hoffman R, et al: A descriptive study of an epidemic of poisoning caused by heroin adulterated with scopolamine. J Toxicol Clin Toxicol 2000;38:597–608. 42. Haum A, Perbix W, Hack HJ, et al: Alcohol and drug abuse in burn patients. Burns 1995;21:194–199. 43. Heimer R, Khoshnood K, Jariwala-Freeman B, et al: Hepatitis in used syringes: The limits of sensitivity of techniques to detect hepatitis B virus DNA, hepatitis C virus RNA, and antibodies to HBV core and HCV antigens. J Infect Dis 1996;4:997–1000. 44. Higgins JP, Wright SW, Wrenn KD: Alcohol, the elderly, and motor vehicle crashes. Am J Emerg Med 1996;14:265–267. 45. HIV/AIDS Surveillance Report. Nation Center for HIV, STD, and TB Prevention. Midyear 2000 Edition. 46. Hoffman I, Stratton J, Lemon S, et al: Hepatitis B among parenteral drug abusers—North Carolina. JAMA 1986;256:1262–1269. 47. Hughes PH, Barker NW, Crawford MA, Jaffe JH: The natural history of a heroin epidemic. Am J Public Health 1972;62:995–1001. 48. Jacob H, Charytan C, Rascoff JH, et al: Amyloidosis secondary to drug abuse and chronic skin suppuration. Arch Intern Med 1978: 138:1150–1151. 49. Jonas S: Heroin utilization: A communicable disease? NY State J Med 1972;72:1292–1299. 50. Kandal DB: Epidemiological trends and implications for understanding the nature of addiction. In: O’Brien CP, Jaffe JH, eds: Addictive States. New York, Raven Press, 1992, pp. 23–40. 51. Kaplan EH, Heimer R: HIV incidence among New Haven needle exchange participants: Updated estimates from syringe tracking and testing data. J Acquir Immune Defic Syndr Hum Retrovirol 1995;10: 175–176. 52. Kirby JM, Maull K, Fain W: Comparability of alcohol and drug use in injured drivers. South Med J 1992;85:800–803.

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53. Klatt EC, Montgomery S, Namiki T, et al: Misrepresentation of stimulant street drugs. A decade of experience in an analysis program. J Toxicol Clin Toxicol 1986;24:441–450. 54. Klein TW, Matsui K, Newton CA, et al: Cocaine suppresses proliferation of phytohemagglutinin-activated human peripheral blood T-cells. Int J Immunopharmacol 1993;1:77–86. 55. Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic parkinsonism in humans due to a byproduct of meperidine analog synthesis. Science 1983;219:979–980. 56. Layon J, Idris A, Warzynski M, et al: Altered T lymphocyte subsets in hospitalized intravenous drug abusers. Arch Intern Med 1984;144: 1376–1380. 57. Lead poisoning associated with intravenous-methamphetamine use— Oregon, 1988. MMWR 1989;38:830–831. 58. Lettau L, McCarthy J, Smith M, et al: Outbreak of severe hepatitis due to delta and hepatitis B viruses in parenteral drug abusers and their contacts. N Engl J Med 1987;317:1256–1262. 59. Levine D, Crane L, Zervos M: Bacteremia in narcotic addicts at the Detroit Medical Center. II. Infectious endocarditis: A prospective comparative study. Rev Infect Dis 1986;8:374–396. 60. Levine D, Sobel J: Infections in Intravenous Drug Abusers. New York, Oxford University Press, 1991. 61. Li G, Chanmugam A, Rothman R, et al: Alcohol and other psychoactive drugs in trauma patients aged 10–14 years. Inj Prev 1999;5: 94–97. 62. Loiselle JM, Baker MD, Templeton JM, et al: Substance abuse in adolescent trauma. Ann Emerg Med 1993;22:1530–1534. 63. Lurie P, Drucker E: An opportunity lost: HIV infections associated with lack of a national needle-exchange programme in the USA. Lancet 1997;349:604–608. 64. MacDonald M, Wodak A, Dolan K, et al: Hepatitis C virus antibody prevalence among injecting drug users at selected needle and syringe programs in Australia, 1995–1997. Med J Aust 2000;172:57–61. 65. Madan AK, Yu K, Beech DJ: Alcohol and drug use in victims of lifethreatening trauma. J Trauma 1999;47:568–571. 66. Mannenbach MS, Hargarten SW, Phelan MB: Alcohol use among injured patients aged 12 to 18 years. Acad Emerg Med 1997;4:40–44. 67. Manoff SB, Vlahov D, Somomon L, et al: Human immunodeficiency virus infection and infective endocarditis among injecting drug users. Epidemiology 1996;7:566–570. 68. Marantz PR, Linzer M, Feiner CJ, et al: Inability to predict diagnosis in febrile intravenous drug abusers. Ann Intern Med 1987;106: 823–828. 69. Marzuk PM, Tardiff K, Leon AC, et al: Fatal injuries after cocaine use as a leading cause of death among young adults in New York City. N Engl J Med 1995;332:1753–1757. 70. Moustoukas NM, Nichols RL, Smith JW, et al: Contaminated street heroin: Relationship to clinical infections. Arch Surg 1983;118: 746–749. 71. Netzer RO, Zollinger E, Seiler C, Cerny A: Infective endocarditis: clinical spectrum, presentation and outcome. An analysis of 212 cases 1980–1995. Heart 2000;84:25–30. 72. O’Connor PG, Samet JH, Stein MD: Management of hospitalized intravenous drug users: Role of the internist. Am J Med 1994;96: 551–558. 73. O’Connor PG, Selwyn PA, Schottenfeld RS: Medical care for injection-drug users with human immunodeficiency virus infection. N Engl J Med 1994;331:450–459. 74. Orsay EM, Doan-Wiggins L, Lewis R, et al: The impaired driver: Hospital and police detection of alcohol and other drugs of abuse in motor vehicle crashes. Ann Emerg Med 1994;24:51–55. 75. Pare JP, Cote G, Fraser RS: Long-term follow-up of drug abusers with intravenous talcosis. Am Rev Respir Dis 1989;139:233–241. 76. Parran TV, Weber E, Tasse J, et al: Mandatory toxicology testing and chemical dependence consultation follow-up in a level-one trauma center. J Trauma 1995;38:278–280.

77. Pellegrino T, Bayer BM: In vivo effects of cocaine on immune cell function. J Neuroimmunol 1998;83:139–147. 78. Piot P, Goilav C, Kegels E: Hepatitis B: Transmission by sexual contact and needle sharing. Vaccine 1990;8S:37–40 79. Pirozhkov SV, Watson RR, Chen GJ: Ethanol enhances immunosuppression induced by cocaine. Alcohol 1992;6:489–494. 80. RachBeisel J, Scott J, Dixon L: Co-occurring severe mental illness and substance use disorders: a review of recent research. Psychiatr Surv 1999;50:1427–1434. 81. Regier DA, Farmer ME, Rae DS, et al: Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA 1990;264:2511–2518. 82. Ribera E, Miro J, Cortes E, et al: Influence of human immunodeficiency virus 1 infection and degree of immunosuppression in the clinical characteristics and outcome of infective endocarditis in intravenous drug users. Arch Intern Med 1998;158:2043–2050. 83. Rivera Del Rio JR, Flores R, Melendez J, et al: Profile of HIV patients with and without bacterial endocarditis. Cell Mol Biol 1997;43: 1153–1160. 84. Robinson DJ, Lazo MC, Davis T, Kufera J: Infective endocarditis in intravenous drug users: does HIV status alter the presenting temperature and white blood cell count? J Emerg Med 2000;19:5–11. 85. Rodriguez-Mendez M, Gonzalez-Quintela A, Aguilera A, Barrio E: Prevalence, patterns, and course of past hepatitis B virus infection in intravenous drug users with HIV-1 infection. Am J Gastroenterol 2000;95:1316–1322. 86. Selwyn PA: Illicit drug use revisited: What a long, strange trip it’s been. Ann Intern Med 1993;119:1044–1045. 87. Shannon M: Clinical toxicity of cocaine adulterants. Ann Emerg Med 1988;17:1243–1247. 88. Soderstrom CA, Smith GS, Dischinger PC, et al: Psychoactive substance use disorders among seriously injured trauma center patients. JAMA 1997;277:1769–1774. 89. Strathdee SA, Patrick DM, Currie SL, et al: Needle exchange is not enough: lessons from the Vancouver injecting drug use study. AIDS 1997;11:59–65. 90. Substance Abuse and Mental Health Services Administration/Office of Applied Studies: 1999 Annual Emergency Department Data. August 2000. Department of Health and Human Services, Rockville, MD. 91. Substance Abuse and Mental Health Services Administration/Office of Applied Studies. 1999 National Household Survey on Drug Abuse. August 2000. Department of Health and Human Services, Rockville, MD. 92. Tortu S, Beardsley M, Deren S, et al: HIV infection and patterns of risk among women drug injectors and crack users in low and high sero-prevalence sites. AIDS Care 2000;12:65–76. 93. Vlahov D, Junge B: The role of needle exchange programs in HIV prevention. Public Health Rep 1998;113(Suppl 1):75–80. 94. Watanakunakorn C: Changing epidemiology and newer aspects of infective endocarditis. Adv Intern Med 1977;22:21–24. 95. Weisse AB, Heller DR, Schimenti RJ, et al: The febrile parenteral drug abuser: A prospective study in 121 patients. Am J Med 1993;94: 274–280. 96. Werner SB, Passaro D, McGee J, et al: Wound botulism in California, 1951–1998: Recent epidemic in heroin injectors. Clin Infect Dis 2000; 31:1018–1024. 97. Williams I: Epidemiology of hepatitis C in the United States. Am J Med 1999;107:2S–9S. 98. Xu W, Flick T, Mitchel J, et al: Cocaine effects on immunocompetent cells: an observation of in vitro cocaine exposure. Int J Imunopharmacol l999;21:463–472.

CHAPTER

110 HEALTHCARE WORKERS Michael I. Greenberg

The numbers and types of potential toxins that healthcare workers may be exposed to are as varied as the occupations and job categories that exist in a modern healthcare facility. Typically, the particular toxic hazards that a worker may be exposed to are related more to the immediate work environment within the healthcare facility such as the ICU, laboratory, or ambulance than to the job or profession itself (eg, nurse, physician, unit receptionist). Although each category of healthcare worker may be exposed to toxins inherent to the performance of the specific duties required, it is important to remember that all healthcare workers also can be exposed to toxins that are generated or exist in areas proximate to their immediate work environment but that have nothing at all to do with the performance of their specific duties.

COMMON TOXIC EXPOSURES Hospital and healthcare workers constitute the largest single group of employees in the United States today.28,35 Job-related health and safety issues for these employees have not received appropriate attention until recently. Large numbers of people pass through hospitals each year as patients, visitors, vendors, delivery personnel, and so forth. Consequently, many people, beyond just those who work in the health care industry, may potentially be exposed to various toxic hazards within the hospital environment. Individuals employed in healthcare occupations can be exposed to a multitude of hazardous toxins and chemicals. Certain work areas as well as specific jobs within those areas in the hospital environment have specific toxic hazards commonly associated with them. Knowing which toxins may be associated with specific jobs will facilitate the formulation of a differential diagnosis list for each exposed patient. Table 110–1 lists the most common potential toxic hazards for workers in the healthcare industry. Table 110–2 cites the locations of greatest risk for exposure. These chemical hazards can be categorized as disinfectants, sterilizing agents, solvents, anesthetic agents, chemotherapeutic agents, latex-containing products, detergents, tissue fixatives, and chemical reagents. They may enter the body by dermal absorption, inhalation, ingestion, or unintentional needle stick, with the most common exposure routes being inhalation (through aerosolization) and skin absorption.

GLUTARALDEHYDE Glutaraldehyde is a saturated dialdehyde compound that is recognized as both a disinfectant and as an effective chemical sterilant (see Chap. 84). Glutaraldehyde finds its most common use as a

disinfectant for medical equipment such as endoscopes, dialysis equipment, and anesthesia and respiratory therapy equipment.42,71 In the hospital, glutaraldehyde is also commonly found in the histology laboratory, where it may be used as a tissue fixative. It is not corrosive to metal and will not damage glass, rubber, or plastic. It is frequently found in concentrated form but is usually employed as a dilute solution. Most studies suggest that 1.0% glutaraldehyde is the minimum effective concentration when the intended use is as a high-level disinfectant.36,37 Although glutaraldehyde is commonly used as a 2% solution in hospitals, it may be found in formulations with concentrations as high as 50%.71 The solution generally should not be used when the concentration is ≤1% glutaraldehyde.37 As a result of evaporation, the concentration of glutaraldehyde baths and shelf solutions may change over time. The higher the concentration of the solution, the greater the volatility at room temperature, and consequently the higher the concentration of airborne chemical. The evaporation of glutaraldehyde is one way in which workers can become exposed to this chemical. Consequently, it is important to frequently monitor the concentration. Glutaraldehyde test kits are commercially available for the purpose of monitoring solution concentration. The germicidal ability of glutaraldehyde results from the alkylation of sulfhydryl, hydroxyl, carboxyl, and amino groups within microbes interfering with RNA, DNA, and protein synthesis.54 Glutaraldehyde-based solutions are widely used in hospitals, primarily because of their superior biocidal activity, efficacy in the presence of organic material, lack of corrosive effects on endoscopy and other equipment, and ability to prevent the coagulation of proteinaceous material on equipment. In aqueous solution this agent tends to be acidic but is not sporicidal in acidic media.87 Only when the pH of the solution is increased to 7.5 to 8.0 does it regain sporicidal activity. However, at alkaline pH, polymerization of the glutaraldehyde molecules occurs, gradually blocking the active aldehyde sites of the glutaraldehyde molecules, which are resposible for the biocidal activity. The polymerization activity in alkaline solution effectively limits the shelf life of glutaraldehyde solutions to a maximum of 28 days. Glutaraldehyde is chemically related to formaldehyde and, on exposure, can cause very similar adverse effects, including irritation of the eyes, respiratory tree, and skin. The irritant effects of glutaraldehyde are related to the pH of the solution, which tends to vary with the manufacturer. In addition, it can cause sensitization resulting in allergic contact dermatitis as well as new-onset asthma.41 Exposure can also result in severe exacerbations of underlying asthma.41 Inhalational exposure resulting in recurrent epistaxis has also been reported.73 In addition, fetal toxicity has been identified in certain animal studies.14

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TABLE 110–1. Chemical and Physical Hazards for Healthcare Workers Chemical hazards Disinfectants Isopropyl alcohol, iodine, povidone, chlorine, phenol Sterilants Formaldehyde, glutaraldehyde, ethylene oxide (EtO) Solvents Acetone, benzoin, ethanol Anesthetic agents Nitrous oxide, enflurane, halothane, isoflurane Chemotherapeutic agents Antineoplastic and cytotoxic drugs Pharmaceuticals Pentamidine, ribavirin Heavy metals Mercury Detergents Tissue fixatives Laboratory reagents

Biomedical adhesives Methyl methacrylate Physical hazards Ionizing radiation Nonionizing radiation Laser hazards Electrocautery smoke Allergic sensitization hazards Latex (as in latex gloves) Lab animal allergy

TABLE 110–2. Toxic Hazards for Healthcare Workers by Location Hospital-wide Disinfectants Isopropyl alcohol, iodine, povidone, chlorine, phenol Sterilants Formaldehyde, glutaraldehyde, ethylene oxide (EtO) Solvents Acetone, benzoin, ethanol Detergents Ionizing radiation Latex-containing materials Operating rooms Anesthetic agents Nitrous oxide, inhalational anesthetics Tissue fixatives, biomedical adhesives (methacrylates) Nonionizing radiation, laser hazards, electrocautery smoke Pharmacy Chemotherapeutic agents, pentamidine, ribavirin Hospital clinical and research laboratories Tissue fixative, laboratory chemicals and reagents, laboratory animal allergy Outpatient/day hospital facilities Chemotherapeutic agents, pentamidine, ribavirin Hospital repair shops Mercury, solvents

Healthcare workers may be exposed to glutaraldehyde vapors in several ways. When equipment is processed in poorly ventilated areas or in open immersion baths or after spills, evaporation of glutaraldehyde may occur, and ambient air levels may easily exceed recommended limits. Various work practice control measures may be helpful in these circumstances, including the use of exhaust hoods ducted to the outside, appropriate lids for immersion baths, and personal protective gloves (nitrile rubber, butyl rubber, polyethylene) and eye protection. In some cases, fitted half-face respirators with organic vapor filters or supplied-air respirators may be appropriate. Recently, automated machinery has come to market for endoscopic disinfection. The use of such equipment is very effective in limiting worker exposure. When exposure is probable, area dosimeters are available for measuring glutaraldehyde levels in the ambient air. In addition to healthcare workers, both hospitalized and outpatients may be exposed to the toxic effects of glutaraldehyde in certain circumstances. For example, proctitis may result when residual glutaraldehyde solution contaminates the air-water channel of the equipment used for lower gastrointestinal endoscopy.29 In a similar way, keratopathy can occur following the use of inadequately rinsed ophthalmic instruments following soaking in glutaraldehyde solution.44 Treatment for glutaraldehyde skin and inhalational exposures requires prompt removal from exposure. For skin exposures copious irrigation with water provides adequate decontamination. Severe inhalation exposures may require hospital admission for observation, suppportive care, and treatment of bronchospasm.

FORMALDEHYDE Formaldehyde, a gas at standard temperature and pressure, is used as a disinfectant and a sterilant in both its liquid and gaseous states. However, formaldehyde is generally found in the hospital setting as an aqueous solution known as formalin, which acts as a bactericide, tuberculocide, fungicide, virucide, and sporicide.123 Formaldehyde acts by alkylating amino and sulfhydryl groups in proteins as well as the ring nitrogen atoms of purines.54 Formalin, the most commonly encountered solution, contains formaldehyde at a concentration of 37% in methanol and water and is used primarily as a fixative for histology specimens and as an embalming material. In addition, formaldehyde-containing solutions are sometimes used as disinfectants. The hospital autopsy room is probably the location that can be expected to demonstrate the highest air levels of formaldehyde gas and students may be similarly exposed during gross anatomy laboratory.31 Significant exposure to formaldehyde occurs in renal transplant units when dialysis equipment is not thoroughly rinsed and tested for the presence of residual formaldehyde.30 In other health-related venues, exposure may occur when formaldehyde is used in the preparation of viral vaccines, as an embalming agent, and for preserving anatomic specimens. In the past, formaldehyde was used as a sterilant for surgical instruments as well. Following ingestion, formalin causes local corrosive injury in the gastrointestinal tract as metabolism of formaldehyde generates formic acid. Elevated formate levels can be associated with circulatory collapse, severe metabolic acidosis, and the development of acute renal failure. Intentional ingestions of formalin may result in

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death within a matter of hours.80 However, if the patient survives for a period of 48 hours, recovery generally can be expected.80 The use of formaldehyde in the hospital is limited to some degree by its irritating fumes and obnoxious odor, which is manifest at rather low ambient levels (6. Officials involved in doping were sure that values would decrease to acceptable levels in time for the event, based on the science of the athlete’s clearance of testosterone esters. Later, preparations of epitestosterone propionate were prepared for injection to bring the T:E ratio back to the acceptable level of 50%.215 Of those athletes living

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and training at altitudes between 2000 and 3000 meters above sea level, 20.5% had hematocrit values exceeding 50%.215 Other studies confirm the increased hematocrits of athletes training at altitudes from 1000 to 6000 meters.20,215,192,193 Although many endurance athletes may have increased blood volume, the hematocrit may be lowered because of the increased plasma volume, which exceeds the red blood cell volume. This dilutional pseudoanemia is sometimes called “sports anemia.”197 Additionally, hematocrit measurements are affected by hydration status, upright versus supine posture, nutrition, and change almost 3% with diurnal variation.191 Because of natural variation between individuals, postural effects, and the ease of manipulation through saline infusion, the indirect detection of EPO use by measurement of hematocrit is fraught with potential for error.162 The ratio between serum soluble transferrin receptors (sTfr) and ferritin (ftn) has been studied as an indirect method of detection of EPO use. Soluble transferrin receptor is released from red blood cell progenitors. EPO stimulates erythropoiesis and causes an increase in sTfr and a decrease in ferritin.88 People with other causes of polycythemia or accelerated erythropoiesis could also exhibit increased ratios and be falsely accused of EPO use. An increased hematocrit with a soluble transferrin receptor above 10 µg/mL and a ratio of sTfr/serum proteins above 153 has been proposed as an indirect measurement of EPO use.13 Erythropoietin has some fibrinolytic activity, and urine total fibrin and fibrinogen degradation products have been proposed, but are currently not well studied, as indirect markers of EPO use.87 A combination of multiple indirect markers of altered erythropoiesis was recently used in the XXVII Olympiad in Sydney, Australia, to detect rHuEPO use.162 Current EPO use is known as the “ON model,” and recent use but no longer using EPO is known as the “OFF model.” Five variables predicted current rHuEPO use: the reticulocyte count, serum erythropoietin, soluble transferrin receptor, hematocrit, and the percentage of macrocytes. A combination of three variables including hematocrit, reticulocyte count, and the measurement of serum EPO, was the best mechanism for detecting recent rHuEPO use.162 An immunoblotting procedure, which takes advantage of the different charges on the natural and rHuEPO isoforms, is now under study. By isoelectric focusing, this technique obtains an image of EPO patterns in the urine.129

Confounding Agents Some agents are available for the sole purpose of interfering with urine testing. Examples of these include urine additives such as “Klear,” which is 90% methanol, and edible substances such as goldenseal tea, which produces colored urine.29 The masking agents prohibited by the International Olympic Committee include bromontan, diuretics, epitestosterone, and probenecid.229 Probenecid blocks the urinary excretion of the glucuronide conjugates of steroids. A number of urine samples were found to contain probenicid at the 1987 Pan American Games, and it was subsequently banned by the IOC.53,218

SUMMARY The primary reason for drug testing in sports is to maintain the integrity and fairness of athletic events. The greatest supporters of drug testing in sport are the athletes themselves.37 Drug testing at-

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tempts to assure a level playing field and create an environment whereby the athletes’ abilities are tested, not their creativity or willingness to risk their health by using performance-enhancing substances.

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220. Wallace JD, Cuneo RC, Baxter R, et al: Responses of the growth hormone (GH) and insulin-like growth factor axis to exercise, GH administration, and GH withdrawal in trained adult males: a potential test for GH abuse in sport. J Clin Endocrinol Metab 1999; 84:3591–3601. 221. Walter E, Mockel J: Images in clinical medicine. Peliosis hepatis. N Engl J Med 1997;337:1603. 222. Wasser WG, Feldman NS, D’Agati VD: Chronic renal failure after ingestion of over-the-counter chromium picolinate. Ann Intern Med 1997;126:410. 223. Wesslen L, Pahlson C, Friman G, et al: Myocarditis caused by Chlamydia pneumoniae (TWAR) and sudden unexpected death in a Swedish elite orienteer. Lancet 1992;340:427–428. 224. Widder RA, Bartz-Schmidt KU, Geyer H, et al: Candida albicans endophthalmitis after anabolic steroid abuse. Lancet 1995;345: 330–331. 225. Wilson JD: Androgen abuse by athletes. Endocr Rev 1988;9: 181–199. 226. Windsor R, Dumitru D: Prevalence of anabolic steroid use by male and female adolescents. Med Sci Sports Exerc 1989;21:494–497. 227. Wu Z, Bidlingmaier M, Dall R, Strasburger CJ: Detection of doping with human growth hormone. Lancet 1999;353:895. 228. www.asda.org.au: Australian Sports Drug Agency, 1999. 229. www.olympic.org: International Olympic Committee, 2000. 230. www.usdoj.gov/dea/concern/steroids.htm: US Drug Enforcement Agency, 2001. 231. Yesalis CE, Kennedy NJ, Kopstein AN, Bahrke MS: Anabolicandrogenic steroid use in the United States. JAMA 1993;270: 1217–1221. 232. Yesalis CE, Streit AL, Vicary JR, et al: Anabolic steroid use: indications of habituation among adolescents. J Drug Educ 1989;19: 103–116. 233. Zelman G, Howland MA, Nelson LS, Hoffman RS: Erythropoietin overdose treated with emergency erythropheresis. J Toxicol Clin Toxicol 1999;37:602–603. 234. Zeman RJ, Ludemann R, Easton TG, Etlinger JD: Slow to fast alterations in skeletal muscle fibers caused by clenbuterol, a beta 2-receptor agonist. Am J Physiol 1988;254:E726–E732. 235. Zuliani U, Bernardini B, Catapano A, et al: Effects of anabolic steroids, testosterone, and HGH on blood lipids and echocardiographic parameters in body builders. Int J Sports Med 1989; 10:62–66.

III. PREVENTIVE, PSYCHOSOCIAL, NURSING, EPIDEMIOLOGIC, RESEARCH,AND LEGAL PERSPECTIVES CHAPTER

113 PANDSYCHOSOCIAL PRINCIPLES IN ASSESSMENT INTERVENTION Frances A. Gautieri / Kenneth O. Brambill

THE HEALTHCARE ENVIRONMENT Healthcare systems in the United States have become larger and more complex as multiple partnerships are formed that expand the scope of services and help to achieve operational efficiencies through consolidation of functions. A parallel emphasis on decentralization of primary care programs seeks to increase access for patients at the community level and encourages development of new resources and joint planning with community-based organizations. To address quality of care concerns in a healthcare environment characterized by large and extended networks, regulatory standards place increasing emphasis on ensuring that services are provided within a comprehensive, reliable, and functional continuum of care. Objectives include clear, appropriate, and effective communication and coordination at each level of care and especially at the transfer points in the process as patients move through multiple settings, assessment of continuing care needs, and provision for all necessary referrals and transfers to aftercare services.18 The key position of emergency departments within healthcare networks places responsibility and offers opportunity to initiate well-coordinated care management with particular attention to continuity and followup. Integrated healthcare systems are made up of many organizations, settings, and levels of care. They include formal and informal linkages to community-based health, mental health, substance abuse treatment, and social service agencies, all of which interact with emergency department interdisciplinary teams in their management of toxicologic emergencies. Even with the highest levels of clinical and technologic expertise applied in the diagnosis and treatment of poisoned or overdosed patients, successful outcomes may be compromised by inadequacies in aftercare and followup. Therefore, it is important for emergency departments to identify and cultivate appropriate referral resources for a wide range of continuing-care services. The emergence of integrated systems with their emphasis on col-

laboration among healthcare and community service agencies has improved information and referral processes and supports shared objectives that include promotion of primary care, effective case management, and continuity among multiple providers in various settings.7 In addition to the clinical and quality-of-care reasons for coordination and collaboration between healthcare providers and community agencies, financing factors related to managed care and other cost containment trends also support the need for integration of services.19 Obstacles to continuity and followup because of gaps in service and access barriers related to lack of coverage persist to varying degrees in all communities despite improvements in delivery systems. This reality presents an ongoing challenge to healthcare providers. Emergency departments may consider these to be opportunities to take initiative in developing specialized resources, working proactively to identify and highlight unmet needs, and advocating for adequate funding and access for the uninsured to continuing care services, in order to support the goal of achieving a comprehensive continuum of care.

HISTORICAL PERSPECTIVE

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The importance of understanding the social and community context for medical conditions and larger public health problems has been recognized in the United States for over 100 years. The rationale for a psychosocial approach in healthcare began to emerge clearly in the first decade of the 20th century as the medical profession perceived the negative and pathogenic conditions in poor, densely populated urban areas and the correlation with the major public health issues of the time. The growing awareness of the linkage between social factors and serious health problems led to the introduction of social service workers as an extension of the hospital into the community, first in 1905 at Massachusetts General Hospital in Boston and then in 1906 at Bellevue Hospital in

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New York City.12 These early outreach workers began to make home visits, educate patients and families about health and nutrition, and offer supportive counseling and concrete services to provide for basic human needs of food, clothing, and shelter in order to improve compliance with medical recommendations and attempt to ameliorate unhealthy conditions in the environment. Their reports about the conditions in which patients were living helped to heighten awareness about social problems and gain support for public health initiatives.26 This early emphasis on the environment or social context as a determinant of pathologic conditions was later refined to incorporate the influence of psychological factors. The term “psychosocial” came to reflect the dynamic interaction of internal and external aspects of a person’s life, personality, and milieu—the person in his or her situation.16 Emotions, feelings, developmental factors, individual coping patterns, family background, cultural differences, and socioeconomic factors came to be recognized as significant variables in patient response to illness or injury. The importance of addressing the psychosocial needs of patients in healthcare settings was well accepted so that by 1930, there were more than 1000 hospital-based social service departments in the United States.9 Professional social workers are present today in all areas of healthcare. The scope of their practice paralleled the growth of medical specialization while adhering to the basic generic principles of the psychosocial evaluation, planning, and intervention process. In the new healthcare environment of integrated networks and closer working relationships with community agencies, social workers may develop, implement, and facilitate the linkages necessary for continuing care and coordination of services.

THE PSYCHOSOCIAL APPROACH IN EMERGENCY MEDICINE Psychosocial factors are significant in the evaluation and treatment of patients with toxicologic emergencies. The patient’s personal history, current situation, patterns of coping, and other psychosocial variables can be essential in understanding what precipitated the emergency event and can affect treatment and continuing care planning, case management, outcome potential, and options for prevention. With the development of comprehensive emergency services in the 1970s, the multidisciplinary healthcare model was adopted. Many emergency departments incorporated social work as part of the basic interdisciplinary team to assist in the assessment and management of acute medical and psychiatric conditions. The liaison or emergency psychiatrist and the social worker became part of the crisis intervention team needed to care for the patient who was poisoned. Emergency medicine as a specialty area of practice has grown rapidly.19 There has been a concomitant movement toward on-site social work coverage for emergency service patients rather than on-call consultation. Many large urban hospitals have moved toward 24-hour coverage by social work staff. The availability of social workers on site in emergency departments has contributed to professional credibility, enhanced team functioning, and improved services for patients and families.17 Social workers are able to engage families and other collateral sources to identify and assess potential support systems, to assist patients in obtaining concrete services, and to make effective referrals for continuing

care. However, in those settings where social workers are not part of the healthcare team, the responsibility for addressing psychosocial needs rests with the attending physician and may be assigned to another discipline based on the particular staffing structure. The increased focus on emergency services is related to the major public health and social welfare problems that continue to escalate in volume and severity and are manifested daily by patients who appear in emergency departments. There is increased public awareness that poverty, homelessness, drug and alcohol use, family breakdown, child abuse and neglect, and violence are phenomena that affect all communities. Transformation of these broad social issues into acute medical or psychiatric problems as well as personal and family crises occurs in hospital emergency departments across the country, in cities, suburbs, small towns, and even rural areas, where the patient may present with an overdose, in withdrawal, as a sexual assault victim who was drugged by the perpetrator in a social setting, or perhaps as a case of a seemingly unintentional pediatric ingestion.

SUBSTANCE USE AND SOCIAL DYSFUNCTION The adult substance user may be dysfunctional in one or several areas of his or her life.15 Substance abuse is often accompanied by difficulties in holding a job, maintaining personal relationships, and carrying out family and child-care responsibilities. It is common in hospital emergency departments to see patients from widely different backgrounds for whom alcohol or drug use has precipitated a crisis. Examples of this diversity might include a wealthy businessman with family supports and solid community ties who fell while intoxicated and suffered a fracture but sees himself as a social drinker and denies any problem with alcohol; a battered housewife, depressed and frightened, who took an overdose of barbiturates in a desperate effort to obtain relief from an intolerable situation; and an undomiciled man, a veteran with no current source of income, long estranged from family and friends, who has fallen into polydrug use that masks long-standing depression. In each of these examples attention to the psychosocial factors is critical to comprehensive case evaluation and differential treatment planning. Social problems are often interrelated. For example, drug or alcohol use or abuse by caregivers is clearly associated with a high risk of child abuse and neglect.5,23 Among women, childhood sexual abuse and domestic violence correlate with increased incidence of substance abuse.14 Maternal drug involvement frequently leads to placement of children.3 Conversely, the fear of losing their children often prevents women from acknowledging substance problems and obtaining needed services.2 It is also known that drug and alcohol use among adolescents and suicidal attempts in this age group usually reflect long-standing family problems and may indicate abuse and neglect, including sexual abuse.22 Among homeless adolescents and those who develop patterns of running away from families or group homes, the pervasiveness of alcohol and drug use is a significant factor.28 As the ability to identify child abuse and neglect improves, it becomes increasingly obvious that childhood incidents, including ingestions, are often correlated with neglect by their caregivers and exacerbated by extraordinary family stress related to marital problems, joblessness, dislocation, and homelessness. Psychoso-

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cial assessment has become an important component in the comprehensive evaluation of patients with toxicologic emergencies and may even be required under state-mandated child protection laws in cases where there is any suspicion that a child’s ingestion or an adolescent’s drug use, alcohol intoxication, or suicide attempt might be related to abuse or neglect by a parent or guardian. The need to recognize indicators of substance use in adolescents cannot be overstated, and screening for drug use should be considered in all medical emergencies including trauma.24 The overdose of an adult who has young children in his or her care raises serious questions about whether his or her drug use has caused a situation in which children are, have been, or could be endangered or neglected. Also, factors related to ethnic and cultural variables, and the particular needs of the elderly, the undomiciled, and other special populations, must be recognized and applied in assessment, treatment, and continuing care planning.11 The relationship between substance use and maternal/child health problems has become evident.10 There is urgent need to develop standardized protocols for the identification of drug use in pregnancy and to intervene expeditiously to improve outcomes for both women and their infants. Women of childbearing age who appear in emergency departments with substance-related conditions require meticulous attention, continuity of care, and active followup. Encounters with the healthcare system in emergencies provide the opportunity for pregnant drug-involved women to access many other services. This is accomplished most effectively through the assistance of social work staff who are in a unique position at the interface between the hospital and the community. They are able to address clinical as well as personal concrete needs such as food, clothing, financial aid, and emergency shelter and to help patients negotiate complex social systems.6

THE EMERGENCY DEPARTMENT CONTACT: OPPORTUNITY FOR INTERVENTION The hospital emergency department is usually the first point of entry into the healthcare system for substance users. Often they are assessed, treated, and released to the same environment in which their drug-taking behavior is supported and reinforced, only to return repeatedly to the emergency department with more evidence of debilitation and dysfunctional behavior. A comprehensive psychosocial approach, including early patient identification and intervention, is a prerequisite for a positive outcome for these apparently intractable, complex, and multicausal cases. Opportunities to intervene should not be lost; the patient’s contact with ED staff offers the hope and possibility of breaking the cycle of drug and/or alcohol abuse.1 Staff should not be deterred by the fact that success rarely occurs following initial contact but rather depends on a gradual, incremental process that includes ready access to a community service network, a flexible case management approach, and active followup.

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intervention. Patients who have alcohol use problems remain in the hospital longer than the nonproblem drinkers.20 The numbers of emergency department visits associated with heroin and cocaine use tend to ebb and flow, depending on the extent of problems experienced among the newest or heaviest users.27 However, frequently someone who has suffered injury or assault simultaneous to intoxication or oversedation has never had the opportunity for a healthcare professional to help him or her examine personal behavior and to focus on the psychosocial consequences, health issues, and treatment options related to chemical dependence. This becomes even more important when, as is sometimes the case, demographic data and psychosocial history had to be obtained from a family member or other collateral source because of incapacitation of the patient. Because information relating to drug and alcohol use carries a social stigma, interviewees often construct elaborate defenses and will invariably deny the existence of a problem. In these instances, if the interviewer has a reasonable suspicion that there is substance involvement, it is wise to offer intervention, referral resources, and counseling as a matter of course. Very frequently if the physician does not provide information about drinking behavior, it may not be obtained or pursued by the treatment team.21 It is important for the patient to receive clear, unambiguous information from sensitive, empathic, and credible healthcare providers about the physical and social consequences of drug and alcohol consumption.4 The emergency episode presents an opportunity for focused education and counseling that has potential for motivating the patient toward change. Social workers who practice case finding are frequently looked to as confidants by substance users for whom they provide supportive counseling. They should not ignore anecdotal information provided during their interactions with active users about the stressors involved in that person’s daily activities, around drug procurement, differential quality of available street drugs, obstacles to rehabilitation, and any new drug-taking trends that could pose health problems for the general patient population in the community. Substance users also confront the risk of HIV. It has been widely recognized that sharing of unsterile injecting paraphernalia while using illicit substances is a principal cause of AIDS. Moreover, many cocaine users claim that cocaine is an aphrodisiac.13 This causes chronic smokers of crack-cocaine in particular to engage in sexual practices for pay and/or pleasure, frequently ignoring the need for safety precautions to prevent AIDS and other sexually transmitted diseases. This activity is believed to be the leading cause of AIDS among women and heterosexual men and, through sex, can lead to infection of others such as spouses and unborn children. It is therefore important to augment screening and counseling about substance and alcohol use with information about AIDS and to offer referrals for HIV testing and, where possible, arrange pretest counseling within the emergency department as rapidly as possible for those who request to be tested.

THE ASSESSMENT PROCESS CONSIDERATIONS IN EMERGENCY CARE OF SUBSTANCE USERS The taking of a comprehensive substance use and alcohol history is of paramount importance in an emergency department because the visit often provides an excellent opportunity for a therapeutic

Any patient who has taken an overdose of a medication, whether prescribed or not, alcohol, or illicit substance or has ingested a poison, whether or not he or she manifests suicidal ideation, requires interdisciplinary assessment, support, and preliminary intervention in the emergency services setting. Decisions about psychiatric consultation, evaluation, and treatment follow medical

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stabilization. However, the social worker may be needed from the point of triage to determine whether there are family or child welfare issues that require immediate attention. For example, if the patient is an unaccompanied child or adolescent, or if the patient is a parent of young children for whom care must be arranged, efforts must be initiated promptly to reach responsible family members or to seek assistance from appropriate child welfare agencies. Patients with toxicologic emergencies are, by definition, high risk, based on accepted psychosocial indices (Table 113–1). The psychosocial evaluation process is fluid and multifaceted (Table 113–2). Psychosocial assessments can be initiated through interviewing of collateral sources before a patient is physically able to respond. Delay in obtaining psychosocial information can have serious consequences, as in cases where an overdosed adult patient may have small children who were left unattended. Psychosocial assessment includes clinical observation and interviewing of the patient and accompanying family members or friends; it may also involve contact with health or social service agencies to which the patient may be known. In cases involving young children, nonverbal modalities using play or drawings may be helpful after the situation is medically stabilized. Observation of interactions between the child and parent or caregiver and the responses of family members to the emergency can be helpful in understanding family dynamics. Assessment efforts are enhanced when therapeutic rapport can be established early in the contact. It is essential to adopt a sensitive, empathic approach in which the social worker clearly explains why personal and family information is needed. In evaluating an adult patient who has overdosed or is in withdrawal from a toxin, it is important to elicit information with regard to the toxin in the patient’s history of drug and alcohol use and any involvement with substance abuse treatment programs, including detoxification, methadone maintenance, and drug-free modalities. Contact with current treatment programs can be very helpful in coordinating the case and should be encouraged, especially in arranging discharge plans. It is also important to differentiate, early in the contact, the adult with no children from the adult with minor children in his or her care. The psychosocial needs of an isolated, undomiciled, middle-aged man are very different from those of a pregnant 24-year-old woman on methadone maintenance with two preschool children. In the latter example, the social worker’s immediate focus must be on the needs of the children, pending medical stabilization of their mother. If the children are present, they should be evaluated. If they are not present, their whereabouts should be determined. Any indication that they

TABLE 113–2.

Psychosocial Evaluation Process

Assessment Perform clinical observation/evaluation Interview patient and collaterals Obtain information on family history and current situation Evaluate minor children for immediate needs Establish drug and alcohol profile, including past treatment attempts Identify potential family and community support Interdisciplinary Develop medical and psychosocial diagnosis Collaboration Plan for intervention based on differential case needs: medical or psychiatric admission, referral for detoxification, report to Child Protective Services Implementation Coordinate case Facilitate intervention plan and advocate for services as needed Refer to community agencies Provide concrete services: food, clothing, financial assistance, transportation Perform crisis counseling Follow up Establish case management and followup plan, either directly or via community agency

may have been left unattended requires immediate contact with local child protection authorities. In any event, the social worker’s assessment must consider the impact of the woman’s drug involvement on her ability to care for the children, her judgment in arranging adequate alternate child care with relatives or friends, and her own medical, counseling, and supportive service needs. The social worker should explore the family and community resources available to the patient, consult with the clinical staff of the woman’s methadone treatment program, consider whether the case comes under state-mandated child protection reporting procedures, and develop a coordinated treatment plan that addresses prenatal needs in addition to a followup related to the patient’s drug-induced emergency and the child welfare issues.

CASE EXAMPLES The following cases support the efficacy of prompt psychosocial assessment as an integral part of comprehensive medical care.

TABLE 113–1. Screening Guide for High-Risk Emergency Department Patients Psychosocial assessment is required whenever the case involves: • Drugs or alcohol • Suspicion of child abuse or neglect • Domestic violence or other crime • Suggestion of suicidal intent • Psychiatric history • Mental retardation or developmental disability • Physical handicap, including vision or hearing impairment • Frail or elderly • Medical conditions with home care needs • Patient with minor children • Homelessness

Patient 1 A 2-year-old boy required admission for treatment following ingestion of antidepressant medication that had been prescribed for his paternal grandmother, with whom he lived. Social work assessment initiated in the emergency service revealed a troubled family, including an absent, drug-addicted natural mother; an inconsistently involved natural father with a history of drug use and incarcerations; the paternal grandmother; a paternal uncle; and an older sibling of the patient. Interviews with the grandmother and uncle initially suggested an unintentional ingestion by an active toddler with appropriate response by the family and prompt accessing of emergency medical care. Further exploration revealed a prior admission to another hospital, also ostensibly for the child’s ingestion of the grandmother’s medication. This raised concerns about the

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adequacy of supervision in the household and need for further evaluation to develop a safe discharge plan. The case was coordinated with Child Protective Services (CPS), and a discharge plan was developed that included home visits, parenting education for the grandmother, followup medical care for the child, and consultation with the grandmother’s mental health provider as needed. It was determined that CPS would carry primary responsibility for case management. Patient 2 A 14-year-old boy ingested acetaminophen and other nonprescription drugs in an apparent suicidal gesture. Initial psychosocial assessment elicited a history of family problems and sexual identity issues. The youngster was admitted for observation and further exploration of family, school, and other potential support systems. It became clear that the one stable person in the patient’s life was his maternal grandmother. She was caring and supportive but unable to manage the boy’s behavior or understand his mood swings. Both the patient and his grandmother agreed to recommendations for followup psychotherapy and family counseling in the adolescent mental health clinic. Interdisciplinary collaboration among three hospital units—the emergency department, the in patient service, and the outpatient clinic—made it possible to develop and implement a prompt, appropriate, and safe discharge plan. Patient 3 A 77-year-old man was brought to the emergency department (ED) by his home health attendant after falling at home. He was immobilized on a board, unable to move his extremities, and had suffered trauma to his right eye as well as minor contusions. Medical examination revealed that the patient had a biliary tract shunt and that he suffered from cirrhosis of the liver. It was also noted that he had been drinking alcohol, was disoriented, and was somewhat agitated. The patient was admitted to the alcohol detoxification unit under close medical supervision. Psychosocial assessment initiated in the ED showed the patient to be a retired hospital worker who lived with his wife and had adult children and grandchildren and a large extended family, all of whom were very supportive. His medical condition had deteriorated following gallbladder surgery, which led to the need for a home health aide for 12 hours per day, 7 days a week. The social worker noted during hospital visits that the patient presided over his family in a patriarchal, often dictatorial manner and gave direction to everyone with whom he came in contact. He had been a vital, active person before the illnesses, which now had him confined to a wheelchair, increasingly dependent on his wife and home health aide, which he strongly resented. They were not always able to keep him away from alcohol despite its potential life-threatening impact on him in his deteriorated physical state. Prompt, effective collaboration between ED and alcoholism service teams led to appropriate care that addressed the medical, emotional, and substance abuse needs of this alcohol-dependent elderly man with depressive features whose strengths included a stable support network and health benefits. On discharge, he was referred to the hospital’s alcohol aftercare treatment program and to the geriatric clinic for coordinated medical and psychiatric followup. A case conference was held with the home health agency to point out the need for vigilance because of the patient’s propensity to sneak a drink of beer, and support was given to the family to reinforce the need to keep the patient engaged in pursuits not related to drinking. Patient 4 A 41-year-old single unemployed man was admitted to hospital through the ED after falling out of bed following a long bout

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of alcohol bingeing. He was discovered on the floor by his brother, with whom he lived. The severity of his withdrawal required intensive care before he could be safely transferred to the alcohol detoxification unit. On arrival on the ward, the patient stated that he had not slept in 72 hours. He constantly paced the hallways, was very tremulous, and had to be patiently counseled against leaving prematurely. Psychosocial assessment showed the patient to be the eldest of three siblings who began alcohol consumption at age 9 and was drinking problematically by age 13. During adolescence, he was sent to a psychiatrist because of his intractable drinking problem. Nonetheless, he managed to complete high school and held restaurant jobs, the most recent one being 10 years before this hospital admission. The patient subsisted through the largesse of his brother, had Medicaid coverage, and had been involved in episodic outpatient alcohol treatment. On admission he was drinking 3 pints or more of vodka daily as well as several 16-ounce bottles of beer. The clinical impression was that of a 41-year-old, docile, chronic alcoholic, possibly with incipient organic brain damage as a result of long-term alcohol abuse. When medically cleared for discharge, he refused to await placement in a short-term rehabilitation program; therefore, the plan was adjusted for the patient to receive outpatient services with an active case management approach at a hospitalbased alcoholism clinic. Patient 5 A 26-year-old woman was brought to emergency services after exposure to numerous substances including heroin, cocaine, marijuana, and alcohol. From psychosocial assessment initiated in the ED, it was determined that she was also suffering from childhood sexual abuse that had occurred within the family and from current domestic violence, the result of her relationship with an abusive boyfriend. Medical problems included persistent anemia, asthma, and developmental disability. She was admitted to an inpatient unit for mentally ill chemical abusers (MICA). Relevant history included that the patient was the youngest of five siblings and lived primarily with her dysfunctional family. She received Supplemental Security Income and Medicaid. She became involved with illicit drugs at an early age and would frequently sleep in the homes of friends who also used drugs. She met her current boyfriend, a heavy user of alcohol and other drugs, when they both attended a sheltered workshop. He began battering her almost immediately, threatened her with weapons, and in some instances injured her so badly she required medical attention, and he was placed under arrest. Several orders of protection were issued for him through the courts. The patient stated she ingested the overdose in her effort of “trying to forget,” that she also tried using crack but “it made my heart beat too fast.” During the course of her treatment on the substance abuse unit, she repeatedly stated that on discharge she wished to continue her relationship with her boyfriend but wanted him to cease his battering behavior. The ED and MICA unit teams worked closely with the hospital’s domestic violence coordinator in the treatment and continuing care planning for this vulnerable patient with limited functioning, numerous medical complaints, in an abusive relationship, and periodically experiencing suicidal depression and repressed rage partly from signs and symptoms of posttraumatic stress disorder. Coordinated efforts on discharge included followup case management to obtain housing with supportive services, substance abuse and mental health counseling, and attempts to engage the boyfriend in order to prevent further domestic violence. Subsequent threats by the boyfriend resulted in his incarceration as a result of the advocacy provided by the domestic violence coordinator who functioned as the primary case manager.

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The patient responded well to the clinical and supportive services and showed signs of generally improved functioning. Good psychosocial assessments form a basis for more effective case management, especially where treatment depends on referral to community agencies for services such as drug or alcohol treatment, family counseling, child welfare services, emergency financial assistance, shelter, or home healthcare. Emergency departments that have formal or informal relationships with community service providers are better able to assure continuity of care. Regularly updated resource lists with clear referral guidelines are invaluable (Table 113–3).

THE ROLE OF THE EMERGENCY DEPARTMENT IN THE CONTINUUM OF CARE The effectiveness of a hospital ED is measured by how well individual cases are evaluated, treated, and managed and to what extent communication and coordination are maintained with other settings and organizations in the community that provide for continuing healthcare and social service needs. Efficacy is enhanced when the ED recognizes its strategic position in the continuum of care, seeks to develop and cultivate working relationships with a wide range of other providers, and makes reasonable efforts to formulate, implement, and follow up on continuing care plans. The morbidity of substance abuse and its relationship to AIDS, the widespread use of drugs and alcohol at all levels of society, including women of childbearing age, the nationwide increase in neglect, maltreatment, and physical and sexual abuse of children, adolescent suicide, domestic violence, and the problems of homelessness are markers everywhere of severe societal distress. Changes in public policy and planning related to these issues are affecting delivery of services to ED patients. Eligibility restrictions on medical and financial assistance deriving from the 1996 Personal Responsibility and Work Opportunity Reconciliation Act, commonly referred to as welfare reform, have exacerbated access problems for continuing care services including substance abuse treatment and resulted in more barriers to the goal of a comprehensive continuum of care.25 The challenge must be met by informed advocacy through awareness and involvement by emergency department staff at many levels beyond the care of the individual patient. Even the best emergency care is limited in efficacy if resources for ongoing treatment and supportive services are nonexistent or inadequate. The individual who is homeless and drug dependent TABLE 113–3.

Emergency Department Basic Resource Guide

Develop resource list and referral protocols for the following: • Drug and alcohol treatment services for all modalities and levels of care: detoxification, sobering up, therapeutic communities, other residential programs, methadone maintenance, drug-free outpatient clinics, 12-step programs • Mental health programs • Family services agencies • Child protective and voluntary child welfare services • Crime victims services • Shelters and emergency housing • Concrete services: food, clothing, financial assistance, transportation • Legal and advocacy services

and must wait weeks or months for entry into an inpatient or outpatient drug treatment program will inevitably continue maladaptive behaviors, which might include the risk of HIV transmission to sexual partners and those sharing needles. Current experience demonstrates the benefit to patients of providing HIV counseling and education in the ED, which is often the sole healthcare resource for this significant group of high-risk patients. The ED encounter presents an opportunity for the patient and the healthcare provider to interact at a higher level of mutual advantage and to the benefit of the community. Addressing the needs of the whole person may interrupt patterns of repeated emergencies. The strategic importance of the ED should not be underestimated in developing effective approaches to current social and public health problems.

REFERENCES 1. Abbott AA, ed: Alcohol, Tobacco, and Other Drugs: Challenging Myths, Assessing Theories, Individualizing Interventions. Washington, NASW Press, 2000. 2. Abbott AA: A feminist approach to substance abuse treatment and service delivery. Soc Work Health Care 1994;19:67–83. 3. Azzi-Lessing L, Olsen LJ: Substance abuse-affected families in the child welfare system: New challenges, new alliances. Soc Work 1996; 41:15–23. 4. Barber J: Working with resistant drug abusers. Soc Work 1995; 40:17–23. 5. Bays J: Substance abuse and child abuse: The impact of addiction on the child. Pediatr Clin North Am 1990;37:881–904. 6. Berger C: Cocaine and pregnancy: A challenge for health care providers. Health Soc Work 1990;15:310–316. 7. Berkman B: The emerging health care world: Implications for social work practice and education. Soc Work 1996;41:541–551. 8. Blending Perspectives and Building Common Ground. A Report to Congress on Substance Abuse and Child Protection. US Department of Health and Human Services. Washington, DC, US Government Printing Office, 1999. 9. Carlton TO: Clinical Social Work in Health Settings. New York, Springer, 1984, p. 4. 10. Chasnoff IJ, Schnoll SH: Consequences of cocaine and other drug use in pregnancy. In: Washton AM, Gold MS, eds: Cocaine: A Clinician’s Handbook. New York, Guilford Press, 1987, pp. 241–251. 11. Dodgen CE, Shea WM: Substance Use Disorders. Assessment and Treatment. New York, Academic Press, 2000. 12. Friedlander WA: Social work in medical and psychiatric settings. In: Introduction to Social Welfare. Englewood Cliffs, NJ, Prentice-Hall, 1961, pp. 389–395. 13. Gold MS: Cocaine (and crack): Clinical aspects. In: Lowinson JH, Ruiz P, Millman RB, eds: Substance Abuse: A Comprehensive Textbook. Baltimore, Williams & Wilkins, 1992, p. 211. 14. Goldberg ME: Substance abusing women: False stereotypes and real needs. Soc Work 1995;40:789–798. 15. Herrington RE, Jacobson GR, Benzer DG, eds: Alcohol and Drug Abuse Handbook. St Louis, WH Green, 1987, pp. 259–260. 16. Hollis F: Casework: A Psychosocial Therapy. New York, Random House, 1965, Chapters 1, 10. 17. Johnson LC, Schwartz CL, Tate DS: Health care and social welfare. In: Social Welfare: A Response to Human Need. Boston, Allyn & Bacon, 1997. 18. Joint Commission on Accreditation of Health Care Organizations: 1999 Comprehensive Accreditation Manual for Hospitals, Update November 2000 Continuum of Care CC-1 to CC-8, Oakbrook Terrace, IL.

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19. Linking Substance Abuse Treatment and Domestic Violence Services: A Guide for Administrators. Based on Treatment Improvement Protocol (TIP)25. Substance Abuse and Mental Health Services Administration; Center for Substance Abuse Treatment. DHHS Publication No.(SMA)00–3391. Washington, DC, US Government Printing Office, 2000. 20. McCusker J, Cherubin E, Zimberg S: Prevalence of alcoholism in general municipal hospital population. NY State J Med 1971;71: 751–754. 21. Niles BL, McCrady BS: Detection of alcohol problems in a hospital setting. J Addict Behav 1991;16:223–233. 22. Riggs S, Alario AG, McHorney C: Health risk behaviors and attempted suicide in adolescents who report prior maltreatment. Pediatrics 1990;116:815–821. 23. Rittner B, Dozier CD: Effects of court ordered substance abuse treatment in Child Protective Services cases. Social Work 2000;45: 131–140.

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24. Screening and Assessing Adolescents for Substance Use Disorders. Treatment Improvement Protocol (TIP) Series 31. Substance Abuse and Mental Health Services Administration; Center for Substance Abuse Treatment. DHHS Publication No. (SMA) 99–3382. Washington, DC, US Government Printing Office, 1999. 25. Soskis CW: Social Work in the Emergency Room. New York, Springer, 1985, pp. 1–11. 26. Starr J: Hospital City. New York, Crown, 1957, pp. 185–193. 27. Treaster JB: Emergency hospital visits rise among drug abusers. New York Times, April 23, 1993. 28. Wyman JR: Drug Abuse Among Runaway and Homeless Youth Calls for Focused Outreach Solutions. NIDA Notes Volume 12, No. 5. September/October 1997. US DHHS, National Institutes of Health. NIH Publication No. 97–3478.

CHAPTER

114 PSYCHIATRIC PRINCIPLES Michael H. Allen / Brett R. Goldberg / Wendy Rives (deceased) / Mark R. Serper

Psychiatric problems may be the cause or the effect of many toxicology presentations. Suicide attempts and aggressive behaviors are commonly associated with intoxications and can be uniquely difficult to assess and manage. These patients are often viewed as either totally voluntary and deliberate or totally “out of control” and irrational. The truth is usually more complex, with some aspects occurring within the patient’s awareness and control and other aspects either unknown or overwhelming to the patient. This chapter attempts to present schemas for understanding suicide and violence in ways that allow the physician to adopt the appropriate role of diagnostician and medical decision maker.

SUICIDE Self-destructive behavior is among the most common and challenging emergency department (ED) presentations. In 1997, the National Center for Injury Prevention and Control (NCIPC) reported that there were only 7529 intentional poisoning deaths in the United States, but the National Center for Health Statistics (NCHS) has reported that self-inflicted injuries accounted for an average of 221,000 ED visits per year from 1992 through 1995, of which 128,000 were intentional poisonings.11 Even so, only a fraction of suicides and suicide attempts ever come to attention. A recent population-based estimate of the 12-month prevalence of suicide attempts was 0.7%, suggesting that perhaps 10 times more attempts occur than present to EDs.19 This does not even include many behaviors such as the predictable but “unintentional” overdoses that accompany the hopelessness and carelessness of the late stages of addiction. Despite the high numbers affected, suicide has only recently been recognized as a major public health problem by the US Surgeon General. The overall rate of about 12/100,000 population per year has remained strikingly consistent for the past 50 years. The rate has declined for the younger elderly population while increasing for children and adolescents. Suicide is now the third leading killer of young people. Suicides, though clearly underreported, significantly outnumber homicides. Identification of the acutely suicidal patient places an extreme burden on the physician to intervene and prevent deaths. Suicidal ideation is quite common. One recent survey estimates a 12-month incidence of suicidal ideation at 5.6%, representing some 10.5 million people.19 Suicidal crises are heterogeneous, with suicide the final outcome of many possible psychiatric conditions and social circumstances. Self-poisoning or deliberate overdosing is a common method of attempting suicide, but this must also be differentiated from unintentional overdose, particularly in the young, the

mentally retarded, the confused elderly, and the chronic drugabusing patient. This distinction is rendered even more complex by the possibility that suicidal ideation may be deliberately concealed. In general, though, it is relatively easy to detect individuals at risk. The challenge is determining which of those of among the 128,000 intentional overdoses are seriously suicidal. Failure to do so has been associated with some of the largest damage awards in emergency medicine. Much is known about the risk of suicide for various groups over time, but little can be said with certainty about individual patients at particular points in time. There is no typical suicidal patient who may be routinely hospitalized. There is no clinically useful test or rating scale. One investigator was able to prospectively identify almost all of those who ultimately died by suicide (97% sensitivity) but only at the cost of overpredicting suicide by almost half (56% specificity).55 However, there is also no patient in distress for whom the risk of suicide is so remote that it need not be considered. Assessment of the potentially suicidal patient is a highly individualized exercise in clinical judgment.

Self-Poisoning Suicide is usually discussed in terms of attempts and completions. When the term “suicide” is used alone, it refers to completed suicide. The two are considered separately because those who attempt and those who complete suicide appear to constitute different groups. Those who attempt suicide are more commonly younger women with personality disorders, and self-poisoning is common in this group. Those who complete suicide, however, are more commonly older men with major depression or alcoholism, and they typically use more violent methods. In 1997, 72% of suicides were white men, and 58% of suicides involved a firearm.11 The methods preferred by women have shifted over time. Selfpoisoning was a very common method of suicide in the 1960s and 1970s, but it has since decreased, perhaps in part because of changing prescription practices and in part because of other social changes. In 1970, 47.9% of female suicides were by poisoning compared to 34.6% in 1993. In 1993, women, like men, were most frequently the victims of self-inflicted gunshot wounds (41.9%).11 Antidepressant medications have been the most common drugs implicated in suicide because of their toxicity and frequent use in the populations at risk. This decline in self-poisoning may be related to decreased use of more lethal medications such as barbiturates and monoamine oxidase inhibitors.18 Data from the Drug Abuse Warning Network suggest that newer antidepressants are significantly safer in overdose. While the risk of an attempt is

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roughly similar, the risk of death is 8.5 times greater with desipramine than fluoxetine.37 When benzodiazepines were more tightly regulated in New York State, there was again a shift to somewhat more consequential overdoses with more dangerous nontriplicate prescription drugs.35

Psychiatric Management of Self-Poisoning Table 114–1 depicts a case of suspected self-poisoning from the starting point of prehospital care through the completion of a comprehensive assessment and treatment planning. The upper row describes the evolving clinical course of the patient while the middle row shows the progression of emergency care provided to the patient. The bottom row lists specific diagnostic and treatment goals that should be completed at various points in the patient’s care.

Focused Psychiatric Assessment At a relatively early point in the patient’s course, a focused psychiatric assessment may be needed to address specific clinical concerns that can arise at this stage. Thorough psychiatric consultation is possible only when a patient is no longer intoxicated or otherwise acutely medically compromised. The determination that the patient has improved cannot be established on the basis of blood levels but should be approached clinically. Psychiatric examination must be postponed until signs of intoxication such as somnolence, slurred speech, and ataxia are no longer present. There are several reasons for this approach. First, the physician should not unequivocally attribute altered mental status to intoxication until signs of intoxication have passed and cognitive functions have returned to normal. Until that time, other medical conditions that might coexist with, or masquerade as, intoxication cannot be excluded. Second, the patient’s cognitive functioning will be too impaired by the drugs and/or alcohol to provide critical historical details reliably. Third, much of what the patient reports will be ephemeral, caused by the predictable temporary effects on mood of the substances ingested. Focused assessment may be necessary to ascertain elopement risk or decisional capacity. Subacute residual CNS effects of ingestions—confusion, fatigue, and fear—can dispose patients to wandering or flight. Additionally, the patient’s intentions remain unclear at this point; the question of unintentional versus inten-

TABLE 114–1.

PSYCHIATRIC PRINCIPLES

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tional ingestion cannot be completely resolved. For these reasons, a high level of supervision should be maintained, and patients should not be allowed to leave until assessment has been done of their mental status. Depending on the physical plant and personnel, it may be sufficient to place the patient in an open area in the direct line of sight of nursing staff. If such an arrangement is not possible, or the patient is agitated and disruptive, it may be necessary to separate the patient from the general population. Under these circumstances, an individual aide should be assigned to observe the patient. Some form of restraint may be necessary to prevent further injury. In general, patients are presumed competent and must consent to treatment, but the issue of decisional capacity frequently arises at this point. Patients may request their discharge, refuse care, or become aggressive. Aggression may arise from lingering effects of toxic ingestions, severe anxiety, fear, anger at the loss of autonomy, or the discomfort of unpleasant procedures. Although patients may respond to verbal limit setting and repeated explanations of their care, they may also require sedation, restraint, and involuntary treatment. This chapter later discusses management of the violent patient. Patients are not allowed to make poor healthcare decisions if their ability to weigh the risks and benefits of the proposed care is limited by cognitive deficits or mental illness. In the setting of intoxication, appropriate care may be provided under the doctrine of implied consent. The emergency exception to the doctrine of informed consent may also apply in circumstances where self-injury is suspected. The emergency exception permits forcible detention, restraint, medication over objection, and necessary medical care until psychiatric assessment can be accomplished. After the management of the immediate medical emergency and resolution of intoxication, suspected self-injury is sufficient evidence of impaired decisional capacity for the emergency physician to hold a patient for further psychiatric assessment. The emergency physician should note the patient’s objections in the record and indicate the basis for the determination of diminished capacity. After the self-poisoned patient is stabilized, there may be a need for a more thorough assessment of decisional capacity; psychiatric consultation may be useful at this stage to help document the degree of impairment, determine the etiology, and predict the likely course.

Case Presentation Case

Evolution

Patient course

Patient found in the community. Unresponsive

Patient monitored in the ED. Vital signs stable. Still unresponsive

Treatment course

Prehospital

Physician course

Patient identification Search for prescription drugs, drug paraphernalia Assessment of cardiac and respiratory functions

Triage Medical assessment Orogastric lavage, activated charcoal Diagnostic testing (blood studies, ECG, toxicology) Contact collateral sources for history. Prior records

Disposition Patient lethargic but following commands Answers simple questions Observation and monitoring Focused psychiatric assessment: elopement, aggressive behavior, decisional capacity, addressing confidentiality, and immediate suicide risk.

Patient fully awake and alert.

Evaluation complete

Formal psychiatric evaluation Comprehensive psychiatric assessment: diagnostic interviewing, risk factors, future risk.

Treatment planning Treatments: medication, hospitalization, substance abuse, crisis intervention, family therapy

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Immediate Risk. After these safety considerations have been addressed, the aim of the focused psychiatric assessment moves toward a determination of immediate suicide risk. This examination should answer the following questions: 1. What is the patient’s attitude toward life-saving care? 2. What are the patient’s current wishes with regard to living or dying? 3. What are the patient’s thoughts about his or her rescue and likely recovery? These questions can only be answered in the course of a frank discussion between the patient and the emergency physician. Do not be concerned about “provoking” further self-injurious impulses with this vital discussion; many patients will be relieved that the caregiver is speaking directly about their distress. Reliability and Confidentiality. Mention should be made here about the difficult issues of reliability and confidentiality with regard to gathering history. Evasiveness, lack of detail, inconsistency, and improbability taken together suggest an unreliable history. It is appropriate to confront the patient with the implausible aspects of the history provided and offer an opportunity to provide more useful information. This is often successful, although subsequent reports are, of course, equally suspect. The most important step from the standpoint of both clinical care and risk management is to locate other sources of information to clarify the patient’s situation. A careful review of any previous records is critical. Any pattern to a patient’s presentations such as increasing frequency, more aggravated behavior, or disheveled appearance should be noted. Collateral contacts are another important source of information, though the level of involvement, sophistication, and reliability of the collaterals must also be taken into account. The mere fact that a person is a patient at a hospital is not considered confidential, and hence, the ED may make contacts that are limited to soliciting information without specific consent. An effort should be made to obtain consent for any broader discussion with family, friends, or other treaters. The patient may express concern about the ED staff contacting a family member or counselor. Any information to be imparted to third parties can be negotiated in advance with the patient. The patient may restrict consent to receiving information only and may withhold consent to impart certain information. More caution is indicated in contacting an employer. Although disclosing information about the patient without his or her consent is a breach of confidentiality, a physician may do so in the interest of protecting the patient.5

Comprehensive Psychiatric Assessment The comprehensive psychiatric assessment includes a characterization of the suicidal ideation present, exploration of certain socalled risk factors, and the formulation of a diagnostic impression. These three elements help to determine the attendant risk and guide treatment planning. Stress Vulnerability Model. The best understanding of suicide at this time is that it results from intrinsic vulnerability factors interacting with extrinsic circumstances. Intrinsic vulnerability may be conferred by a variety of traits such as impulsivity or conditions such as depression, anxiety, and hopelessness. Extrinsic factors in-

clude stressful life events, access to lethal means, and a host of other factors, positive and negative.

Characterization of Suicidal Ideation. The core of the suicide risk assessment is a detailed discussion of the patient’s suicidal thoughts and urges. This must be included in every mental status examination. It is important to establish rapport and introduce the topic in an appropriate context in order to improve the patient’s candor. This requires significant time and skillful interviewing, for which there is no substitute. This approach will enhance the therapeutic quality of the interview as well as its reliability. For example, almost everyone has had some period in life when he or she was discouraged. The clinician may spend a few moments talking with the patient about the point in life when he or she was most disheartened. This is done by asking the patient if he or she has been feeling “down” lately; and then, if the patient has, by asking if this is the worst the patient has ever felt. If the patient denies recent depression altogether or indicates that this is not the worst, it is helpful, for several reasons, to ask the patient to describe the point in his or her life when the patient felt worst, which may or may not be the current episode. Depression fluctuates a great deal, and characterizing the worst period assures that a prior history of major depression will not be overlooked. At some point, the physician might ask if, during that worst period in the patient’s life, the patient ever felt that perhaps things would never get better (hopelessness), that he or she could not go on (helplessness), or perhaps that he or she would be better off dead (passive suicidal ideation). If failing others was involved in the patient’s demoralization (guilt), the physician might ask if the patient felt at any time as if others would be better off without him or her. These are common thoughts that most people can endorse without much difficulty and lay the groundwork for discussing more troublesome ideas in the suicidal spectrum. Ultimately, the patient must be asked directly if he or she has ever felt like “killing” himself or herself (active suicidal ideation). Nothing else will do. The more generic form, “hurting” himself or herself, which might seem to cover more, is in fact confusing to patients— even those who wish to die do not usually consciously intend to be hurt in the process. The latter is more typical of multiple suicide attempters than suicide completers. For those patients who have felt like killing themselves at some point, the next step in this scenario might be to establish how the patient is currently and to compare this to a prior episode(s). One dimension to assess is the progression from passive to active suicidal ideation. Suicidal feelings may take the form of a relatively inchoate wish to die, perhaps from a fatal disease or injury, and then proceed to consideration of various active means of hastening death. Planning might range from fleeting thoughts or images of a variety of methods from which the patient recoils to a more detailed consideration of a particular, realistic method of choice to serious planning concerning acquisition of the means, and socalled last acts. At some point the patient goes beyond thinking to acting by hoarding pills or completing his or her will. An astute family member may observe a series of odd conversations including phone calls to distant friends and family members as the suicidal individual begins to implement the plan with a series of vague farewells. In psychological autopsy studies, approximately 50 to 70% of completed suicides gave some warning of their intention; 30 to 40% of completed suicides disclosed a direct and specific intent to kill themselves.7,58

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Other dimensions to assess include frequency, urgency, chronicity, reactivity to positive and negative external events, and subjective distress. A schema for the detailed characterization of suicidal ideation appears in Table 114–2. The communication of suicidal ideas either directly or indirectly should not be misconstrued as a “cry for help” and hence evidence of lower risk. Communication is probably related to the degree of preoccupation with morbid thoughts and to personality characteristics that dispose individuals to revealing their thoughts to various degrees.38 Multiaxial Diagnosis. Diagnostic assessment also weighs heavily in the overall risk analysis, as there is a group of treatable psychiatric disorders associated with a high risk of suicide. Psychological autopsy studies in the United States and Europe over the years have consistently revealed major psychiatric illness to be a factor in suicide, present in 93% of adult suicide cases by some reports.56,59 This is also true of those who make medically serious attempts.8 In particular, prospective cohort studies and retrospective case control investigations have revealed clinical depression to dramatically increase suicide risk.13,31,48 For affective disorders, factors correlated with acute suicidality have included current depression, severe anxiety, anhedonia, panic, insomnia, ambivalence, and acute alcohol abuse. Responsibility for child care is inversely correlated with risk, suggesting a protective effect.23 After affective disorders, chronic alcoholism is the most commonly reported disorder, present in about 20% of cases. Moreover, alcoholic patients who also suffer from periodic episodes of depression are at more risk for suicide than patients who present with either disorder separately. As a result, any assessment conducted on patients with a substance abuse history must include an examination of symptoms of major depression.23 Schizophrenic patients are also at increased risk for suicide compared to the general population. Approximately 10% of schizophrenic patients will commit suicide.13 Additionally, between 5 and 18% of patients with severe borderline personality disorder (especially patients who are comorbid for depression) ultimately kill themselves.25,64 The odds of suicide attendant to various conditions are shown in Fig. 114–1.36 The ability to treat the two conditions most strongly associated with suicide—major affective disorder and alcoholism—suggests

PSYCHIATRIC PRINCIPLES

that most suicides are preventable. Indeed, a suicide prevention program directed at general practitioners in Sweden was able to demonstrate prevention based on the detection and treatment of depression.57 The possibility of preventing suicide necessitates a comprehensive psychiatric assessment to identify contributory psychiatric disorders. Risk Factors. A complete assessment should also include an examination of risk factors. Factors have been identified empirically that place groups of individuals at high risk for suicide. Although this level of prediction is actuarial and reflective of groups rather than individuals, knowledge of these risk factors is important.45 Although not specifically predictive, suicide is statistically more common in men than women and in whites than in nonwhites. Younger black men, however, have approximately the same suicide rate as white men the same age. Suicide rates for both black and white adolescents (15 to 19 years of age) have been increasing. In contrast, suicide rates in the elderly have decreased threefold since 1940 but still occur in disproportionately high numbers.68 Previous suicide attempts are an obvious risk factor. However, those who attempt suicide appear to be a somewhat different group demographically and diagnostically. Parasuicidal behavior is more common in 25- to 44-year-olds than in the elderly, and more common in women than men. Existing data also indicate that nonfatal suicide attempters are equally prevalent across racial and ethnic groups.22,49 Most individuals who kill themselves seem to do so on the first attempt. Although that suicide attempt is still the strongest predictor of suicidal outcome, only about 1 in 10 attempters is ultimately successful.32,55, Multiple attempters also appear to have higher risk than those who make a single attempt.29 Medically serious attempts may be a better marker of risk. Those who make serious attempts tend to share with completers a higher rate of serious mental illness.8 A number of avenues of inquiry suggest that violent attempts are associated with a persistent deficiency in brain serotonin levels. Impulsive types of aggression, for example, have been linked to serotonergic dysfunction in prefrontal cortical regions of the brain.20 This deficiency has been measured in postmortem brains and spinal fluid of suicide victims and survivors of violent attempts compared to nonviolent attempters and other patients. Serotonergic deficiencies persist during periods of acute psychi-

TABLE 114–2.

Characterization of Suicidal Ideation

Dimension

Benign

Intermediate

Malignant

Onset Frequency Pesistence Urgency Complexity Activity Emotional response Circumstances

None Occasional Fleeting thoughts Disinterested Simple Passive ideas Death repellent

Chronic, stable Daily Persistent thoughts Engaged Some detail Plans without action Ambivalent

New or fluctuating Constant Preoccupation Intense Elaborate Action Death desirable

Victim identifies one clear precipitant Some, realistic Recognizes remediable psychologic problem Opposed to suicide

Several complex contributory stressors Few, problematic Overvalued ideas present, temporarily reassured Suicide acceptable but prefers to live

Either noncontributory or overwhelming stressors Seems hopeless Morbid delusions present, reassurance impossible Resolutely suicidal

Alternatives Insight Intent

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Figure 114–1. Increased likelihood of suicide for various conditions. (Data from Inskip HM, Harris EC, Barraclough B: Lifetime risk of suicide for affective disorder, alcoholism and schizophrenia. Br J Psychiatry 1998; 172:35–37.)

atric illness as well as remission. Relatedly, low levels of serum cholesterol have also been associated with increased risk for violent suicidal behavior and aggression towards others.30 Low serum cholesterol level may interfere with serotonergic functioning and may also serve as a marker for future violent behavior. Unfortunately, these finding have not yet developed into a clinical tool. Hopelessness has also received a significant amount of study as a potential predictor of suicide. However, hopelessness appears to have high sensitivity but low specificity.9 Identifying hopelessness as a problem also suggests possible interventions. Ultimately, most persons belonging to a high-risk group do not commit suicide, and some individuals with no apparent risk factors do. Many risk factors are not modifiable. This type of information, then, weighs most heavily in the assessment in the absence of other more specific data, early in the hospital course, or in the case of the uncooperative or hostile patient. The best foundation for treatment planning and clinical decision making is direct examination and clinical diagnosis.

Treatment Following the comprehensive psychiatric assessment, the next step is deciding on treatment alternatives. Any patient who has made a suicide attempt must be considered to be at risk, and some further intervention is warranted. The risk of a subsequent lethal attempt is approximately 1% per year over the first 10 years. The risk is highest in the first 1 month to 1 year. The treatment alternatives available will depend on the psychiatric sophistication of the staff available to the ED at any given time. The following section describes the commonly used interventions in the emergency department; they can be used singly or in combination. Medications can be used acutely in the treatment of severe anxiety or psychosis; however, in the case of antidepressants, a period of weeks is required for therapeutic effect, so their immediate use is not indicated in the ED. In fact, there are concerns about prescribing medications with relatively high potential for lethality in overdose, such as tricyclic antidepressants and monoamine oxidase inhibitors, to persons who have recently attempted suicide. However, newer antidepressants, and particularly the selective

serotonin reuptake inhibitors (SSRIs), can be used as first-line drugs for treatment of most depressions, and they are relatively safe in overdose. A marked drop in the number of deaths per million antidepressant prescriptions was observed between 1970 and 1974 in Europe.34 Nonetheless, the initiation of antidepressant therapy by the nonpsychiatric physician is not recommended unless a tight linkage can be made between discharge and immediate (within days) aftercare by either a community outreach team or a crisis clinic. Patients with depressive disorders may suffer from significant anxiety; also, patients with overwhelming situational stressors (job loss, new financial hardship, bereavement or divorce) may have episodic anxiety or insomnia. The prescription of a short course of a benzodiazepine may provide significant relief to the patient in crisis. After the patient’s immediate symptoms have been treated in the emergency department, the next treatment decision is determining the setting in which further treatment may safely be provided. Not all patients with suicidal ideation or even significant attempts necessarily require hospitalization, and there is still a substantial stigma attached to psychiatric hospitalization. In general, it should be the treatment used if less restrictive measures cannot insure the patient’s safety. If significant doubt exists about the safety of outpatient treatment, the patient should be held in the ED for further evaluation, admitted to a general hospital with close nursing supervision, or admitted to a psychiatric unit. “Holding beds” now available in some larger psychiatric emergency services are ideal for this purpose. Some localities may also have crisis outreach services that follow the patient after discharge from the ED and improve appropriate monitoring and continuity of care. Patients most likely to respond to interventions in the ED are individuals who until recently have been stable but who, as a result of some external event, find their way of life threatened. This results in a painful state of anxiety and the mobilization of some combination of adaptive and maladaptive coping strategies. Finally, a second event, the precipitant, intensifies the anxiety to the point that the patient cannot tolerate it and is thrown into crisis. The patient then feels desperate and may be completely immobilized or vulnerable to various strong impulses including the impulse to run away, strike out at someone else, or kill himself or herself. Reality testing is preserved, and no major psychiatric syndrome is present. The patient accurately perceives his or her situation, understands that the current reaction is a psychological problem, and is highly motivated to obtain help. The crisis may last for a matter of hours or weeks before the ED presentation and will ultimately resolve. Such patients respond well to crisis intervention and may actually undergo some positive development in the course of treatment. By contrast, patients whose condition has been deteriorating for some time in the absence of significant stressors, and who appear on examination to be suffering from severe depressive symptoms, are unlikely to benefit rapidly from supportive techniques. If such patients present with suicidal ideation or attempts, it will be difficult, though not impossible, to manage them outside the hospital. Outpatient settings have the advantage of maintaining the patient’s functioning as much as possible. Work and child care responsibilities, financial obligations, and social relationships are not disrupted. Unnecessary regression is halted. The patient is able to assume more responsibility for his or her outcome, and inde-

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pendence helps preserve self-esteem. These individuals remain closer to and more engaged with the people and situations with which they must learn to cope. Their morale may be rapidly improved by the combination of support, planning, and modest early treatment successes. In some cases, though, these same factors may be disadvantageous. Routine tasks may seem overwhelming. High levels of conflict may render major relationships at least temporarily unworkable. Inpatient settings offer the advantage of respite, high levels of structure, more intensive professional and peer support, constant supervision, and usually, more rapid pharmacologic and psychosocial intervention. The physical plant also reduces, though it cannot eliminate, the possible means of suicide. The choice of inpatient or outpatient setting will depend on the balance of strengths and weaknesses of the patient, the involvement and competence of family or friends, the availability of a therapist in the community, and the ongoing stresses in the patient’s life. This decision is best made by a psychiatrist after performing his or her own examination. Many facilities will not have a psychiatrist available much of the time. However, a trained mental health professional should be on call to every emergency department. This may be a psychiatric social worker, nurse clinician, or psychologist supervised on a regular basis by a psychiatrist or with a psychiatric consultant available by phone. When such services are not available, it is appropriate to detain patients in the ED until a practitioner with specific competence is available or to transfer the patient to another facility for evaluation. Every state has laws that provide for the involuntary commitment of the mentally ill under circumstances that vary from state to state. Any acute, deliberate self-injurious behavior would generally qualify. Chronic, repetitive dangerous behavior that is not “deliberate,” such as frequent unintentional opioid or sedative-hypnotic overdoses, warrant careful evaluation; but in the absence of psychiatric illness, involuntary treatment is usually not an option. The practitioner should be familiar with the criteria for commitment and the classes of healthcare providers so empowered under state law. There are other treatment interventions that can be provided in the emergency setting; these include crisis intervention, substance abuse counseling, and family therapy. A single session in the ED may be sufficient to defuse a crisis or to spur the drug-abusing patient to seek help; alternatively, the intervention may be begun in the ED and continued in another setting. Crisis intervention is a brief, highly focused therapy that seeks to deconstruct how a crisis occurred, with an eye toward examining the patient’s role. Often, patients have distorted perceptions of the crisis, and a gentle “correction” of catastrophic thinking can be extremely helpful. (Here is an example. Patient: “I’m going to be broke and unemployed the rest of my life.” Physician: “How did you get your last job?” Patient: “Well, I interviewed a couple of times.” Physician: “So people have hired you in the past, right?”) The crisis is presented to the patient as an unfortunate and perhaps tragic experience that he or she can overcome. Ideally, the patient should have a relief of symptoms and learn how crises may be avoided in the future. This intervention will likely fail for patients with severe depression because of the presence of profound hopelessness. It is best utilized for patients who give a history of high functioning just prior to the crisis. Substance abuse treatment is ultimately an intermediate(weeks to months) to long-term (months to years) intervention. However, there are powerful initial steps that the emergency physician can take. Chief among these is confronting the patient

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about the medical consequences of substance use. This can take the form of discussion only, or the physician can invite the patient to examine clinical laboratory results or view remarkable clinician/diagnostic findings (hepatomegaly, repeated fractures from falls, increased liver enzymes or evidence of “silent” past myocardial infarction). There is little to be lost from a respectful but blunt confrontation of the patient’s deterioration, and he or she may listen to a physician rather than family or friends. Peer counseling is particularly useful in addictive disorders; if possible, patients should be referred to community 12-step programs such as Alcoholics Anonymous. Family therapy can occur as a series of sessions over the long term or can be useful in the emergency setting to defuse a crisis, reinstate social supports for the patient, or educate families about mental illness. It is most important to respect a patient’s request as to the level of family involvement; it may often occur in the emergency setting that patients are either too angry or ashamed to confront their families. At this point, it is prudent to defer and to assure the family that the patient is safe and that you will keep them informed as confidentiality and discretion allow.

VIOLENCE The violent patient also presents unique challenges to the emergency physician. Violent patients are difficult to treat, and they tend to elicit strong negative reactions in ED personnel. In one study of violence in the ED, directors of residency programs in emergency medicine were surveyed as to the frequency of verbal threats, physical attacks, and the presence of weaponry in the area. Of the 127 institutions, 74.7% of the residency directors responded; 41 (32%) reported receiving at least one verbal threat each day; moreover, 23 (18%) reported that weapons were displayed as a threat at least once each month. Fifty-five program directors (43%) noted that a physical attack on medical staff occurred at least once a month.41 In a second study, the authors conducted a retrospective review of university police log records and ED staff incident reports to examine the problem of violence in the ED setting. Almost 75% of the incidents occurred during the evening or night. Of the 686 episodes of violence in this study, more than 25% required physical restraint or removal from the premises; additionally, it was found that the police responded to the ED nearly twice daily.54 These studies underscore the need for timely identification of the violent patient as well as appropriate management for this diagnostically heterogeneous group. The assessment and management of the violent patient should include provisions for patient and staff safety as well as a thorough search for the cause of violent behavior. This section addresses the differential diagnosis of violent behavior, the pharmacotherapy of aggressive and/or agitated behavior, and the use of seclusion and restraint. It also provides an overview of potential risk factors for violent behavior.

Stress-Vulnerability Model of Aggression As with suicide, there are many and varied causes of violent behavior, some more social and some more medical in nature. It is most helpful to think of violence as the outcome of a dynamic interaction among numerous factors both intrinsic and extrinsic to the individual, some of which promote and some of which ameliorate the potential for violent behavior at any given moment. This is

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a stress-vulnerability model. Education may provide alternatives to violence, but delirium may cause an otherwise nonviolent person to misinterpret healthcare efforts. Their education is of no benefit in the delirious state. Hence, they become violent under circumstances that would not normally be sufficient to provoke a violent outburst. Some patients, on the other hand, come from cultures in which violence is viewed positively, and these patients require little stress or provocation before responding violently. In the ED, likely medical sources of vulnerability include metabolic derangements, drug and/or alcohol intoxication, withdrawal syndromes, seizure disorders, head trauma, psychotic states, and personality disorders. Additionally, patients with severe pain, delirium, or extreme anxiety can respond to the efforts of emergency personnel with resistance, hostility, or frank aggression.

Prediction Research on risk factors for community violence may not apply to the prediction of inpatient violence. Some researchers have postulated that violence committed outside the hospital may not be predictive of inpatient violence and that hospital violence may result from the interaction of patients with specific factors found in the hospital environment.33 However, other studies support the notion that the best predictor of future violence is still past violence.63, 53 Adding to the confusion of the issue, a study conducted in Germany examined the violence potential of nearly 18,000 inpatients:63 8.3% of incoming patients had a history of previous violence, but only 2.7% of inpatients in their study actually committed a violent act in the hospital. Even if prior violence is a good predictor of future violence, it is not a perfect predictor. Other factors, such as mental illness and substance abuse, need to be examined in order to make meaningful predictions of inpatient violence for each individual case. One study found that the most common types of hospital violence were incidents of aggression against objects in the hospital (56.7%), violence directed against the hospital staff (27.8%), and violence directed against other patients (14.4%).62 In this study, men were not found to be committing significantly greater incidents of violence than women. Other studies concur that male patients are not necessarily more of a risk for inpatient violence than female inpatients. For example, another study examining inpatient violence found that close to half of the violent incidents were committed by female patients.39 Furthermore, they found that the number of violence-related injuries committed by male and female inpatients was almost proportional to the ratio of male and female inpatients on the unit. They concluded that gender should not be considered a risk factor for inpatient violence. Long hospitalization was not considered a factor predictive of violence for the majority of inpatients. As with outpatient violence, the correlation of violence with younger age appears to hold true in the inpatient setting.53, 62

Substance Use The association between substance use and violence is well established. Alcohol is found in the offender, the victim, or both in onehalf to two-thirds of homicides and serious assaults.17 Substance abuse is seldom the sole cause, but it may contribute to violence in a number of ways. The direct pharmacologic effects include disinhibition and misinterpretation, suspiciousness, or paranoia. Psy-

chological effects of substance use include cultural expectations of appropriate behavior under the influence and the ability to excuse or disavow inappropriate behavior that occurs while intoxicated. Substance use then interacts with other physiologic, cognitive, psychological, situational, and cultural factors including any mental illness. A tripartite model has been described: (1) systemic violence related to drug distribution, (2) economic compulsive violence associated with the criminal activity necessary to sustain a drug habit, and (3) psychopharmacologic violence resulting from the direct effects of the particular drug or toxin.28

Mental Illness The relationship between mental illness and violence is also complex. Efforts made to destigmatize mental illness have confused the issue, but it seems clear that mental illness is associated with a greater risk for violence. In one large epidemiologic study, the prevalence of violence for those with no disorder was 2%. Schizophrenia was associated with an 8% rate of violent behavior, and other mental disorders were all similar at approximately 12%. But of all respondents reporting violent behaviors, 42% had a substance use disorder. Substance use more than tripled the rate of violence for schizophrenics. For various reasons, mental illness appears to reduce the threshold for aggression, and the more comorbid conditions present, the greater the risk.65 For whatever reason, researchers are consistently finding a greater prevalence of personality disorders among violent inpatients than nonviolent inpatients.50 However, antisocial personality is the condition most strongly associated with both substance abuse and aggression. In one study, when the history of juvenile deviance was controlled, alcohol—the drug most commonly associated with violence—accounted for only 2% of the violent behavior. In conclusion, some aggressive behavior is attributable to the direct pharmacologic effects of substances but probably represents a modest fraction. Substances are also a part of the setting of violent behavior in the community, a coincidental part of the life style of violent individuals; and both substance use and violence are related to common underlying characteristics such as character disorder.

Medication Noncompliance Many research studies currently list medication noncompliance as a risk factor for violence that is as serious as substance use or mental illness. One study associated medication noncompliance and substance use with increased violence risk in the mentally ill.67 They suggest that medication noncompliance may lead to self-medicating through the use of illicit substances, and substance use may lead to further medication noncompliance. These two factors together may then have the effect of increasing violence for the mentally ill. This study also suggested that low insight into their illness can be associated with greater violence. However, they found that poor insight was correlated with substance use and medication noncompliance, so it is unclear if poor insight is truly predictive. Other studies have replicated these findings.66 Patients entering the ED who did not adhere to their medications as outpatients may be more of a risk for inpatient violence. Furthermore, inpatients who refuse to adhere to medication prescribed in the hospital also are more of a risk for violence, especially when comorbid with substance abuse disorders.

CHAPTER 114

Additional Factors in Violent Behavior Many of the factors correlated with aggression are easy to observe and monitor in the hospital. However, some additional factors that influence violent behavior may not be as easy to detect. For example, one study examining violent behavior found that most violent incidents in the hospital occur on Mondays and Fridays, with very few on the weekends.40 They pointed out that this finding reflected findings of violence research in the general population and postulated that the explanation for the inpatient violence is the same as that for the general population. Mondays and Fridays have special significance in the workweek, and weekends are usually less stressful. This finding illustrates the point that seemingly minor social stressors can be as conducive to violent behavior as any other factor. Furthermore, researchers have postulated a seasonal variation of violence.16 They reported finding an increase in the frequency of assaults by inpatients during the winter months and hypothesized that increased population density, cold temperature, and less sunlight during the day could account for the increased violence. This finding is in contrast to the literature on outpatient violence, which has reported greater incidence of violence during the hot months.6 However, this same review conceded that any extreme temperature could evoke aggressive feelings and frustration. A third study examined temperature and violence and found that more aggressive acts occur during the summer months, both in the hospital and in the community.24 They cited several explanations, one of which was that the high rate of staff turnover, as vacations are taken, disrupts the social networks the patients have established, evoking aggressive feelings. Although it is unclear whether the cold can provoke aggression as much as it has been established that heat can, it does seem clear that overcrowding and social stressors can lead to violent behavior. If the effects of temperature and social stressors (eg, holidays) correlate so drastically with violence in the community, it is likely that such effects would have even more impact when comorbid with severe mental illness, substance use, or any of the other risk factors of aggression. Physicians would be wise to keep that in mind when dealing with potentially dangerous inpatients.

Assessment The comprehensive evaluation of the violent patient should include a complete physical examination. The examination may reveal the underlying cause of the violent behavior as well as insuring the treatment of any secondary patient injuries. Laboratory analysis of blood chemistry, a complete blood count, and diagnostic imaging as guided by the examination and available clinical history may also be helpful. Illicit drug and alcohol use often present with symptoms of violence. Acute intoxication with cocaine can produce extreme psychomotor agitation, delirium, and transient psychosis characterized by paranoia and hallucinations; a clinically indistinguishable syndrome can be seen following the ingestion of amphetamines. Phencyclidine intoxication is manifested by assaultiveness, muscle rigidity, dysarthria, nystagmus, autonomic instability, and ataxia. Alcohol intoxication is characterized by typical signs of cerebellar dysfunction (slurred speech, gait ataxia, and incoordination); however, persons who are intoxicated are also at risk for violent behavior. Cannabis does not typically pro-

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duce violent or aggressive behavior; however, paranoia can occur with intoxication and can secondarily promote reactions of extreme fear associated with distorted perception; the same can be said for intoxication with LSD and psilocybin, particularly in the naive user. Withdrawal syndromes from specific drugs can also promote aggressive behavior as a consequence of physical discomfort or anticipatory anxiety. Opioid withdrawal is characterized by myalgias, rhinorrhea, and piloerection; alcohol, benzodiazepines, and barbiturates share a common syndrome of autonomic hyperreactivity and subsequent delirium. Patients suffering from any of these signs and symptoms may become aggressive, verbally abusive, or threatening. Prompt recognition of these syndromes and immediate treatment can prevent some aggressive outbursts. Because drug use is often concealed, is difficult to ascertain on clinical grounds, and frequently contributes to violent behavior, urine toxicologic studies may be useful to enhance the understanding and long-range treatment of some patients. Delirium can be a cause of aggression. Patients are often suddenly confused, frightened, or frankly psychotic as a result of impaired perception. Patients may require sedation or restraint in order to prevent injury; some guidelines for this are presented in the next section. Although persons suffering from psychotic disorders are not generally aggressive, there are aspects of the psychotic state that place patients at risk for aggressive behavior. Paranoid ideation can serve to promote misperceptions of impending bodily harm (“They’re trying to kill me”), sexual victimization (“Men and women are raping me”), and humiliation (“Everyone is laughing at me”). It follows that these fearful perceptions might provoke violent reactions in a patient. Hallucinations can cause aggression, either as a result of command hallucinations or in reaction to the anxiety and irritation that patients experience with loud or persistent “voices.” Persons with either borderline or antisocial personality disorder are at risk for violent acting-out as a result of poor impulse control. Violence risk has also been associated with cognitive dysfunction. Both acute mental illness and chronic substance use can result in neurologic impairment. Psychiatric patients with compromised cognitive abilities such as impaired attention, memory, or executive functioning (ie, reasoning and planning) have been found to be at increased risk for violence.61 Patients presenting with cognitive impairment may also be at increased risk for committing acts of violence in the ED.

Treatment The acute pharmacotherapy of violent behavior is directed simply at reducing the level of arousal. A recent review of this issue proposed a model for the efficient use of medication for the control of episodic as opposed to chronic agitation and aggression.3 In this model, agitation and violent outbursts are viewed as transient disturbances of the usual treatment relationship between the physician and patient. Pharmacotherapy and seclusion or restraint are to be used only as needed to restore that relationship, for the benefit of the patient as well as other members of the milieu. The restoration of the treatment relationship is necessary in order to take measures to understand and deal with the cause of the agitation, with the input and consent of the patient, thus preventing future incidents. For this reason, sleep is considered an undesirable use of

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medication. Sleep delays rather than promotes assessment, may further frighten or anger the patient, and does not even guarantee elimination of the agitated state on awakening. As aggression derives from varied and multiple etiologies, it follows that there is much debate about the specific sedative used, the route of administration, and the dosing interval. Studies examining the treatment of aggression and/or agitation have included such diverse populations as schizophrenics, acutely intoxicated patients (alcohol), trauma patients, postoperative patients, patients in alcohol withdrawal, and patients with presumed personality disorders. Treatment settings for these studies included psychiatric inpatient units, intensive care units, and the ED.1,14,42–44 An excellent review examined a number of these studies and found that both benzodiazepines and antipsychotics afforded relief of agitation and aggression.21 It seems, however, that there are specific clinical situations when benzodiazepines and neuroleptics might be preferentially used. Haloperidol has been safely used in the treatment of agitation and aggression in patients with psychoses, alcohol intoxication, and delirium.2,14,42,43 The drug can be administered orally, intravenously, or intramuscularly; dosing intervals range from 30 minutes to 2 hours. The usual regimen is 5 mg haloperidol given every 30 to 60 minutes; most patients respond after 1 to 3 doses. The dose of haloperidol needed to achieve sedation rarely exceeds a total of 50 mg. Benzodiazepines are also quite effective for tranquilization; their use has been examined in patients with psychoses, stimulant intoxication, and postoperative agitation.1,26,46,47 Lorazepam 1 to 2 mg may be given orally or parenterally and repeated at 30- or 60-minute intervals, respectively, until the patient is calm. Because diazepam is poorly absorbed from intramuscular sites, the preferred route of administration is intravenous or oral. Diazepam may be given as 5 to 10 mg IV with repeat dosing as needed; concerns about respiratory depression mandate careful observation of patients receiving tranquilization with these agents. Diazepam may have a unique role in the treatment of agitation secondary to cocaine intoxication, as seizures may emerge in this syndrome (see Chap. 67). Antipsychotics, particularly low-potency antipsychotics, are known to lower seizure threshold in animals, so their use for patients with cocaine intoxication may be limited. Studies have examined the use of combinations of lorazepam with antipsychotics in patients with psychiatric illness and delirium; it appears that the combination of benzodiazepine and antipsychotics afforded relief of psychotic symptoms while allowing for a reduced dose of antipsychotic medications.2,15,60

Physical Restraint Seclusion and restraint are also used in the treatment of violent behavior. Seclusion can help to diminish environmental stimuli and thereby reduce hyperreactivity; it is not commonly used in the medical ED, so its use is not discussed in great detail here. However, a few reminders are worthwhile to mention: as seclusion is defined by a condition of very limited interactive and environmental cues, it is not indicated for patients with unstable medical conditions, delirium, dementia, self-injurious behavior (cutting, head banging), or who are suffering extrapyramidal reactions to antipsychotic medication.4 Restraint is used to prevent patient and staff injury. All facilities should have clear written policy guidelines for restraint that address monitoring, provisions for patient comfort, and documentation. (Chap. 115)

Training Finally, it has been shown that training in the management of aggression helps to reduce violence and injuries through the early identification of impending episodes of violence, use of verbal techniques to defuse incidents, and appropriate physical techniques to minimize injuries in those that occur. It behooves the healthcare provider to maintain his or her skills through training and to advocate for continuing medical education on this topic at the workplace.12

SUMMARY Both violent and suicidal behavior in the ED may be the cause or the effect of many toxicologic presentations. Patients presenting with suicidal or aggressive behavior pose unique problems for the clinician who must make appropriate assessment and management decisions. Identifying risk factors for suicide and aggression can aid the clinician in employing preventive or early intervention strategies in the ED. Important risk factors for both suicidal and violent behavior include past history of the behavior, comorbid mental illness, substance intoxication, and young age groups. Mental status examination for suicidality should focus on extrinsic factors such as current ideation, intent, lethality of plan, current life stressors, as well as intrinsic vulnerability factors such as comorbid mental illness, feelings of hopelessness, and impulsivity. In terms of violence risk assessment, substance intoxication, mental illness and psychiatric medication noncompliance, alone or in combination, are robust predictors of aggressive behavior in the ED and other inpatient settings. Early detection and rapid intervention for patients at risk for suicide or violence is, to date, the best means for preventing injury or death.

ACKNOWLEDGMENT Cherie Elfenbein contributed to this chapter in a previous edition.

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10. Bick PA, Hannah AL: Intramuscular lorazepam to restrain violent patients [letter]. Lancet 1986;1:206. 11. Burt C, Fingerhut L: Injury visits to hospital emergency departments: United States, 1992–1995. Vital Health Statistics 1998;13(131). Washington, DC, National Center for Health Statistics, 1998. 12. Carmel H, Hunter M: Compliance with training in managing assaultive behavior and injuries from inpatient violence. Hosp Commun Psychiatry 1990;41:558–560. 13. Clayton PJ: Suicide. Psychiatr Clin North Am 1985;8:203–214. 14. Clinton JE, Sterner S, Steimachers Z, Ruiz E: Haloperidol for sedation of disruptive emergency patients. Ann Emerg Med 1987;16: 319–322. 15. Cohen S, Khan A, Johnson S: Pharmacological management of manic psychosis in an unlocked setting. J Clin Psychopharmacol 1987;7: 261–264. 16. Coldwell JB, Naismith LJ: Violent incidents in special hospitals. Br J Psychiatry 1989;154:270. 17. Collins JJ, Schlenger WE: Acute and chronic effects of alcohol use on violence. J Stud Alcohol 1988;49:516–522. 18. Crome P: The toxicity of drugs used for suicide. Acta Psychiatr Scand 1993;371(Suppl):33–37. 19. Crosby AE, Cheltenham MP, Sacks, JJ: Incidence of suicidal ideation and behavior in the United States. Suicide Life Threat Behav 1999; 29:131–140. 20. Davidson RJ, Putnam, KM, Larson CL: Dysfunction in the neural circuitry of emotion regulation: A possible prelude to violence. Science 2000;289:591–594. 21. Dubin W: Rapid tranquilization: Antipsychotics or benzodiazepines? J Clin Psychiatry 1988;49(Suppl 12):5–12. 22. Fawcett J, Clark DC, Busch KA: Assessing and treating the patient at risk for suicide. Psychiatr Ann 1993;23:244–255. 23. Fawcett J, Scheftner WA, Fogg L, et al: Time-related predictors of suicide in major affective disorder. Am J Psychiatry 1990;144: 923–926. 24. Flannery RB, Penk WE: Cyclical variations in psychiatric patient-tostaff assaults: Preliminary inquiry. Psychol Rep 1993;72:642. 25. Frances A, Blumenthal S: Personality as a predictor of youthful suicide. In: Risk Factors for Youth Suicide. Report of the Secretary’s Task Force on Youth Suicide, Vol. 2. Alcohol, Drug Abuse, and Mental Health Administration. DHHS pub. No. (ADM) 89–1624. Washington, DC, US Government Printing Office, 1989, pp. 160–171. 26. Garza-Trevino E, Hollister LE, Overall JE, Alexander WF: Efficacy of combinations of intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation. Am J Psychiatry 1989;146: 1598–1601. 27. Goldfrank LR, Hoffman RS: The cardiovascular effects of cocaine. Ann Emerg Med 1991;20:165–175. 28. Goldstein PJ: The drugs–violence nexus: A tripartite conceptual framework. J Drug Issues 1986;15:493–506. 29. Goldstein R., Black D, Nasrallah,A, Winokur G: The prediction of suicide, Sensitivity, specificity, and predictive value of a multivariate model applied to suicide among 1906 patients with affective disorders. Arch Gen Psychiatry 1991;48:418–422. 30. Golomb BA, Stattin H, Mednick S: Low cholesterol and violent crime. J Psychiatry Res 2000;34:301–309. 31. Hagnell O, Lanke J, Rorsman B: Suicide rates in the Lundby study: Mental illness as a risk factor for suicide. Neuropsychobiology 1981; 7:248–253. 32. Harris EC, Barraclough B: Suicide as an outcome for mental disorders: A meta-analysis. Br J Psychiatry 1997;170:205–227. 33. Hassan SD, Sobel RN: Violence in the community as a predictor of violence in the hospital. Psychiatr Serv 2001;52:240–241. 34. Henry JA: A fatal toxicity index for antidepressant poisoning. Acta Psychiatr Scand 1989;354:37–45. 35. Hoffman RS, Wipfler MG, Maddaloni MA, Weisman RS: The effect of the triplicate benzodiazepine prescription regulation on sedativehypnotic overdoses. NY State J Med 1991;91:436–439.

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36. Inskip HM, Harris EC, Barraclough B: Lifetime risk of suicide for affective disorder, alcoholism and schizophrenia. Br J Psychiatry1998; 172:35–37. 37. Kapur S, Mieczkowski T, Mann JJ: Antidepressant medications and the relative risk of suicide attempt and suicide. JAMA 1992;268: 3441–3445. 38. Kovacs M, Beck A, Weissman A: The communication of suicidal intent. Arch Gen Psychiatry 1976;33:198–201. 39. Lam JN, McNiel DE, Binder RL: The relationship between patients’ gender and violence leading to injuries. Psychiatr Serv 2000;51: 1167–1170. 40. Larkin E, Murtagh S, Jones S: A preliminary study of violent incidents in a special hospital (Rampton). Br J Psychiatry 1988;153: 226–231. 41. Lavoie F, Carter G, Danzi D, Berg R: Emergency department violence in United States teaching hospitals. Ann Emerg Med 1988;17: 1227–1233. 42. Lenehan G, Gastfriend DR, Stetler C: Use of haloperidol in the management of agitated or violent, alcohol-intoxicated patients in the emergency department: A pilot study. J Emerg Nurs 1985;11:72–79. 43. Lerner Y, Lwow E, Levitin A, Belmaker R: Acute high-dose parenteral haloperidol treatment of psychosis. Am J Psychiatry 1979;136: 1061–1064. 44. McClish A, Andrew D, Tetreault L: Intravenous diazepam for psychiatric reactions following open heart surgery. Can Anaesth Soc J 1968; 15:63–79. 45. Meehl PE: Psychodiagnosis: Selected Papers. Minneapolis, University of Minnesota Press, 1973. 46. Modell JG: Further experience and observations with lorazepam in the management of behavioral agitation [letter]. J Clin Psychopharmacol 1986;6:385–387. 47. Modell JG, Lenox RH, Weiner S: Inpatient clinical trial of lorazepam for the management of manic agitation. J Clin Psychopharmacol 1985;5:109–113. 48. Monk M: Epidemiology of suicide. Epidemiol Rev 1987;9:51–69. 49. Moscicki EK, O’Carroll P, Rae DS, et al: Suicide attempts in the Epidemiologic Catchment Area Study. Yale J Biol Med 1988;61: 259–268. 50. National Center for Injury Prevention and Control: Suicide in the United States. http://www.cdc.gov/ncipc/factsheets/suifacts.htm. 51. Nolan KA, Volavka J, Mohr P, et al: Psychopathy and violent behavior among patients with schizophrenia or schizoaffective disorder. Psychiatr Serv 1999;50:787–792. 52. Nutter DO, Massumi RA: Diazepam in cardioversion. N Engl J Med 1965;273:650–651. 53. Owen C, Tarantello C, Jones M, et al: Violence and aggression in psychiatric units. Psychiatr Serv 1998;49:1452–1457. 54. Pane G, Winiarski A, Salness K: Aggression directed toward emergency department staff at a university teaching hospital. Ann Emerg Med 1991;20:283–286. 55. Pokorny AD: Prediction of suicide in psychiatric patients. Arch Gen Psychiatry 1983;40:249–257. 56. Rich CL, Young D, Fowler RC: San Diego suicide study, I: Young vs. old subjects. Arch Gen Psychiatry 1986;43:577–582. 57. Rihmer Z, Rutz W, Pihlgren H: Depression and suicide on Gotland: An intensive study of all suicides before and after a depression-training programme for general practitioners. J Affect Disord 1995;35: 147–152. 58. Robins E, Gassner S, Kayes J, et al: The communication of suicidal intent: A study of 134 consecutive cases of successful (completed) suicide. Am J Psychiatry 1959;115:724–733. 59. Robins E, Murphy GE, Wilkinson RH, et al: Some clinical considerations in the prevention of suicide based on a study of 134 successful suicides. Am J Public Health 1959;49:888–889. 60. Salzman C, Green A, Rodriguez-Villa F, et al: Benzodiazepines combined with neuroleptics for management of severe disruptive behavior. Psychosomatics 1986;27(Suppl):17–21.

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61. Serper M, Bergman AJ, Copersino ML, Chou J, Richarme D, Cancro R: Learning and memory impairment in cocaine dependent and comorbid schizophrenic patients. Psychiatry Res 2000;93:21–32. 62. Soliman AE-D, Reza H: Risk factors and correlates of violence among acutely ill adult psychiatric inpatients. Psychiatr Serv 2001;52: 75–80. 63. Spiessl H, Krischker S, Cording C: Aggression in the psychiatric hospital. A psychiatric basic documentation based 6-year study of 17,943 inpatient admissions. Psychiatr Prax 1998;25:227–230. 64. Stone MH: The course of borderline personality disorder. In: Tasman A, Hales RE, Frances AJ, eds: Review of Psychiatry, Vol. 8. Washington, DC, American Psychiatric Press, 1987, pp. 103–122.

65. Swanson J, Holzer C, Ganju V, Jono R: Violence and psychiaric disorder in the community: Evidence from the Epidemiologic Catchment Area Survey. Hosp Commun Psychiatry 1990;41:761–770. 66. Swanson JW, Swartz MS, Borum R, et al: Involuntary out-patient commitment and reduction of violent behavior in persons with severe mental illness. Br J Psychiatry 2000;176:324–331. 67. Swartz MS, Swanson JW, Hiday VA, et al: Violence and severe mental illness: the effects of substance abuse and nonadherence to medication. Am J Psychiatry 1998;155:226–231. 68. US Department of Commerce: Statistical Abstracts of the United States, 116th ed. Washington, DC, US Government Printing Office, 1996.

CHAPTER

115 NURSING PRINCIPLES Susan Callaghan-Montella / Barbara E. Soppet

Management of the poisoned patient requires an integrated response on the part of healthcare providers of all disciplines. This chapter offers specific considerations with regard to general nursing management and a detailed approach to patient evaluation. The discussion is not intended to be specific only to nurses, nor does it assume that the nurse’s role in care is limited to these points. The collaborative roles of all emergency care providers consistently overlap, and it is this spontaneous team response that is essential for successful resuscitation. The necessity of professional collaboration is particularly evident in the areas of assessment, physical findings, toxidrome identification, and in the implementation of all aspects of standard medical management (see Chap. 3 and 31). The optimal approach to the poisoned patient, as a nursing process, is assessment, planning, implementation, and evaluation. However, as in the medical management of the poisoned or overdosed patient (Chap. 3 and 31), the customary sequence of evaluation must sometimes be altered to address each particular clinical situation. With respect to the patient with an altered level of consciousness, even before the full assessment is performed, the airway must be stabilized, the cervical spine protected, and supplemental oxygen, dextrose, thiamine, and naloxone must be administered as indicated. In the case of a severely agitated patient who is breathing but combative, physical and chemical restraints to assure patient and staff safety may preclude a full patient assessment. Only after immediate life-threatening issues are addressed can the formal nursing process begin. If the patient arrives in the emergency department (ED) awake, alert, and oriented, the standardized clinical approach should be initiated immediately (Table 115–1).

intervention. The practitioner’s ability to obtain and use the vital signs, together with the information provided to the examiner’s senses of sight, touch, and smell, can provide valuable clues to the nature of an ingestion. The first priority of the triage nurse is to initiate a primary survey and identify any immediate life-threatening problems necessitating treatment. Immediate airway management with appropriate attention to the possibility of head/cervical spine injury must be accomplished before assessment proceeds. Once airway, breathing, bleeding, and circulation are assessed and stabilized (see “General Acute Management” later in this chapter, Chap. 3 and 31, and Fig. 3–1), the next task is to establish the database necessary for ongoing management of the patient. The questions that need to be asked as part of patient assessment and the sequence of delivery of care are covered in the next sections.

Who Is This Patient?

TRIAGE: INITIAL ASSESSMENT OF THE PATIENT

The patient’s age, sex, general appearance, hygiene, mental status, physical findings, and social, family, and medical history all will assist in the development of a differential diagnosis, the development of a priority assessment, and the preparation of a plan of care. Unfortunately, in poisoned patients, a history is not always readily available. Often the patient is unaccompanied and unable to offer details of his or her illness. Hence, prehospital teams become potential sources of very valuable data: Were there family, friends, or neighbors present? Was any important information secured from this source? What relevant prehospital clinical data are available? What was the condition at the scene? Was there a suicide note? Were there any signs of ingestion—pill bottles, “syringes,” tablets, capsules, or bottles or containers that might contain or have contained a toxin? Remember that the label may not reflect the substance that was actually in the bottle. The need to initiate therapy rapidly often precludes waiting for laboratory results. Changes in level of consciousness, associated with pupillary findings and vital signs, may assist the nurse in the recognition of a toxidrome (see Chap. 17 and Table 17–2). If the patient has ingested a toxic substance, what drug or substance was taken? Is there any characteristic odor that might indicate a specific ingestion or clinical condition? The odor of vomitus, sweat, and urine, as well as the color and quality of stool, can be diagnostic. Are there characteristic physical signs? The ingestion of multiple substances may have toxicologic effects. Is alcohol responsible for the patient’s condition? Has it been ingested in addition to other substances, and can it potentiate their effects? Were any remedies initiated by the family or friends? Are there

Often, the first healthcare professional to evaluate a patient in the ED is the triage nurse. Information crucial to diagnosis and treatment may be available only at this early encounter, before the patient’s consciousness becomes altered as a result of a central nervous system (CNS) depressant. An astute, inquisitive, and intuitive triage assessment often results in initiation of the necessary therapy and avoidance of subsequent mortality and morbidity. The triage (from the French “to sort”) nurse separates the emergent and urgent patients from the nonurgent and establishes the priority of care. In doing this, the nurse must perform another vital function, which is to sort out critical information that may identify a particular toxic syndrome, thus allowing for more timely

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TABLE 115–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY Standard Emergency Department Nursing Care Plan for the Poisoned Adult Patient

Assessment Objective: Triage examination (categorize patient’s emergency) Check Airway: Is it open and clear? Can patient speak, cough? Are there obvious signs of head or neck trauma? Breathing: Presence or absence, rate, rhythm, abnormal breath sounds? Circulation: Assess pulse, blood pressure, skin color and temperature, capillary refill, cutaneous moisture. Neurologic status: Level of consciousness, pupils, movement of extremities, gag reflex. General appearance: Dress, body size, tissue turgor, cleanliness, wounds, bruises, marks on skin, odor on breath. Subjective: Brief History (from patient if alert and/or obtain details from those accompanying patient) Chief complaint Name of substance taken Route of administration Amount taken Time taken Time of onset of symptoms Past medical history Maintenance medications Allergies, risk factors Prehospital treatment initiated at the scene by EMS personnel. Intervention (see Fig. 3–1) Administer oxygen via nasal cannula or face mask (if patient is breathing), or initiate respirations with pocket mask or bag valve-mask with 100% oxygen (if patient is not breathing) If pulse absent, proceed with appropriate resuscitation care plan; remove all clothing Stabilize cervical spine as appropriate Insert oral or nasal airway as necessary Clear patient’s secretions with suction if necessary Check equipment for proper functioning; assist physician with intubation Request chest radiograph Obtain vital signs, including rectal temperature; attach the patient to a cardiac monitor and pulse oximeter Initiate IV therapy using a macrodrip initially and D5W or 0.9% sodium chloride solution Draw blood for serum glucose, CBC, BUN, electrolytes, ABGs, and appropriate toxicology testing; test blood with glucose indicator strip;
-HCG testing if appropriate Obtain 12-lead ECG Prepare naloxone first and then D50W and thiamine for administration Rapidly evaluate patient’s response, neurologic status, and vital signs Evaluate the need for physical restraint if patients’s mental status is altered and/or he is a danger to himself or others If patient is conscious Check gag reflex Prepare to administer activated charcoal if appropriate Have functional suction unit available Keep the patient in an open, observable area If patient is unconscious Protect airway with intubation, when indicated Prepare for orogastric lavage with orogastric tube, if appropriate (Chaps. 3 and 31) Following lavage, administer activated charcoal and a cathartic Consider need for a specific antidote. Evaluation: Monitor Vital signs, include a repeat temperature Cardiac monitoring, pulse oximetry; 12-lead ECG Rapid head-to-toe assessment Response to emetic (if given) or orogastric lavage and cathartic Oral and IV fluids given (input) Urine amount (output) Emotional status: evaluate the need for psychiatric consultation and/or social service assessment if patient is stable. Prepare patient for admission to hospital or continued observation; notify family and friends in accordance with patient wishes. If patient is discharged, after medical and psychiatric clearance, provide patient (and family if appropriate) with discharge instructions and followup care; ensure, through feedback, that instructions are understood.

CHAPTER 115

any clinical conditions, other than a toxic ingestion, that might present in this fashion, and, if so, how must immediate management be altered? What additional tests are necessary to evaluate the patient? If alcohol is present as a suspect or confounding substance, a blood alcohol level may be indicated. Reporting to the poison center offers the potential for a discussion with experts and provides for clinical followup in cases of toxic ingestions. Collaboration with these specialists will improve immediate patient management and clinical followup. The poison control staff’s awareness of new trends and “fad” drugs can assist clinicians in the initial understanding and management.

Where Did the Exposure Occur? Is the time of the exposure known? Was the patient at home, alone, at a social gathering or at work? Was the ingestion taken in a secluded or hidden place? Such information may reveal whether there was a purpose to the patient’s exposure. Was it an intentional or unintentional exposure? A toxic ingestion taken in a secluded hotel room should suggest the possibility of a suicide attempt, which would necessitate additional clinical interventions, both acute and long term. A positive pregnancy test in a patient of childbearing age may be a determining factor in decisions about specific supportive measures. Is a pregnancy responsible for the ED presentation, or is it a coincidental finding? Does the pregnancy contraindicate any otherwise routine therapies?

When Did the Exposure Occur? It is necessary to determine how much time has elapsed since the exposure and how much of the drug can be expected to be absorbed. These factors affect general management (eg, activated charcoal or orogastric lavage followed by activated charcoal) as well as decisions regarding toxin-specific antidotes or tertiary care procedures (eg, hemoperfusion and hemodialysis). The time of year and climatic conditions must be appreciated, especially in the case of patients found on the street. Environmental conditions can rapidly alter thermoregulation in the drugoverdosed patient. Hypothermia or hyperthermia requires a comprehensive care plan. The need for a core temperature is therefore an integral part of admission vital signs. If the patient’s temperature is at either extreme of a traditional thermometer, and there is a suspicion of hypothermia or hyperthermia, or the patient is agitated or uncooperative, an indwelling temperature device that can monitor the extremes of temperature of 60 to 120°F (15.5 to 48.9°C) should be used. Both hypothermia and hyperthermia may cause an altered mental status and may prevent a response or signs of a response to appropriate therapeutics. In addition, the patient’s temperature may provide clues to the possibility of a preexisting or concomitant disease process that must be considered in developing a plan of care.

How Did This Emergency Occur? What route of exposure was used? Was it intentional or unintentional and a result of ignorance or impaired judgment? Was this event a manifestation of chronic abuse? What implements were used? Were any other substances taken that might potentiate the effects of the toxic substances? Any patient presenting with an altered mental status that compromises airway and circulation should be triaged as emergent and afforded prompt attention.

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GENERAL ACUTE MANAGEMENT: PLANNING AND INTERVENTION The nursing and medical roles in this phase of care are quite similar and interdependent, and thus, the nurse should be reasonably comfortable with the recognition of common toxic syndromes so as to anticipate tasks of care and facilitate their delivery. The nurse must coordinate the patient’s immediate physical care as it relates to immediate survival as well as overall well-being (Tables 115–1 and 115–2). Priority must be given to life-threatening aspects. Assessment, plan implementation/intervention, and evaluation may, therefore, be applied in a systematic manner to both immediate and ongoing therapeutic considerations. (Nursing care interventions for emergency management: a quick reference tool, may be found in Table 115–3.) As in the case of any resuscitative measure, adequacy of the patient’s airway is clearly the first therapeutic consideration. Patients with suspected toxic exposures who enter the hospital with respiratory depression initially require assisted ventilation. The American Heart Association’s guidelines suggest that a mouth-tomask equipped with one-way valve, or bag valve mask techniques be used to minimize any possibility of infectious disease contamination. Whenever possible, two people should be present, one controlling ventilation with the bag and the other maintaining head position and face-mask seal. An oxygen reservoir and 100% oxygen should be attached to the bag. In cases in which respiratory arrest occurs and intubation is necessary, 100% oxygen with tidal volumes of 10 to 15 mL/kg should be delivered. In the event that respiratory arrest occurs in a patient with opioid toxicity, naloxone must be used judiciously. In these cases aggressive airway control may be preferred to the rapid reversal of respiratory depression with naloxone. Vomiting, which also occurs with this reversal, poses the further risk of aspiration in a patient with CNS depression. Insertion of an oropharyngeal airway and aggressive airway management with mouth-to-mask or bag valve mask devices may be all that is required until an improved level of consciousness is achieved. In the event that naloxone is used, the doses should be given in 0.05-mg increments to avoid the complications of rapid reversal in a patient where airway control is necessary. For pa-

TABLE 115–2. Examples of Nursing Diagnosis in Toxicologic Emergencies Airway clearance (ineffective) Aspiration Body temperature (altered) Bowel elimination (altered) Breathing pattern (ineffective) Cardiac output (decreased) Coping ineffective Fear Gas exchange (impaired) Hypothermia/hyperthermia Infection Injury Poisoning Self-esteem disturbance Sensory perceptual alteration Tissue perfusion (altered) Violence Volume deficit (fluid)

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY TABLE 115–3. Alphabetic Tool in the Assessment and Stabilization of the Poisoned Patient with a Toxicologic Emergency Airway and Antidote

Breathing and Behavior control

Circulation and Coma antidotes

Drug elimination

Expose, Examine, Evaluate Fluid management

Get vital signs and tests

Head-to-toe and History Initiate consultation

Control airway using C-spine precautions as needed Consider need for immediate and specific antidote by history or examination eg, naloxone, cyanide antidote kit, removal and/or irrigation of noxious topical agents). Place on O2 mask (bag valve mask as needed) Does mental status/behavior require physical restraint/chemical restraint or antidotal care? Are there any contraindications? Check pulse; start CPR if absent Start IV Place on cardiac monitor and pulse oximetry Administer D50W, thiamine, and naloxone only if indicated Decontaminate; emesis or orogastric lavage if indicated Administer activated charcoal and cathartic as needed Continue irrigation to achieve topical decontamination Consider specific antidote, if not already initiated Perform a quick examination after completely undressing the patient Is the patient in need of a fluid bolus? Are there any specific intravenous infusions that should be initiated (eg, naloxone or sodium bicarbonate)? Obtain a complete set of vital signs including a core temperature to exclude hypothermia/hyperthermia Obtain routine blood work, U/A; consider blood and urine for toxicology testing Obtain ABG, ECG, chest radiograph Consider other radiographs or tests that may be needed to exclude other injury or complications (eg, C-spine radiograph, head CT, carboxyhemoglobin level) Look for hidden clues; do a complete and thorough reevaluation of the patient Obtain a detailed history from ambulance personnel and/or significant others Contact psychiatric or social service consults; consider other specialty consultation as necessary

tients who do not require intubation, oral airways are tolerated only by unconscious patients lacking a gag reflex. Nasal airways should be used in conscious patients who require an airway but have an intact gag reflex. For a conscious but lethargic patient who needs only supplemental oxygen, many types of airway adjuncts are available. It is important not to confuse the nonrebreathing mask, delivering 95 to 100% oxygen, with the rebreather mask, which delivers an FIO2 of only 50 to 60%. Awareness of the idiosyncrasies of various types of Venturi masks and the manufacturer’s recommendations for assembly eliminates unnecessary confusion under emergent circumstances. Some patients may tolerate nasal cannulas better than face masks because they are less confining, but “mouth breathers” fare better clinically with masks. When a nurse receives a patient who is intubated and being ventilated via bag valve mask, tube placement and the presence of breath sounds should be verified. Reassessment includes vital signs, pulse oximetry, level of consciousness, cardiovascular and neurologic status, and the approach to maintaining adequate circulation. Respiratory therapy should be notified to provide ongoing ventilatory support and continuous monitoring of ventilation–perfusion adequacy. The patient must then be undressed completely, and a rapid head-to-toe assessment performed. The presence of a gag reflex, speech quality, recall of events, and emotional state are evaluated. Pupil size and reactivity, extraocular movements, and the presence of nystagmus, tremors, weakness, paralysis, and paresthesias should be noted as well as any other physical findings.

Prompt attention to the “ABCs” is standard emergency procedure. Ongoing reassessment yields valuable data, which provide clues to the presence of particular toxins, the need for emergent intervention, and the likelihood of complications. After immediate lifesaving measures and a secondary assessment have been completed, a 12-lead electrocardiogram (ECG) should be done to search for dysrhythmias and/or conduction abnormalities. Cardiac monitoring in the poisoned or overdosed patient is essential, with monitor rate alarms set and functioning. Cardiac rate and function as part of a toxidrome can offer valuable clues to the identification of the substance. The presence of a cardiac dysrhythmia in and of itself may indicate the presence of a particular substance, or it may assist in the management of a concomitant problem or complication. For instance, heroin could certainly be responsible for a patient’s near respiratory arrest, but one would not expect a tachydysrhythmia without suspecting other concomitant drug use or complications, such as dehydration, aspiration pneumonitis, endocarditis, or a mixed heroin-cocaine overdose. Cocaine is often associated with atrial and ventricular dysrhythmias as well as acute myocardial infarctions, but any of these findings are suggestive not diagnostic. This information, when corrrelated with additional data, helps provide the information for nursing diagnosis and ongoing plan of care. When frequent blood pressure evaluation is necessary, an external blood pressure monitor or arterial line should be considered. Once an IV has been established and fluid replacement initiated, specific management may necessitate IV medication administra-

CHAPTER 115

tion. Many nurses develop shortcuts in the calculation of IV fluid infusion time and flow rates. Some emergency departments continue to use preprinted, readily accessible IV “drip tickets” in the ED for drugs that are frequently infused intravenously. These precalculated dose charts also serve as markers on the IV bottles, but infusion pumps that automatically calculate and deliver doses in a predetermined time frame are ideal for use in a busy ED. Any drip used for hemodynamic support or antidotal therapy should utilize an infusion pump for delivery. If thiamine, 50% dextrose, and naloxone are administered intravenously, documentation of the patient’s response to therapy and anticipation of the need for further interventions and complications of care become the priorities of the nurse. A patient with a depressed level of consciousness secondary to hypoglycemia or opioid overdose may respond rapidly to the antidotes D50W and naloxone, respectively, whereas a patient with Wernicke’s encephalopathy will have an immediate biochemical benefit and a delayed clinical response to thiamine. When and how the patient responds, as well as the duration of the response, yield clues to the etiology of the obtundation and thus to further management strategies. If the only etiology is an injected opioid, then an immediate response to naloxone is anticipated, varying in intensity from slow, appropriate movement to violent thrashing, associated with retching and coughing. If the patient has been intubated, the nurse must be alert to these possibilities to prevent tube dislocation or self-inflicted injury by the patient, and if the patient is not intubated prevention of aspiration is essential. The nurse then reevaluates any change in status to determine whether additional therapies are appropriate or whether previous interventions may be discontinued (Table 115–4). In the event that an IV line is not readily accessible, naloxone, as well as atropine, epinephrine, and lidocaine, can be administered via the endotracheal tube. Though an intravenous route is preferable, each of these agents is well absorbed from the tracheobronchial tree. The presence of persistent CNS alteration requires attention to the possibility that toxic substances present in the gastrointestinal (GI) tract may require evacuation or adsorption to prevent further toxin absorption. Coexisting illnesses or injuries can also complicate management decisions. Consideration must be given to whether additional diagnostic studies, such as a head CT, might provide further information significant for the treatment plan. Ongoing neurologic assessment is essential. Activated charcoal is administered by mouth in the conscious, intact patient or via the nasogastric or orogastric tube in the patient who is unable to take medications by mouth or in any patient without an intact gag reflex. Naloxone, if indicated, may be administered in bolus doses or as a continuous infusion. The nursing considerations for the most common antidotes used in the emergency setting are presented in Table 115–4. A more in-depth discussion of these agents is presented in the individual Antidotes in Depth as well as throughout the text. Orogastric lavage is described in detail in Chap. 31 and Table 31–1. The goal is to create a siphon effect and ensure uninterrupted flow. A large enough age appropriate orogastric tube with multiple distal and lateral openings should be used. Nasogastric tubes are not adequate for overdose management (except liquids). After passage of the orogastric tube, these patients are placed in the left lateral decubitus position for administration of 0.9% NaCl solutions, drainage, and subsequent administration of activated charcoal. Lavage tubes are now available with special ports to permit a more efficient, cleaner method of medication administration,

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which is especially desirable for giving activated charcoal. Lavage tubes with preestablished bite blocks are also available if preferred. Patients who are alert and have an intact gag reflex may choose to drink the activated charcoal. Because activated charcoal is unattractive in appearance, some clinicians prefer to administer it to the patient in an opaque cup (or prepackaged opaque plastic bottle) with an opaque flexible straw. When a cup is used, it should be held away from the patient to conceal the appearance. A washcloth should be provided to wipe the patient’s face when the emergency situation has passed, as activated charcoal will transiently discolor the skin. (For dosing of activated charcoal, see Chap. 31 and Table 31–2.) Magnesium or sorbitol cathartics, although rarely indicated (see Chap. 31 and Table 31–3), may be given simultaneously with activated charcoal, and administered orally or via an orogastric or nasogastric tube. The nurse should be prepared to handle the resultant diarrhea with a bedpan and wash basin. Should the patient be discharged soon after cathartic administration, he or she should be advised to expect copious black diarrhea because of the rapid transit of activated charcoal. During gastric decontamination, the role of the nurse includes the continuous monitoring and reassessment of the patient’s clinical status, anticipating changes that might occur in response to or in spite of therapy. Verification of the initial placement of the orogastric tube as well as continued patency and accuracy of placement is essential to avoid aspiration. In lavaging children and agitated patients, additional assistance may be necessary to minimize trauma during insertion and to avoid complications that might result from the tube being dislodged from the esophagus. In general, agitated patients should not be lavaged before sedation to limit the potential trauma to the patients’ upper airway and GI tract. In cases in which the patient is obtunded, endotracheal intubation may offer protection of the airway and prevent aspiration from tube displacement or posttherapy vomiting. Even the patient with a normal level of consciousness requires continuous monitoring of vital signs and ventilatory status. Serial neurologic and pulmonary evaluation must be done and documented. Patients who are combative must be prevented from terminating any essential aspect of care prematurely. If the patient can understand and is willing to accept a reasonable explanation for the discomfort associated with therapy, reassurance and explanation may be all that are necessary to achieve patient compliance. On the other hand, patients who are disoriented or refuse to accept a reasonable explanation for essential therapy must be protected from potential risks associated with unplanned withdrawal of therapy. It is essential that a patient whose impaired capacity to make a decision is secondary to a toxicologic effect (hypoxia, hypoglycemia, etc) not be permitted to terminate care, as it would be likely to adversely affect outcome. Although standard precautions should be used for all patients, it is important to emphasize the measures necessary to avoid contamination from the poisoned patient. Parenteral drug use is known to be associated with a risk for both HIV infection and hepatitis. Alcohol and drug use are known to increase the risk for tuberculosis. Healthcare workers may also risk danger from exposure to toxic topical substances when decontaminating a patient (see Chap. 93 and 110). For these reasons, the resuscitation team should apply gowns, gloves, masks, and protective eyewear before approaching the patient. Needleless devices and needles with shields or retraction devices should be used whenever possible for both drug adminis-

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PART D

TABLE 115–4.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY Antidotes for Toxicologic Management

Antidote: Antivenoms Toxin: Snake and spider envenomations Action Complexation and inhibition of target toxin. Nursing considerations Beware: High incidence of hypersensitivity reactions including urticaria, anaphylaxis, and serum sickness. Allergic reaction development is directly proportional to rate, amount, and allergenicity (ie, horse vs human) of antivenom administered. Keep diphenhydramine, epinephrine, and corticosteroids readily available. Get a good history of allergies and previous antivenom exposure. Skin testing for sensitivity before administration is controversial. Antivenom is given slowly intravenously. Initial vial should be diluted 1:10–1:100 in 0.9% sodium chloride and administered at approximately 50 mL/h. In the absence of an allergic reaction, subsequent vials may be reconstituted 1:2 or 1:4, and infusion rates may be judiciously increased and titrated to patient response/reaction. The process of reconstitution is time consuming, and the availability of the antivenom is restricted. Be sure to consider this time constraint and plan early for timely utilization. Antidote: Atropine Toxin: Acetylcholinesterase inhibitors (organic phosphorus pesticides and carbamate insecticides) Action Antagonist to acetylcholine; blocks muscarinic and CNS manifestations. Nursing considerations If patient is placed on a drip, use 20-mL vials. Hundreds of milligrams may be used in massive poisoning. Maximal oxygenation should be achieved before atropine administration to avoid risk of ventricular tachydysrhythmias associated with atropine. This may not be achievable, however, without atropine, when copious secretions and bronchospasm are present. Tachycardia is not a contraindication (may be caused by hypoxia and autonomic stimulation). Heart rate may actually slow as oxygenation improves, although increases of 10–20 beats/min are not uncommon. Has no effect on skeletal muscle weakness or paralysis. Pupillary dilation is an early response and is not a therapeutic endpoint. Glycopyrrolate (Robinul) may be substituted for atropine if the patient shows signs of CNS atropine toxicity (ie, agitation, hallucinations). Antidote: Calcium chloride, calcium gluconate Toxin: Ethylene glycol Action Combats systemic hypocalcemia caused when metabolism of ethylene glycol produces oxalic acid, which combines with calcium and precipitates in the brain, kidneys, etc. Nursing considerations Calcuim chloride is never given intramuscularly or subcutaneously. Parenteral use is IV only. Avoid extravasation of calcium preparations. Calcium gluconate is preferred. Administer slowly—rapid infusion causes vasodilation, nausea/vomiting, dysrhythmias, bradycardia, syncope, a shortened QT interval on ECG, and may cause cardiac arrest. Place patient on cardiac monitor. Monitor patient’s vital signs. Antidote: Calcium chloride, calcium gluconate Toxin: Hydrofluoric acid Action Combats tissue destruction and hypocalcemia caused by complexation of fluoride with calcium. Nursing considerations Intravenous calcium considerations are as noted under ethylene glycol. For hydrofluoric dermal burns, infiltration of the affected tisssues with calcium gluconate is recommended until pain subsides. Recurrence of pain may indicate the need for additional subcutaneous or intraarterial dosing of calcium gluconate. Topical treatment of hydrofluoric acid burns is accomplished by the mixing of calcium with K-Y jelly to make a calcium paste, which is applied to the affected area. Burns of the hand may be treated by filling a surgical glove with the paste and placing it on the hand. Antidote: Cyanide antidote kit (amyl nitrite pearls, 3% sodium nitrite, and 25% sodium thiosulfate) Toxin: Cyanide Action Nitrite-induced methemoglobin binds with cyanide to make cyanomethemoglobin. With the addition of thiosulfate and the enzyme rhodanese, the cyanomethemoglobin is converted to methemoglobin and thiocyanate, the latter being excreted in the urine. Nursing considerations Check expiration dates of kit components (amyl nitrite has shortest shelf life). Sodium nitrite intravenously is preferable to the amyl nitrite for immediate use. For adults, 10 mL of a 3% sodium nitrite solution is administered intravenously, followed by 50 mL of 25% aqueous solution of sodium thiosulfate in the same line. Amyl nitrite pearls are used as an immediate measure until the IV insertion necessary for sodium nitrite. The pearls are crushed into a piece of gauze and inhaled. If IV insertion is delayed, a new amyl nitrite pearl should be used every 3 minutes because of rapid dissipation. In the case of an unconscious patient, the amyl nitrite–soaked gauze is placed in the reservoir of the bag valve mask. Maintain airway control, watch for nitrite-induced hypotension, and continue appropriate supportive therapy. Have vasopressors available. Creation of thiocyanate in the presence of renal failure may cause abdominal pain, vomiting, and CNS dysfunction, but would be rare after one or two doses. Pulse oximetry is unreliable as a measurement because of the creation of methemoglobin. Administration of 100% oxygen treats patient hypoxia and potentiates the action of antidotes. Check the package insert for dosing of nitrites in children and for those with anemia. In unclear cases, or where coexisting carboxyhemoglobinemia is suspected, thiosulfate can be administered alone without nitrites. Cyanide poisoning may be a complication of nitroprusside administration.

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TABLE 115–4.

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Antidotes for Toxicologic Management (continued)

Antidote: Deferoxamine Toxin: Iron Action Chelates excessive iron. Nursing considerations Dosing may be IM or IV depending on degree of toxicity. Severe toxicity requires intravenous dosing at 15 mg/kg/h reconstituted in D5W, lactated Ringer solution, or normal saline to a usual maximum of 6–8 g/d. Dosing should continue as long as the patient is ill, urine remains red-orange color, but not longer than 24–36 hours. Monitor vital signs. High doses and rapid rates of infusion can cause hypotension; hypersensitivity can manifest as urticaria. Prolonged use of intravenous form may contribute to ARDS. Intramuscular dosing causes pain and induration at site. Rotate sites of injection; reconstitute until completely dissolved with 2 mL sterile water. Solution will remain stable for 1 week at room temperature. Oral dose is not FDA approved and is not recommended. Antidote: Dextrose Toxin: Hypoglycemic agents, ethanol Action Increase glucose availability for utilization Nursing considerations Should be considered for any patient with altered mental status. Whenever possible rapid bedside glucose level determination should be done. D50W is available in 50- to 100-mL prefilled syringes (25 g per 50 mL); a large volume and viscous, often messy, and difficult (slow) to administer. Children require more dilute solutions; 20–25% concentrations. All individuals should be given doses of 0.5–1 g/kg. Antidote: Digibind (digoxin-specific antibody fragments) Toxin: Digoxin Action Binds digoxin, digitoxin, and other plant or animal derived digoxinlike cardioactive steroids, effectively reducing the amount of free drug available in the circulation and allowing for excretion in the urine. Nursing considerations Dosing of antibodies depends on ingested dose and total body load. Each vial (38 mg) will bind 0.5 mg of digoxin. The required amount is reconstituted with 4 mL of sterile water as a bolus dose intravenously or, in more stable clinical situations, administered over 30 minutes. Children require additional dilution. Use immediately or within 4 hours if refrigerated. Monitor vital signs and cardiac rhythm! Until free digoxin levels decrease, patients may manifest nausea, vomiting, and dizziness. Cardiac abnormalities include SA node block, ventricular dysrhythmias, bradycardias, and/or ventricular tachycardias caused by reentrant excitation. Observe for potential (but rare) allergic reactions and hypokalemia. Antidote: Dimercaprol (British antilewisite, BAL) Toxin: Arsenic, lead, mercury Action Heavy metal chelator Nursing considerations Contact of drug with skin may cause reactions, and therefore, this drug must be administered by deep IM injection. May cause pain or abscess at injection site; rotate sites. Prolonged use of BAL may cause chelation of essential trace metals—limit use to 5-day courses. Maintaining alkaline urine may protect kidney from damage; monitor I&O. Has many adverse affects including hypertension, fever, diaphoresis, nausea, vomiting, headaches, salivation and lacrimation, and burning feeling of lips, mouth, and throat. Avoid in patients with peanut allergy (formulated in peanut oil) and G-6-PD deficiency (may cause hemolysis). Antidote: Fomepizole Toxin: Ethylene glycol, methanol Action Blocks alcohol dehydrogenase (ADH), which metabolizes ethylene glycol and methanol to toxic metabolites. This enzymatic blockade by fomepizole prevents the formation of the toxic metabolites responsible for patient morbidity and mortality. Nursing considerations Give 15 mg/kg over 30 minutes then 10mg/kg every 12 hours for 48 hours, followed by 15 mg/kg every 12 hours until ethylene glycol and methanol levels approximate zero. Fomepizole may be used as sole therapy or in conjunction with hemodialysis. If used in conjunction with hemodialysis, 15 mg/kg should be given q4h because hemodialysis eliminates the antidote as well as the toxin. Therapy should be initiated immediatedly on diagnosis. Headache, nausea, and dizziness may occur during treatment After mixing, fomepizole can be refrigerated, but room temperature storage is acceptable. Do not store undiluted in refrigerator, as undiluted fomepizole must be passively warmed in order to facilitate dilution. If refrigerated, reconstituted solution is stable for 48 hours. (continued )

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PART D

TABLE 115–4.

Antidotes for Toxicologic Management (continued)

Antidote: Glucagon Toxin:
-Adrenergic antagonists, calcium channel blockers Action Glucagon is a polypeptide hormone that stimulates the mobilization of glycogen to increase glucose levels and by increasing cyclic AMP levels in the heart. This latter action causes an increase in the inotropic and chronotropic activity of the heart, antagonizing
-adrenergic antagonist and calcium channel blocker effects on the heart. Nursing considerations Glucagon is packaged as a powder to be reconstituted. An initial bolus dose of 50 g/kg of glucagon is recommended and infused over 1 minute. Additional bolus or infusion doses may be necessary. Watch for hypersensitivity, generalized allergic reactions. Nausea and vomiting can occur. Monitor cardiac status and vital signs for changes induced by inotropic and chronotropic effects. Glucagon may induce hyperglycemia and/or hypokalemia. Check electrolytes and watch for ECG changes or problems related to electrolyte shifts. Antidote: Methylene blue Toxin: Methemoglobin Action Methylene blue is reduced to leukomethylene, which in turn reduces methemoglobin to hemoglobin. The presence of methylene blue enhances the reduction of methemoglobin and makes it the treatment of choice. Nursing considerations Methemoglobin has a greater affinity for oxygen than hemoglobin and does not allow dissociation of oxygen to the tissue. Pulse oximetry is helpful in detection but is not a true measure of clinical status. Although oxygen saturation will register below normal, it often does not reflect severely toxic levels. The oxygen saturation will fall to approximately 85% but not continue to fall despite additional rise in methemoglobin levels. Arterial oxygen levels of blood gases (Po2) are normal. Blood gases reflect measurements of partial pressure, not oxygen-carrying capacity. Do not depend on ABGs to detect hypoxemia. Do not rely on pulse oximetry to convey severity of symptoms. Give methylene blue 1% solution as soon as possible at 1–2 mg/kg, which for a 70-kg person is 70–140 mg or 7–14 mL of the 1% solution. This should be given slowly intravenously over 5 minutes. Pain at the site of infusion can be minimized with slow infusion and by following with a flush of saline. The patient’s urine will become greenish blue. Pulse oximetry measurement will fall abruptly and then should improve. Antidote: N-Acetylcysteine (NAC, Mucomyst) Toxin: Acetaminophen Action Detoxifies metabolite (enhances glutathione synthesis) early and mediates inflammatory response late (>24h) after ingestion. Nursing considerations Unpleasant odor. Shold be diluted to a 5% concentration from a 20% solution by mixing 1 part 20% NAC solution and 3 parts diluent (ie, water, fruit juice, or carbonated beverage). Must be used within 1 hour of dilution. After opening, can be stored in refrigerator for 96 hours. Repeat dose if vomiting occurs within 1 hour of administration. May try antiemetic (metoclopramide or a serotonin antagonist such as ondansetron) or NG tube for persistent vomiting. If repeat dose of activated charcoal is indicated for a coingestant, separate by at least 1–2 hours. Although not FDA approved, the oral dose can be administered as IV N-acetylcysteine in extreme cases (see dosing schedule in Chap. 32). Antidote: Naloxone Toxin: Opioids Action Competes with opioids at the receptor sites; reverses respiratory depressant effects and improves blood pressure and CNS manifestations. Nursing considerations Patients withdrawing from opioids exhibit nausea, vomiting, agitation, restlessness, diaphoresis, abdominal pain, and piloerection. Careful attention must be paid to issues of airway protection and patient safety. Concentrations of naloxone may vary with manafacturer. Available also in neonatal concentration, but this preparation has no use in the ED for treatment of drug overdoses. Prepackaged bolus doses containing 2 mg facilitate rapid titration from 0.05 to 2.0 mg in opioid-dependent patients and is an appropriate dose for the management of the suspected opioid overdose. Antidote: Octreotide Toxin: Oral hypoglycemic agents Action Suppresses the release of endogenous insulin stores. It is especially useful in treating hypoglycemia caused by agents that stimulate the release of endogenous insulin such as the sulfonylureas. Nursing considerations May be given subcutaneously or intravenously. For subcutaneous administration, 50 g every 6 hours is recommended for adults. Children’s dose of 4–5 g/kg/d (up to 50 g) should be administered in divided doses every 6 hours. Subcutaneous administration sites should be rotated. For intravenous administration, dilute octreotide in sterile 0.9% NaCl or dextrose and infuse over 15–30 minutes or administer IV bolus over 3 minutes. Patients may experience stinging at the IV site, which rarely lasts more than 15 minutes. Gastrointestinal symptoms include nausea, abdominal pain, and diarrhea. Octreotide should be refrigerated for prolonged storage but it is stable at room temperature for 14 days as long as it is protected from light. Octreotide should be administered at room temperature. Refrigerated ampules should be passively rewarmed before administration. (continued )

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TABLE 115–4.

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Antidotes for Toxicologic Management (continued)

Antidote: Physostigmine salicylate Toxin: Anticholinergics (eg, antihistamines, atropine, scopolamine, and some plants and mushrooms) Action Reverses coma, seizures, and severe myoclonic and choreoathetoid activity from anticholinergic agents. Nursing considerations Use only clear, colorless solutions. IM route is unacceptable because of erratic absorption. Establish airway, ventilation, and hemodynamic stabilization first. Patient should have a narrow QRS complex on both ECG and current monitor strip. Excessive use or too rapid administration may cause SLUDGE, bronchorrhea, seizures, bradycardia, and respiratory depression. Have atropine on hand, equal to one-half the dose of physostigmine given, to reverse cholinergic activity. Antidote: Pralidoxime chloride (2-PAM-chloride, Protopam) Toxin: Acetylcholinesterase inhibitors (organic phosphorus pesticides and carbamate insecticides) Action Restores acetylcholinesterase activity and detoxifies remaining organic phosphorus molecules. Nursing considerations Protect the airway! After regaining consciousness, patients may become agitated. Transient dizziness and blurred vision may be related to the rate of infusion. Avoid rapid IV bolus; respiratory and cardiac arrest may occur. Reduce rate or stop infusion if hypotension occurs. Rarely used alone. Works synergistically with atropine. Avoid dermal contact with the patient to avoid pesticide self-contamination. Wash all dermal areas exposed to pesticides with copious amounts of water. Wear protective clothing (gloves, gown). Dispose of contaminated clothing and leather. Antidote: Sodium bicarbonate Toxin: Amantadine, carbamazepine, chlorphenoxy herbicides, chlorpropamide, cocaine, encainide, flecainide, methotrexate, phenobarbital, phenothiazines, procainamide, propoxyphene, quinidine, salicylates, and tricyclic antidepressants Action By reversing Na channel blockade NaHCO3 treats the widened QRS seen on ECG in amantadine, carbamazepime, cocaine, encainide, flecainide, phenothiazines, procainamide, propoxyphene, quinidine, salicylates, and tricyclic antidepressants. For chlorphenoxy herbicides, chlorpropamide, formic acid derived from methanol, methotrexate, phenobarbital, and salicylates, alkalinization facilitates ion trapping and enhances urinary elimination of these drugs. Nursing considerations Give 1–2 mEq/kg of sodium bicarbonate as a bolus. Place two or three ampules (88–132 mEq) of sodium bicarbonate in 1 L of D5W. IV should run at 1.5–2 times the maintenance fluid range (alkalinizes serum and urine). Alkalemia, hypokalemia, and decreased ionized calcium occur with bicarbonate therapy. Monitor pH (blood and urine) and electrolytes closely and replace as needed. Maintain serum pH between 7.50 and 7.55. Maintain urine pH at 7.5–8.0. Observe patient’s neurologic status. Hyperosmolarity, hypernatremia, and paradoxic CSF acidosis may occur. Give patients supplemental oxygen to decrease tissue hypoxia. Sodium bicarbonate causes precipitation of calcium salts and may inactivate catecholamines. Use separate IV access. Antidote: Thiamine hydrochloride Toxin: Alcohol, alcoholism/malnutrition Action Facilitates aerobic metabolism of glucose to produce ATP; links glycolysis to the Krebs cycle. Also has a role in maintaining normal neuronal conduction. Nursing considerations Given in conjunction with D50W to treat or to avoid development of Wernicke encephalopathy in adults and adolescents. Thiamine is not routinely administered to children unless they are malnourished. Antidote: Vitamin K1 (mephyton, aquamephyton) Toxin: Anticoagulants (warfarin, superwarfarins) Action Required for blood clotting; reverses anticoagulant deficiency and is indicated for long-term control of bleeding due to vitamin K deficiency. Nursing considerations Unless a patient is critically ill, give by other means than IV route; IV route may cause anaphylactoid reaction and in rare instances death. Dilute only in D5W, 0.9% NaCl or D5 0.9% NaCl, or D5NS preservative-free solutions and infuse slowly to decrease risk of anaphylactoid reactions. Use oral preparations for longterm care. Restrict volume of SC doses to 5 mL per site. Avoid IM administration to avoid hematoma formation. Onset of action is slow, even following IV administration. (continued )

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tration and any arterial or venous puncture. Irrigation and lavage equipment with splashguards should be considered.

RESTRAINING THE AGITATED PATIENT Increased public awareness of patient’s rights and a heightened sensitivity toward the appropriate use of restraints have been promoted by HCFA, JCAHO, and other credentialing bodies. Their efforts have led to the development of specific restraint and seclusion guidelines that became effective January 1, 2001, which urge all practitioners to make every effort to avoid unnecessary restraint use. The standards do support the emergency use of chemical and physical restraints to prevent a patient from harming heror himself or others. In these cases, the patient must be a danger to himself or another and not aware of his illness or the ramifications of his actions. Restraints, physical or chemical, may never be used as a method of coercion, threat, or restriction of a competent patient’s wishes, even if the ultimate outcome might be adverse. Overdosed or poisoned patients who have an altered level of consciousness, who become agitated and uncooperative, or who exhibit violent behavior as a result of poisoning often require the application of physical restraints until their condition stabilizes and they are capable of understanding the value of essential interventions (see Chap. 118). All efforts at verbal reassurance, using staff members who may have developed a rapport with the patient, must be employed. If this fails, and the impaired patient continues to refuse and thwart important care, physical restraint may be necessary as a primary therapy or until chemical restraint can be administered safely. Basic patient care objectives are to protect the patient from self-injury and to protect others from injury by the patient. Restraints should be used only when there is absolutely no other alternative, and the least restrictive method that assures safety should be employed. The decision to physically restrain a patient must be made only after all other attempts at calming the patient have failed and there is a true threat to patient (pulling out an intravenous line or endotracheal tube) or staff safety. A conscientious humane interaction may help to defuse a potentially volatile situation, allowing the patient to maintain some control in his or her care. A skilled interviewer must recognize the patient’s feelings of powerlessness, fear, misunderstanding, and, in some cases, embarrassment or anger. Identifying these feelings while describing your understanding of the patient’s personal needs and offering to provide information to allay the patient’s concerns are often helpful. If the patient continues to pose a threat to himself or herself or others, the clinician must impose limits and inform the patient that such behavior cannot be tolerated. It may be suggested that the patient’s inability to maintain a peaceful and cooperative demeanor may necessitate the summoning of “a specially trained crisis group” that will assist in regaining control. At this point, sometimes the mere presence of an organized group of individuals will help the patient rethink his or her behavior and reestablish selfcontrol. If all of these measures fail, and physical restraint becomes necessary, clear, objective documentation of the events leading to physical restraint must be entered in the chart. Knowledge of certain toxidromes will alert the clinician to substances that increase the likelihood for violent behavior. The patient’s medical condition, including alertness, orientation, and thought process, should be noted, along with a detailed description of the measures used to secure the patient’s cooperation before the appli-

cation of physical restraints. A physician’s written order must be present on the chart. In an emergency situation a verbal order may be acceptable as an interim measure. However, a physician (or licensed practitioner) must evaluate the patient and write an order for the physical restraint within 1 hour of the initiation of the intervention. Less restrictive methods such as mittens should be considered, and the approach documented as inappropriate or ineffective, before limb or chemical restraints are used. Because all inappropriate patients” have the right to be free from restraints of any form that are not medically necessary or are used as a means of coercion, discipline, convenience, or retaliation,...” practitioners must document the absolute need, all prior less restrictive attempts, and an ongoing assessment to achieve release of restraint in the continuing nursing care. Clinical staff and security personnel expected to participate as members of the restraint team should be given formal training in technique and philosophy. This preparation allows for clear definition and understanding of roles and responsibilities before mobilization for crisis intervention. A team approach to the application of restraints, with a team leader in control, is essential. If possible, a team of five staff members should be gathered. Each of the first four is responsible for securing one extremity, while the fifth, who assumes the role of leader, is positioned at the patient’s head. The team leader’s role is critical and should be assumed by the staff member most experienced in crisis intervention techniques and restraint application. In approaching the patient requiring restraint, it is important to ensure that all potentially dangerous items such as keys, shoes, pens, pins, and stethoscopes are removed from the patient’s immediate accessibility. The team leader should secure the patient’s head by grasping the forehead with one hand and securing the chin with the other (Fig. 115–1). This immobilizes the patient’s head, minimizing the leverage he or she gains by lifting the head, shoulders, and chest. The leader should speak calmly to the patient, explaining the necessity for the procedure and requesting the patient’s help.

Figure 115–1. Appropriate approach by the team leader to secure the patient’s head by grasping the forehead with one hand and securing the chin with the other. (Universal precautions should be utilized at all times.)

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The other members must be agile, clear as to strategy, and firm in their approach. The team members’ strength is not as important as proper hand placement and technique. The limb should be grasped securely, with one hand just above the joint and one hand immediately below, so as to immobilize elbows and knees in extension, thus restricting movement (Fig. 115–2). Pressure directly on the joint should be avoided, as it is painful, may cause injury, and will initiate a response from the patient that may inhibit successful restraint. The restraints should be applied sequentially, starting with the upper extremities, so that the other limbs remain well immobilized while each is being restrained. The lower extremities are bound together to create three-point restraint. Initiating restraint with the arms prevents the patient from attempting to vault off the stretcher with only his or her feet restrained and potentially incurring head and facial trauma. If a sixth team member is available, he or she may apply the restraints while the others continue to secure the limbs. Otherwise, the team leader should identify which limb to restrain and direct specific team members to assist each other. The team leader should take note of any individual who is unable to control his or her assigned limb, necessitating additional assistance. Throughout this effort, the team leader should constantly reassure the patient in a calm, firm manner and maintain a secure hold on the patient’s head and chin. Many institutions continue to use metal or leather restraints. These restraints increase the risk of injury to a patient’s extremities, particularly in an emergency situation. Although some institutions prefer to use lamb’s wool and roller gauze, in the setting of

Figure 115–2. Appropriate approach to limb restraint, using one hand just proximal and one hand just distal to the joint. This immobilizes both elbows and knees in extension and effectively restricts movement. (Universal precautions should be utilized at all times.)

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the ED, this method is acceptable only as an interim measure, as this form of restraint is not secure enough to sustain continued, safe control of the agitated patient. The use of cloth restraints with padded centers allows for both flexibility and security without patient injury. A hitch knot1 should be slipped over the extremity, but direct pressure should not be placed over any joint (Fig. 115–3). The ends of each restraint should be securely fastened to a nonmovable part of the stretcher with a slip knot, which allows rapid removal of the restraint if necessary. The loose ends of each restraint must be tucked under the mattress, well out of reach of the patient (Fig. 115–4). After the restraints are secured (Fig. 115–5), each limb should be checked for discoloration and any compromise of pulse and capillary refill. The clinician must be able to place two fingers easily under the restraint, assuring that circulation is not impaired. At no time should the patient’s face, mouth, or neck be covered or restrained in any manner under any circumstances. In addition, restraint of the chest is not recommended, as it may impair respirations. The patient should be told why the restraints were applied and what change in behavior is expected to allow him or her to regain independent responsibility and minimize the length of time that the restraints are required. Once the environment is made safer for the patient and staff, chemical restraint should be considered. Patients under the influence of drugs and/or alcohol are often incapable of making critical decisions and controlling behavior. Chemical restraint with the use of intravenous benzodiazepines in situations where these agents are not contraindicated will help reestablish a calm, safe environment and minimize the complications of tachycardia and hyperthermia associated with hyperactivity (see Chap. 67 and 72). A note should be made in the patient’s chart that three-point restraints were applied because of a specific patient behavior. The patient’s initial response to the intervention and current condition must be noted. Continued observation must then be part of the care plan. The restraints should be checked on a periodic basis to assure that the patient remains protected, that essential clinical needs are being met, and that circulation and pulse remain intact. Each periodic reassessment requires documentation to validate the need for continued physical restraint and why the therapy cannot as yet be terminated. Patients presenting with altered levels of consciousness often arrive with concomitant trauma, compartment syndromes, and/or decubiti secondary to their prior immobility. Accurate observation and intervention to prevent further injury are essential, especially in cases where restraint may further immobilize the patient. The documentation of preexistent conditions will prevent misallocation of responsibility. A restraint flow sheet should be developed to satisfy documentation requirements and to serve as a clinical reminder to fulfill the patients’ basic personal needs at regular intervals. A regularly scheduled systematic retrospective review of the data with corrective recommendations should be part of the ED’s Quality Performance Program. If data secured during treatment suggest any suspicion of selfdestructive or suicidal behavior, the patient should be placed on a 1:1 suicide watch until further psychiatric evaluation can be accomplished. This level of care requires that the individual be placed under the direct observation of one staff member, who then documents on an hourly basis (at a minimum) the patient’s behavior, comments, and actions. A full psychiatric evaluation should be

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Figure 115–3. Restraints must have a padded center. A hitch knot is slipped over the extremity. The sequence of securing the extremity applies no direct pressure over the joint. (Universal precautions should be utilized at all times.)

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done as soon as the patient is alert and cooperative enough to answer questions and discuss the events leading up to hospitalization (see Chap. 114). Removal of the patient’s clothing and property and dressing the patient in a hospital gown may also act as a deterrent to patient elopement.

DISPOSITION: ACUTE AND LONG TERM Continued reassessment of the patient’s condition yields information that will constitute the nursing documentation of the patient’s ongoing status and ultimate disposition. The nurse must begin planning for disposition at a very early stage in the patient’s care. Immediately following the acute phase of intervention, attention must be given to notification of the individual’s family. In the case of a patient who is responsible for the care of children, careful consideration must be made as to the children’s safety and welfare. In the case of a substance-using parent, the social services staff must be notified to assure an immediate home assessment and followup after patient hospitalization (see Chap. 113). The patient’s property must be secured and protected, even if the patient is not admitted. Caution must be exercised while undressing patients. Searching pockets and property may result in exposure to dangerous items such as needles, syringes, knives, razor blades, and drugs, which pose a threat to staff safety. Gloves should always be worn, and dangerous items should be turned over to security personnel. Familiarity with the pattern of toxicologic symptoms allows the nurse to suspect a likely toxin. Consideration of the clinical manifestations of the particular substance(s) allows the nurse to anticipate not only ongoing care needs but also those that will affect the patient at the time of discharge. Patients not requiring medical admission to the hospital must be alert and communicative before psychiatric consultation is recommended. Referral sources for rehabilitation of substance users should be available. Finally, clear, concise, specific discharge instructions must be given to the patient. Details of these instructions must be noted, and a signature indicating patient understanding must be entered on the chart. In many cases, duplicate instruction sheets are used to minimize omissions and standardize the individual effort. A copy is given to the patient for reference on discharge, and a signed copy attached to the permanent record. This level of documentation is particularly important in verifying the patient’s capacity to understand, especially in a previously impaired patient. This documentation is important not only from a medical-legal point of view but also from a quality management perspective.

DISCHARGE INSTRUCTIONS

Figure 115–4. The technique for applying a slip knot. The ends of the restraint are securely fastened to a nonmovable part of the stretcher with a slip knot so that rapid removal can be accomplished. All loose ends must be tucked under the mattress, out of the patient’s reach.

Each patient to be discharged should have individualized instructions. Considerations when giving the instructions include the patient’s level of comprehension from a healthcare, cultural, and linguistic perspective. The same level of understanding is necessary of the caregiver’s level of comprehension, if the patient’s care is to be entrusted to another. Social factors such as whether the patient has a home, whether the patient is pregnant, whether the patient is responsible for living children, and, if so, whether he or she is able to provide necessary care, must be considered in the discharge plan. Before release from the institution, the patient must

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Figure 115–5. When the restraints are secured, each limb must be checked for discoloration and any compromise of pulse and capillary refill. The clinician must be able to place two fingers under the restraint. The patient’s face, mouth, and neck must not be covered or restrained.

be provided with clothing appropriate for the weather through family contact or, in some institutions, through the support of social services. Instruction with regard to poison prevention must be given both verbally and in written format. This is paramount, especially in cases where poisoning was unintentional. Followup must be arranged and stressed with the patient and caregiver. Hospital-based performance improvement assurance mechanisms for recall must be in place and readily activated in the event that the patient fails to follow up as instructed. All teaching issues should be rediscussed with the patient at the time of discharge. Questions addressed during an earlier phase of treatment, when the patient may have had an altered sensorium, must be readdressed to assure understanding. Psychiatric consultation is essential before discharge in any case where personal destructive behavior is suspected. In cases of drug or alcohol abuse, referral should be available for outpatient drug or alcohol treatment; it should be recommended, and its utilization facilitated.

DOCUMENTATION Staffing deficiencies, particularly in EDs, have made ongoing documentation extremely difficult, especially when patients remain many hours before a final disposition. The use of checklists optimizes continued periodic documentation and minimizes the need for extensive, detailed notes.

EVALUATION OF THE POISONED PATIENT AND THE QUALITY OF CARE RENDERED The evaluation of care entails an appraisal not only of the nursing care received by the patient but also of the overall quality of care. The assessment of the patient’s physical and emotional status and

evaluation of the patient’s response to the nursing care plan are measured in terms of desired patient outcomes, based on an established standard of care. Specific desired patient outcomes can also be based on the individual nursing diagnoses (see Table 115–2). For a diagnosis of ineffective airway clearance, the expected outcome of effective gas exchange would be evidenced by a PO2 value greater than 80 mm Hg on room air, for example. In altered tissue perfusion, the presence of strong palpable pulses demonstrates adequate circulatory function. Ongoing reassessment of the patient’s vital signs and neurologic status is essential to evaluate the patient’s response to therapy. The second part of the process, evaluation of the overall quality of care, is an assessment of the nurse’s adherence to the care plan and to the nursing standard of care. Regulatory agencies mandate that written care plans and measurable nursing standards be developed and that adherence to the established standard be documented in both prospective and retrospective audits. To meet this requirement, care must be taken to ensure that the standard of care is meaningful and reasonable for the staff nurse. Once the standard guidelines have been established, an evaluation tool should be generated to test whether or not the set criteria have been met. This quality management program may be complex. Emergency patients do not necessarily have a clearly defined diagnosis. Many patients present with an array of complaints, and others are unable to give any history. A poisoned patient may initially have to be placed into a more generic category such as “altered mental status,” until a specific diagnosis is confirmed. This problem-oriented approach may necessitate multiple interventions to define the appropriate management strategy. The ED is always an environment with unpredictable demands. Few options are available such as ambulance diversion, or supplemental staff to bring order out of chaos when overcrowding occurs. The variation in occupancy of the ED as well as patient acuity greatly affects the quality and thoroughness of patient care given. When a care plan or standard is established, it must be flex-

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Figure 115–6.

Example of a retrospective chart audit.

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ible enough to be useful and valid whether the ED is peaceful or exceedingly busy, and it must be independent of the patient’s severity of illness. Many patient interventions must be accomplished in a relatively brief period of time. Outcome is often measured by an analysis of short-term goals. In many hospitals, however, admitted patients may be delayed for prolonged periods of time in the ED or kept in observation units. Under these circumstances, newly developed distinct standards may become appropriate. Because emergent patients continually arrive without warning, achieving a standard such as the measurement of vital signs every 4 hours becomes a difficult task. However, a standard should not simply be monitored. A mechanism must also be established whereby noncompliance can be addressed and corrective actions implemented. Once corrective actions are initiated, their effectiveness must also be evaluated. Not only must standards be flexible and measurable, but also the personnel responsible for initiating corrective actions must have the ultimate authority with the staff for interpreting and implementing the standard in the plan of care. Finally, the principles of the standardized care plan (suggested in Table 115–1) must be routinely assessed and reevaluated. This audit analyzes both the conscious and unconscious patient in a sin-

gle plan. We believe that the standard quality management project should be as simple as possible without compromising standards. This allows staff participation in the project to be less tedious while serving as a positive personal learning experience. By use of this chart audit, a threshold for performance can be established. Any value falling below this threshold requires further evaluation because the established standard of care is not as yet achieved. Specific objective criteria should be developed for each problematic area; the data collected can then be evaluated, and corrective action initiated. Constant reevaluation should continue until the threshold is met. Figure 115–6 is suggested as an objective retrospective chart audit.

ACKNOWLEDGMENT The graphics for this chapter were done by William P. Callaghan.

REFERENCE 1. Cassidy J: The Klutz Book of Knots: How to tie the world’s 25 most useful hitches, ties, wraps, and knots. Palo Alto, CA: Klutz Press, 1989.

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116 PANDOISONP INFORMATION CENTERS OISON EPIDEMIOLOGY

Robert S. Hoffman

HISTORY In 1950, the American Academy of Pediatrics created a Committee on Accident Prevention in order to explore methods to reduce injuries in young children. A subsequent survey by that committee demonstrated that injuries resulting from unintentional poisoning were a significant cause of childhood morbidity. Simultaneously came the realizations that a source of reliable information on the active ingredients of common household agents was lacking and that there were few accepted methods for treating poisoned patients. In response to this void, the first poison information center was created in Chicago in 1953.53 Although initially designed to provide information to healthcare providers, both the popularity and the success of this center stimulated a poison information center movement, which rapidly spread across the country. The myriad of new poison information centers not only offered product content information to healthcare providers but also began to offer first aid and prevention information to members of the community. Approximately 40 years have passed, and in that short time, countless achievements have been realized by a relatively small group of remarkably altruistic individuals. Many of these legislative and educational accomplishments, which are chronicled in Chapter 1, have directly reduced the incidence and severity of poisoning in all age groups.52,56,58 Concurrently, the number, configuration, and specific role of poison information centers has shifted in response to public and professional needs.21,61 Regional centers are staffed by highly trained and certified health professionals who are assisted by extensive information systems. Support is provided by 24-hour access to board-certified medical toxicologists and consultants from all disciplines of medicine as well as from industry. The poison information center of today is charged with many of the same mandates as the original centers. These responsibilities include maintaining a database, providing information to public and health professionals, collecting epidemiologic data on the incidence and severity of poisoning, preventing unnecessary hospitalizations following exposure, and educating healthcare professionals on the diagnosis and treatment of poisoning. This chapter explores some of these critical roles and offers a vision of the future.

MAINTAINING A DATABASE ON PRODUCT CONTENTS AND POISON MANAGEMENT The first toxicology database created in the United States was a set of cumbersome 5” × 8” index cards produced in the 1950s by the United States National Clearinghouse of Poison Control Centers.53 When it grew to include more than 16,000 cards, the sheer volume of space required to store this information, as well as the extensive time it took to hand-search through these cards, created the necessity of a central repository, such as a poison information center. The quantity of information continued to grow in concert with a rapid expansion of information technology, and the unwieldy index card database was privatized and transformed into microfiche. Even though this source was substantially smaller, specialized equipment was still required, and searching remained time consuming. Numerous encyclopedic and clinical textbooks were written to supplement the database and provide resources for the office or the bedside. With the growth of the computer age and the Internet, the product known as Poisindex took hold as the major source of data on the contents of innumerable household and industrial products, drugs, and plant and animal toxins. Poisindex also provides unified management strategies for many potentially toxic exposures. With this evolution of information technology, poison information centers are no longer perceived as the sole guardians of toxicology information. Although these services are still essential for the public at large, and those professionals away from their computers, a predictable decline in poison center utilization has paralleled this growth in availability of information. A 1991 study in Utah demonstrated that 82.6% of emergency physicians who had Poisindex available in their institution often did not consult the poison information center.9 A similar 1994 New York State study suggested that 76% of physicians who had Poisindex in their emergency departments perceived that this decreased their own use of their poison information center.59 Superficially, it might seem that this is an acceptable trend in that it allows poison information centers to be more available to those individuals who do not have access to the information. However, this practice not only undermines the efforts of poison infor-

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mation centers to gather epidemiologic data (see below), it also creates an understanding gap. In other words, the interpretation of the data may be more essential than the data itself. For example, some commonly used sources of toxicology information such as the Physicians’ Desk Reference (PDR) and material safety data sheets (MSDS) occasionally provide information that is frankly inaccurate, potentially misleading, or significantly limited.25,50 There may be similar limitations with regard to wider access to Poisindex. For example, consider the case of a clinician caring for a lethargic child whose only medication is Zantac syrup. After the other causes of altered mental status have been excluded, the clinician considers drug toxicity. Consultation with references suggests that altered consciousness would not be expected with use of this medication. However, a certified poison information specialist at a regional poison center recognized the potential for drug error and had the physician review the syrup bottle in question and call the pharmacy where the drug was provided. Although the prescription was written for Zantac (ranitidine), the bottle actually contained Zyrtec syrup (cetirizine). Thus, although originally designed as providers of information, poison information centers must now be considered valued consultants, with staff who not only provide content information but also interpret clinical material and link both to appropriate management strategies. This goal is achieved only through rigorous training and certification criteria designed to provide a valued interaction with healthcare professionals.2 Another illustrative example of the value of poison information centers can be drawn from the use of flumazenil for benzodiazepine overdose (see Chap. 63). Although it may easily be determined by anyone capable of using an index that flumazenil is an antidote for benzodiazepine overdoses, many subtle characteristics of the patient or the overdose often contraindicate its use. A prospective study determined that when flumazenil was used before consultation with the poison information center, it was used despite the presence of contraindications in 10/14 (71%) cases, resulting in one serious adverse event.8 In the study mentioned earlier, although physicians with access to Poisindex were less likely to call the poison information center, 86.7% still felt that using the poison information center to gain access to a physician toxicologist was a valued resource.9 Current efforts are under way to link poison information centers with centers for poison treatment (CPT), which are healthcare facilities that can provide both bedside consultation and unique diagnostic and therapeutic interventions for a subset of patients with severe or complex poisoning.1 Preliminary data suggest that direct bedside consultation and care help reduce length of hospital stay and healthcare costs.15

significant poisoning results in either hospitalization or fatality, data from poison information centers appear to offer a unique perspective. Unfortunately, the term “poisoning” is often defined differently and therefore may be confusing. For the purposes of this text, “poisoning” is any exposure to a drug, toxin, chemical, or naturally occurring substance that results in injury. Yet the data collected and disseminated by poison information centers is limited to exposures.38–47 Many exposures are of no consequence because of the properties of the substance involved, the magnitude or duration of the exposure, or confusion about whether an actual exposure has occurred; therefore, data collected by poison information centers are inherently flawed. The situation is further confounded by multiple biases that are introduced by the reporting process itself. To begin with, reporting is voluntary. Because the majority of calls concern self-reported data that come from the home and are never subsequently confirmed, large statistical errors can be introduced into the database. A significant percentage of existing data may actually represent potential or possible exposures. Also, current events, hoaxes, and media awareness campaigns all may influence self-reporting rates. Additionally, in order to report, a caller must have a telephone and probably speak English. Although telecommunications devices for the hearing impaired and translation services exist, they are rarely used. When hospitals report to the poison center, a comparison of the hospital chart with the poison center record shows good agreement.30 Unfortunately, a reporting bias similar to that described above is well recognized with regard to professional utilization of poison information centers and has been called the “Pollyanna phenomenon.”26 For example, in the spring of 1995, poison centers in the northeast United States began to receive numerous reports of severe psychomotor agitation and other manifestations of anticholinergic syndrome in heroin users. In the beginning, most of these calls were for help in establishing a diagnosis, determining possible etiologic agents, and questions regarding treatment with physostigmine.27 Although the epidemic continued for many months, once the media announced that the heroin supply was tainted with scopolamine, and clinicians became familiar with the indications and administration of physostigmine, calls began to taper off. Stated simply, healthcare professionals are less likely to call the poison information center regarding issues with which they are familiar, are of little clinical consequence, or are not recognized as being related to a poison. Thus, a bias is introduced that results in overreporting of new and serious events and underreporting of the familiar or very common, the extremely rare and unrecognized, and the inconsequential. Numerous comparisons support this contention.

COLLECTING POISON EPIDEMIOLOGY DATA

Fatal Poisoning

Recent data demonstrate that poisoning is the third leading cause of injury-related fatalities, ranking behind motor vehicle crash and firearm use.22 Understanding the evolving trends in poisoning is essential to the development of enhanced surveillance, prevention, and education programs designed to reduce unintentional poisoning. Although data can be analyzed from numerous sources such as death certificates, hospital discharge coding records, and poison information centers, it is essential to recognize the biases that are inherent in each of these reports (see Chap. 120). Because not all

A 4-year study compared deaths from poisoning reported to the Rhode Island Medical Examiner with those reported to the area poison information center.37 Not surprisingly, the Medical Examiner reported many more deaths: 369 compared to 45 reported by the poison information center. Although the majority of the cases not reported to the poison information center were victims who died at home, were pronounced dead on arrival to the hospital, or those in whom poisoning was not suspected until the postmortem analysis, 79 unreported fatalities were admitted to the hospital with a suspected poisoning. In 10 of these cases, the authors concluded

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that a toxicology consultation might have altered the outcome. Examples of interventions that, if recommended and performed, might have resulted in a more favorable outcome included the proper use of antidotes such as naloxone, N-acetylcysteine for acetaminophen poisoning, the cyanide antidote kit, sodium bicarbonate for a tricyclic antidepressant overdose, and hyperbaric oxygen for carbon monoxide as well as hemoperfusion for a theophylline overdose and hemodialysis for a lithium overdose. Similarly, when medical examiner data were analyzed in Massachusetts, over 47% of poison fatalities had not been reported to the poison information center.55 Similarly, a California study evaluating 358 poisoning fatalities reported to the medical examiner showed that only 10 poison center fatalities had been reported over a similar time period, demonstrating a similar reporting gap.4 Once again in this study, whereas the majority of underreporting was with respect to prehospital deaths (68%), only 5 of 113 hospital patients who ultimately died were reported to the poison information center. Additionally, a cross-sectional comparison of national mortality with poison information center data for agricultural chemical poisoning demonstrated a similar trend of underreporting of fatalities to poison information centers.34 Finally, when data for an entire year from the National Center for Health Statistics (NCHS) were compared to the same 1 year of data from the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS), it was apparent that TESS captured only about 5% of annual poison fatalities.29 It is logical to assume that similar barriers exist to reporting nonfatal poisonings.

Nonfatal Poisoning An early outreach study in Massachusetts determined that hospitals geographically close to a poison information center reported their cases almost twice as often as hospitals remotely located (46% vs 27% of total cases).10 Additionally, the authors noted that private physicians were less likely to report cases than residents in training. A 1-year retrospective review demonstrated that only 26% (123/470) of poisoned patients who were treated in a particular emergency department were reported to the poison information center.28 Interestingly, only 3% of inhalational exposures were reported, compared with 95% of cyclic antidepressant ingestions. The authors also noted, as suggested above, that reporting decreased when exposures tended to cluster. Finally, in the physician survey study cited earlier, physicians reported that they would “almost never” contact the poison information center for asymptomatic exposures (62.9%), chronic toxicity (50.4%), or simply for the purposes of reporting to the database (90.2%).9

Occupational Exposures Toxin exposure is an all too common event at the workplace. As a result of the long-recognized association between occupational exposure and illness, a number of federal and state governmentfunded agencies, such as NIOSH, OSHA, and ATSDR, exist to prevent occupational illness, educate the public, and to collect data on exposures to occupational toxins. Legislation provides for mandatory reporting in some instances and offers workers job protection for voluntary reporting. Poison information centers also provide information on occupational exposures and collect data. Once again, there are discrepancies between poison information data and the data collected by governmental agencies. A 6-month survey in California noted that only 15.9% of the occupational cases reported to the poison information center were captured by a

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state reporting system.6 These cases tended to underrepresent dermatitis, the most common occupational toxicologic illness. A followup study by the same authors demonstrated that over a third of calls came directly from the individual, 70% of whom were unaware of the link between their occupation and their symptoms.5 Although these data suggest that poison information centers can provide a valuable service for occupational exposures, one author expressed concern, noting in a followup study that the poison information center failed to identify an average of 12 people per workplace who were also potentially exposed in addition to the index case.7

Adverse Drug Events Recent data suggest that a striking number of adverse drug events (ADEs) occur each year in the United States, with many resulting in death.13,36 The ease of 24-hour telephone access, combined with the ability to consult with a health professional, make poison information centers ideal resources for reporting of ADEs.14 Yet, over 76% of physicians surveyed stated that they would “almost never” contact the poison information center regarding adverse drug reactions.9 Moreover, 30/56 (53.6%) poison information centers surveyed stated that they had not submitted any of their ADE data to the Food and Drug Administration’s MedWatch program.12 Many of the other centers reported only partial compliance with the MedWatch system.

Drugs of Abuse Poison information centers also collect data on exposures to drugs of abuse. These data consist largely of calls for information from the concerned public and reports of overdose requiring healthcare intervention. Although ethanol and tobacco are the most common substances used in society, these cases are rarely reflected in poison information data, with the exception of unintentional exposures in children. In fact, because most substance abuse does not result in immediate interactions with the healthcare system, other databases such as the NIDA Household Survey might better reflect substance abuse trends.17 Yet even this database has significant limitations.3,24 However, because poison information centers are more focused on immediate healthcare effects of exposures, it could be argued that only those cases where healthcare interaction is required are of value in the database. Whereas poison information center data is collected passively, the Drug Abuse Warning Network (DAWN) provides an active surveillance system of a sample of hospital visits and deaths that relate to substance abuse. Unfortunately, because DAWN data uses hospital chart “mentions,” which are infrequently validated, the data have been significantly criticized.57 As such, it is clear that none of these three systems accurately encompasses the scope of the substance abuse problem.

Data Summary With the current limitations of the TESS data, it should be clear that neither the numerator nor the denominator of poisoning can be easily appreciated. Analysis of these data for trends may be more useful because the inherent biases involved in TESS reporting are probably consistent over many years. Efforts should be directed to encourage reporting by such enhanced access methods as Web-based forms, direct laboratory interfaces, etc. Additional resources should be directed at improved case definitions (distin-

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guishing asymptomatic exposure from poisoning) and integration with other essential databases such as MedWatch and the NCHS. Despite its limitations, TESS data have significant utility. It is often an exposure rather than an actual poisoning that provides the impetus for contact with healthcare. For those exposures that are unlikely to be consequential, the poison information center can intervene to prevent potentially harmful attempts at home decontamination and costly unnecessary visits to healthcare providers. For those exposures that may result in poisoning, the time immediately following exposure is ideal moment to initiate first aid measures designed to prevent or lessen the severity of poisoning. Thus, the cost, benefits, and efficacy of poison information centers especially with regard to home calls must be measured in terms of exposures and not poisonings (see below).

PREVENTING UNNECESSARY HOSPITALIZATIONS FOLLOWING EXPOSURE When visits to pediatric emergency departments for acute poisoning were analyzed, one study demonstrated that 95% of parents had not contacted the poison information center before coming to the hospital.11 Sixty-four percent of those children required no hospital services. In contrast, when parents called the poison information center first, fewer than 1% subsequently went to the hospital. When 589 callers to one poison information center were surveyed, 464 (79%) stated that they would have utilized the emergency care system if the poison information center was unavailable.32 TESS data confirm that approximately 75% of exposures that originate outside of healthcare facilities can be safely managed on site with limited telephone followup (TESS). Suggesting simple techniques or reassurance can successfully reduce hospital visits, although it should be remembered than in many of these cases, only a potential exposure occurred. Unfortunately, many barriers prevent a person from calling a poison center, including a lack of familiarity, intellectual and cultural factors, language difficulties, and confidentiality concerns. Also, recent survey data demonstrate the additional barriers of caregiver comfort with the hands-on contact provided by the healthcare system and a concern over implications of child abuse or neglect when reporting to agencies with governmental ties.54 The national average cost to the poison information center for a single human exposure call is less than $35.61 A federally funded study concluded that in 1 year, poison information centers reduced the number of patients who were treated and not hospitalized by 350,000 and reduced hospitalizations by an additional 40,000 patients.49 Each call to a poison information center prevented at least $175 in subsequent medical costs, providing strong theoretical evidence to support the cost efficacy of poison information centers. In fact, two natural experiments support these calculations: In 1988, Louisiana closed its state-sponsored poison information center. During the year that followed, the cost of emergency medical services for poisoning in Louisiana increased by more than $1.4 million. This additional expenditure represented a greater than threefold increase above the operating cost of that center.33 Similarly, because of financial disputes in California, direct access to the San Francisco poison information center was electronically restricted for one major county, with a recording referring callers instead to the 911 system for assistance.51 The result of each

blocked call was to increase healthcare costs by approximately $33. Moreover, these calculations do not account for unmeasured benefits to society from poison information center interventions such as reduced waiting times for ambulances and hospital treatments because of lower volumes, money saved by the prevention or reduction of injury from early intervention, or lives saved by enhancing access to or utilization of the healthcare system for seriously poisoned patients.

PROVIDING EDUCATION FOR THE PUBLIC AND HEALTH PROFESSIONALS Poison center staff work closely with physicians, community health educators, community support groups, and parent-teacher associations to develop poison prevention activities.48 Common strategies advocated to prevent poisoning are listed in Table 116–1. Poison information centers are also actively involved in enhancing training programs for paramedics,20 medical students,31 pharmacy students,16 and resident physicians16,60 and form an integral part of postgraduate training programs in medical toxicology fellowships. As stated previously, there is an inherent risk in both enhanced public and professional education programs. Currently, decreased telephone utilization of the poison information center could equally be the result of a decrease in the incidence of exposure or poisoning or an enhanced understanding of the prevention, diagnosis, and treatment of poisoning. Although education should never be viewed as detrimental, programs must include an emphasis on the continued use of poison information centers to ensure access to current information in a rapidly changing discipline. In actuality, as a result of the ongoing analysis of incoming calls, the knowledge base has the potential to change as rapidly as the calls are reported. Thus, additional emphasis should be applied to routine utilization of the poison information center as a public health tool to improve the accuracy of epidemiologic data. Reporting of rare or suspected events can serve as sentinel efforts that help TABLE 116–1. Common Strategies Advocated to Help Prevent Poisoning All medications and toxic substances should be kept in their original containers. Food and drink containers should never be used for the excess of a toxic substance. Never store toxic substances in unlocked cabinets under the sink. Apply locks to medicine cabinets that are within reach. In the absence of a lock, the more toxic medications and pharmaceuticals should be stored on the highest shelves. Medications should never be left in the glove compartment of the family car. Parents should buy or accept medication only if it is in a child-resistant container. Medication should be considered as medicine, not a plaything and certainly not candy. Adults should not take their medications in front of children. This will limit exposure to drug-taking role models that may become objects of imitative behavior. Unused portions of prescription medications should be discarded by flushing down the toilet at the completion of drug therapy. Syrup of ipecac and activated charcoal should be readily available in the home for use if directed by a poison information specialist or physician. It should be anticipated that about 10% of children who have ingested a poison will do so again within a year.

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identify consequential adverse drug events long before normal postmarketing surveillance tools identify areas of concern.

DEVELOPMENT OF PUBLIC HEALTH INITIATIVES The early public health efforts of poison information centers focused on attempts to alter product concentration and to enhance product labeling and packaging. These clearly beneficial endeavors still continue. However, current events have also increased poison center activities in preparedness for disasters resulting from nuclear, biologic, and chemical terrorism.23,35 The need for 24hour rapid access to centralized information, existing data entry and retrieval systems, and links to experts in medical toxicology and emergency medicine helps to place poison information centers in critical roles in both local and national initiatives. Early contributions have included development of triage and treatment protocols and assessments of antidote supplies.18,19

TABLE 116–2. Goals for Improving Poisoning Epidemiology Data Removal of barriers to reporting Multiple methods of reporting Telephone Facsimile Internet based or e-mail Communications devices for the hearing impaired Rapid access to translation services Standard mail Uniform access to a single toll-free number Enhanced awareness of the public health role of poison information centers Enhanced education of caregivers and healthcare professionals Public health legislation requiring professional reporting of exposures Distinguishing potential exposures form actual exposures Create category for unconfirmed exposures Divide confirmed exposures by certainty Confirmed by history Confirmed by physical examination Confirmed by quantitative and qualitative laboratory analysis Integration with other databases Utilization of standardized data collection instrument (include ICD codes, for example) Interact with data from Hospital and commercial laboratories Pharmacy ADE reports Hospital discharges Public health departments Such as with lead screening programs Fire departments and hazardous materials responders Industry Workplace exposures Death certificates Drug abuse monitoring systems Provide real-time analysis Enhance speed of data collection and reporting Analyze data as it is reported, to identify emerging trends Mandate use of proper epidemiologic and statistical analyses of data Provide rapid and regular feedback to primary reporters Issue timely analyses and reports

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SUMMARY Poison information centers provide unique benefits to society. Public education efforts help reduce the likelihood of exposure. Provision of first aid advice helps to diminish the consequences of a poisoning once an exposure has occurred. Reassurance and proper first aid help to curtail unnecessary utilization of expensive healthcare. Interactions with healthcare professionals streamline the care of poisoned patients and improve access to toxicologically specific antidotes and the services of medical toxicologists. Data on exposures are used effectively to create legislation to further limit poisoning by altering contents or improving packaging or labeling. Goals for the continued success of poison information centers must include providing uniform ease of access for the entire country through a single toll-free number, maintaining a uniformly high quality of service, and working to improve the accuracy of the TESS database. Poison information centers must publicize the need for reporting all poisonings including ADEs and strive to develop real-time systems of active surveillance. Finally, TESS reporting must be integrated with other databases so that the true numerator and denominator of poisoning can be understood and so that a concerted response to poisoning and poison prevention can be made. These and other initiatives are summarized in Table 116–2.

ACKNOWLEDGMENT Richard S. Weisman, PharmD, contributed to Table 116–1 in the previous edition of this book.

REFERENCES 1. American Academy of Clinical Toxicology: Facility assessment guidelines for regional toxicology treatment centers. J Toxicol Clin Toxicol 1993;31:211–217. 2. American Association of Poison Control Centers: Criteria for certification as a regional poison control center, October 1991. Vet Hum Toxicol 1978;20:117–118. 3. Biemer PP, Witt M: Repeated measures estimation of measurement bias for self-reported drug use with applications to the National Household Survey on Drug Abuse. NIDA Res Monogr 1997;167: 439–476. 4. Blanc PD, Kearney TE, Olson KR: Underreporting of fatal cases to a regional poison control center. West J Med 1995;162:505–509. 5. Blanc PD, Maizlish N, Hiatt P, Olson KR, Rempel D: Occupational illness and poison control centers. Referral patterns and service needs. West J Med 1990;152:181–184. 6. Blanc PD, Olson KR: Occupationally related illness reported to a regional poison control center. Am J Public Health 1986;76:1303–1307. 7. Bresnitz EA: Poison Control Center follow-up of occupational disease. Am J Public Health 1990;80:711–712. 8. Burda T, Leikin JB, Fischbein C, et al: Emergency department use of flumazenil prior to poison center consultation. Vet Hum Toxicol 1997;39:245–247. 9. Caravati EM, McElwee NE: Use of clinical toxicology resources by emergency physicians and its impact on poison control centers. Ann Emerg Med 1991;20:147–150. 10. Chafee-Bahamon C, Caplan DL, Lovejoy FH: Patterns in hospitals’ use of a regional poison information center. Am J Public Health 1983; 73:396–400. 11. Chafee-Bahamon C, Lovejoy FH: Effectiveness of a regional poison center in reducing excess emergency room visits for children’s poisonings. Pediatrics 1983;72:164–169.

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12. Chyka PA, McCommon SW: Reporting of adverse drug reactions by poison control centers in the US. Drug Safety 2000;23:87–93. 13. Chyka PA: How many deaths occur annually from adverse drug reactions in the United States. Am J Med 2000;109:122–130. 14. Chyka PA: Role of US poison centers in adverse drug reactions monitoring. Vet Hum Toxicol 1999;41:400–402. 15. Clark RF, Williams SR, Nordt SP, Pearigen PD, Deutsch R: Resource-use analysis of a medical toxicology consultation service. Ann Emerg Med 1998;31:705–709. 16. Cobaugh DJ, Goetz CM, Lopez GP, et al: Assessment of learning by emergency medicine residents and pharmacy students participating in a poison center clerkship. Vet Hum Toxicol 1997;39:173–175. 17. Crider RA: Heroin incidence: a trend comparison between National Household Survey data and indicator data. NIDA Res Monogr 1985; 57:125–140. 18. Dart RC, Goldfrank LR, Chyka PA, et al: Combined evidence-based literature analysis and consensus guidelines for stocking of emergency antidotes in the United States. Ann Emerg Med 2000;36:126–132. 19. Dart RC, Stark Y, Fulton B, et al: Insufficient stocking of poisoning antidotes in hospital pharmacies. JAMA 1996;276:1508–1510. 20. Davis CO, Cobaugh DJ, Leahey NF, Wax PM: Toxicology training of paramedic students in the United States. Am J Emerg Med 1999;17: 138–140. 21. Felberg L, Litovitz TL, Morgan J: State of the nation’s poison centers: 1995 American Association of Poison Control Centers Survey of US Poison Centers. Vet Hum Toxicol 1996;38:445–453. 22. Fingerhut LA, Cox CS: Poisoning mortality, 1985–1995. Public Health Rep 1998;113:218–233. 23. Geller RJ, Lopez GP: Poison center planning for mass gatherings: The Georgia Poison Center experience with the 1996 Centennial Olympic Games. J Toxicol Clin Toxicol 1999;37:315–319. 24. Gfroerer J, Lessler J, Parsley T: Studies of nonresponse and measurement error in the national household survey on drug abuse. NIDA Res Monogr 1997;167:273–295. 25. Greenberg MI, Cone DC, Roberts JR: Material safety data sheet: A useful resource for the emergency physician. Ann Emerg Med 1996; 27:347–352. 26. Hamilton RJ, Goldfrank LR: Poison center data and the Pollyanna phenomenon. J Toxicol Clin Toxicol 1997;35:21–23. 27. Hamilton RJ, Perrone J, Hoffman RS, et al: A descriptive study of an epidemic of poisoning caused by heroin adulterated with scopolamine. J Toxicol Clin Toxicol 2000;38:597–608. 28. Harchelroad F, Clark RF, Dean B, Krenzelok EP: Treated vs reported toxic exposures: Discrepancies between a poison control center and a member hospital. Vet Hum Toxicol 1990;32:156–159. 29. Hoppe-Roberts JM, Lloyd LM, Chyka PA: Poisoning mortality in the United States: Comparison of national mortality statistics and poison control center reports. Ann Emerg Med 2000;35:440–448. 30. Hoyt BT, Rasmussen R, Giffin S, Smilkstein MJ: Poison center data accuracy: A comparison of rural hospital chart data with the TESS database. Acad Emerg Med 1999;6:851–855. 31. Jordan JK, Dean BS, Krenzelok EP: Poison center rotation for health science students. Vet Hum Toxicol 1987;29:174–175. 32. Kearney TE, Olson KR, Bero LA, et al: Healthcare cost effects of public use of a regional poison control center. West J Med 1995;162: 499–504. 33. King WD, Palmisano PA: Poison control centers: Can their value be measured? South Med J 1991;84:722–726. 34. Klein-Schwartz W, Smith GS: Agricultural and horticultural chemical poisonings: Mortality and morbidity in the United States. Ann Emerg Med 1997;29:232–238. 35. Krenzelok EP, Allswede MP, Mrvos R: The poison center role in biological and chemical terrorism. Vet Hum Toxicol 2000;45:297–300. 36. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 1998;279:1200–1205. 37. Linakis JG, Frederick KA: Poisoning deaths not reported to the regional poison control center. Ann Emerg Med 1993;22:42–48.

38. Litovitz TL, Bailey KM, Schmitz BF, et al: 1990 Annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1991;9:461–509. 39. Litovitz TL, Clark LR, Soloway RA: 1993 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1994;12:546–584. 40. Litovitz TL, Felberg L, Soloway RA, et al: 1994 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1995;13:551–597. 41. Litovitz TL, Felberg L, White S, et al: 1995 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1996;14:487–537. 42. Litovitz TL, Holm KC, Bailey KM, Schmitz BF: 1991 Annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1992;10:452–505. 43. Litovitz TL, Holm KC, Clancy C, et al: 1992 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1993;11:494–555. 44. Litovitz TL, Klein-Schwartz W, Caravati EM, et al: 1998 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1999;17:435–487. 45. Litovitz TL, Klein-Schwartz W, Dyer KS, et al: 1997 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1998;16:443–497. 46. Litovitz TL, Klein-Schwartz W, White S, et al: 1999 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2000;18:517–574. 47. Litovitz TL, Smilkstein M, Felberg L, et al: 1996 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1997;15:447–500. 48. Lovejoy FH, Robertson WO, Woolf AD: Poison centers, poison prevention and the pediatrician. Pediatrics 1994;94:220–224. 49. Miller TR, Lestina DC: Costs of poisoning in the United States and savings from poison control centers: A benefit-cost analysis. Ann Emerg Med. 1997;29:239–245. 50. Mullen WH, Anderson IB, Kim SY, et al: Incorrect overdose management advice in the Physicians’ Desk Reference. Ann Emerg Med 1997;29:255–261. 51. Phillips KA, Homan RK, Hiatt PH, et al: The costs and outcomes of restricting public access to poison centers. Results from a natural experiment. Med Care 1998;36:271–280. 52. Rodgers GB: The safety effects of child-resistant packaging for oral prescription drugs: Two decades of experience. JAMA 1996;275: 1661–1665. 53. Scherz RG, Robertson WO: The history of poison control centers in the United States. Clin Toxicol 1978;12:291–296. 54. Schwartz L, Howland MA, Mercurio-Zappala M, Hoffman R: The use of focus groups to plan poison prevention programs [abstract]. J Toxicol Clin Toxicol 2000;38:558. 55. Soslow AR, Woolf AD: Reliability of data sources for poisoning deaths in Massachusetts. Am J Emerg Med 1992;10:124–127. 56. Temple AR: Testing of child-resistant containers. Clin Toxicol 1978; 12:35–66. 57. Ungerleider JT, Lundberg GD, Sunshine I, Walberg CB: DAWN: Drug Abuse Warning Network or data about worthless numbers? J Anal Toxicol 1980;4:269–271. 58. Waltar WW: An evaluation of the poison prevention packaging act. Pediatrics 1982;69:363–370. 59. Wax PM, Rodewald L, Lawrence R: The arrival of the ED-based POISINDEX: Perceived impact on poison control center use. Am J Emerg Med 1994;12:537–540. 60. Wolf LR, Hamilton GC: Objectives to direct the training of emergency medicine residents of off-service rotations: Toxicology. J Emerg Med. 1994;12:391–405. 61. Youniss J, Litovitz T, Vilanueva P: Characterization of US poison centers: A 1998 survey conducted by the American Association of Poison Control Centers. Vet Hum Toxicol 2000;42:43–53.

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117 ADVERSE DRUG EVENTS Louis R. Cantilena, Jr.

Case A 39-year-old woman was brought to the Emergency Department (ED) after several episodes of syncope. These episodes began approximately 2 days before admission and were accompanied by a witnessed 4- to 5-second loss of consciousness with spontaneous recovery. There were no postictal symptoms or loss of bowel or bladder sphincter control associated with these episodes. At least one episode occurred when the patient was lying down and was preceded by palpitations, dyspnea, and diaphoresis. There was no prior history of trauma and no history of cardiac or neurologic illness. The patient denied suicidal ideation or intentions, dieting, or use of nonprescription or dietary supplement products. Ten days earlier, terfenadine, 60 mg twice daily, and cefaclor, 250 mg three times daily, had been prescribed for the treatment of recurrent sinusitis. On the eighth day of this combined therapy, the patient began taking ketoconazole, 200 mg twice daily, left over from an old prescription for vaginitis. The patient had experienced past episodes of yeast vaginitis, usually in this same setting of prolonged antibiotic therapy. There was no family history of cardiac disease. The patient had a normal electrocardiogram approximately 15 years before this admission. Other medications included medroxyprogesterone acetate, 2.5 mg per day for 10 days of the patient’s menstrual cycle. In the ED, the patient’s vital signs were: blood pressure 106/72 (without orthostatic changes); pulse regular, 88 beats per minute; respiratory rate 16/min; and oral temperature was 37.2°C (99°F). The physical examination was entirely normal. An electrocardiogram was remarkable for a corrected QT interval of 655 milliseconds, prominent T-U waves throughout the precordial leads, and nonspecific ST-T–wave abnormalities. The remainder of the laboratory examination was within normal limits. All medications were discontinued, and the patient was admitted to the telemetry unit for observation. Approximately 10 hours after admission, the patient experienced paroxysmal episodes of palpitations and dyspnea and a near syncopal episode identical to the one she had experienced before admission. Figure 117–1 shows the recording from her telemetry monitor, indicating torsades de pointes. The patient spontaneously recovered from this episode and remained in the hospital for approximately 5 days, during which time her QT interval gradually returned to normal. A full cardiac evaluation including echocardiogram and exercise stress testing was normal. Following discharge, outpatient 24-hour Holter monitoring revealed no abnormalities. The patient’s plasma from the time of admission was subsequently analyzed for unmetabolized terfenadine and its primary metabolite. These results revealed a markedly increased concentration of parent terfenadine, which is normally not found in patients taking this antihistamine.28

This patient presented in December 1989 at a military hospital in the Washington, DC area. A consultation service in clinical pharmacology and medical toxicology played a vital role in establishing the diagnosis of an adverse drug event caused a drug-drug interaction with terfenadine and ketoconazole. The drug terfenadine (Seldane) was approved for marketing in 1985 and was widely regarded as a safe, nonsedating antihistamine. At the time this case occurred, the drug was the eighth most frequently prescribed drug in the United States. The possibility of making this drug available without prescription was being discussed in the pharmaceutical press at the time. The drug was widely regarded as safe and had been marketed for nearly 6 years, with millions of dosages taken worldwide. The availability of a medical subspecialty with expertise in drug-induced disease and knowledge of drug metabolism proved to be an important component of the case of terfenadine. In 1989 the drug label for terfenadine mentioned the possibility of torsades de pointes occurring only in the setting of overdose with the antihistamine. The potential for life-threatening drug interactions with terfenadine was unrecognized at that time. Subsequently, the Food and Drug Administration (FDA) funded prospective research that demonstrated a significant drug-drug interaction involving terfenadine and inhibitors of the cytochrome P450 3A (CYP3A) system.17, 18 Several years later, the FDA announced their intention to withdraw terfenadine from the marketplace, citing the risk of dangerous drug-drug interactions, which had caused several deaths, as the primary reason.12 The manufacturer voluntarily withdrew Seldane from the market before final regulatory action could be taken. This case is an example of the discovery of a serious, lifethreatening adverse drug event (based on a drug-drug interaction) found during the postapproval period for a widely used drug. Terfenadine proved to be the first of several agents that would eventually be withdrawn from the United States market because of potentially lethal drug-drug interactions resulting in cardiac dysrhythmias. After the terfenadine withdrawal, the close attention paid by the FDA to drug effects on cardiac repolarization may make this particular drug-drug interaction problem less likely to occur in the future, but the approval of every drug or medical device carries with it some potential risk. 14 The FDA and the drug industry must always rely on postmarketing surveillance for further safety data regarding the toxicity of an agent after approval. There are systems in place to monitor postapproval drug safety that are intended to detect instances where the safety profile of an approved agent may appear to be different after marketing. Individual pharmaceutical manufacturers are responsible for monitoring the safety of their products and reporting to the FDA, on a

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Figure 117–1. Telemetry recording from the patient taking terfenadine and ketoconazole showing torsades de pointes.(From Monahan BP, Ferguson CL, Killeavy ES, et al: Torsades de pointes occurring in association with terfenadine use. JAMA 1990;264:2788–2790, with permission.)

regular basis, any adverse events that were reported to them. The FDA’s postmarketing surveillance for all medical products is another system in place to monitor drug and medical device safety. Health professionals contribute to ongoing passive surveillance of drug safety. This chapter focuses on drug-induced disease resulting from adverse drug events (ADEs) caused by both inherent drug toxicity and medical therapeutic errors. The topics covered in this chapter include a brief overview of the process for drug approval currently in place in the United States, a discussion about the diagnosis of drug-induced disease, medical errors as a cause of drug-induced disease, and the role of the medical toxicologist in the discovery, reporting,and prevention of ADEs.

HISTORY OF THE UNITED STATES DRUG APPROVAL PROCESS Today in the United States, approvals of new therapeutic agents are occurring at an unprecedented rate. The evolution of the system that currently exists for review of drug applications and approval of new therapeutic agents is the result of significant recent changes in the US drug law. Initially, the drug law evolution was closely linked to a series of medical product disasters that occurred during the 20th century in the United States. Before 1900, there was no legal requirement for a company to test a product for safety or efficacy or even to make valid claims in the drug label. Products such as aspirin containing heroin were sold as cough syrup. Wine with cocaine was marketed to enhance sales of the alcoholic beverage. Further, there was no requirement for systematic testing of products to determine purity or the presence of possible adulterants in product formulations. The Food and Drug Act of

1906 required drugs to meet a standard for strength and purity. The burden of proof, however, was placed on the FDA to show that the drug was incorrectly labeled or that the advertising or label was false or misleading. The Federal Food, Drug and Cosmetic Act of 1938 resulted from a tragedy in which more than 100 patients (mostly children) died from poisoning by an excipient of an oral solution of sulfanilamide. A pharmaceutical company, in an attempt to improve the palatability of a sulfanilamide product for pediatric formulations, introduced the solvent diethylene glycol into the formulation. Diethylene glycol is similar to ethylene glycol, and both produce a sweet-tasting but deadly ingestant. Only after almost a full year of marketing were cases of renal failure and death reported in sufficient numbers to alert authorities to the extremely toxic nature of the product. Ensuing congressional hearings resulted in passage of the Food Drug and Cosmetic Act of 1938. This law required companies (1) to list the ingredients of the product on the product label and (2) to provide the known risks concerning use of the product to physicians or pharmacists, (3) made illegal the misbranding of food or medical products, and (4) for the first time required companies to test their products for safety before being sold. Drugs already marketed before 1938 were exempt from the requirement (see Chap. 1). The next significant chapter in the history of FDA regulatory law occurred during the 1960s. An application for the approval of
-N-phthalylglutaramide (Thalidomide), a sedative that had already been marketed in Europe, was submitted to the Food and Drug Administration. The sedative drug apparently did not affect respiration, had a rapid onset and short duration of action, did not cause a morning-after effect, and was inexpensive. A medical reviewer at the FDA (Dr. F. Kelsey) delayed approval by asking the sponsor to clarify several issues in the reportedly poorly organized

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new drug application (NDA). The delay in US approval turned out to be fortuitous because, in the interim, an article that linked an unusual teratogenic effect of phocomelia to exposure to this agent appeared in the European medical literature. Congressional hearings were again held in the United States, and the Kefauver-Harris act of 1968 became law. This law required a manufacturer or sponsor to (1) file an investigational new drug application (IND) before beginning a clinical study with a drug in humans, (2) demonstrate that the drug was effective for the condition that it was being marketed to treat, and (3) provide adequate directions for safe usage of the drug. Moreover, the act did not exempt drugs that were already on the market. Thus, the evolution of the legal requirements for proving drug safety and efficacy in the United States are closely linked to the occurrence or near-occurrence of significant drug-induced disease. Subsequent US laws that affect the FDA’s review and approval of products include (1) the Orphan Drug Act of 1983, which provides financial incentives to drug manufacturers to develop drugs for the treatment of rare diseases and conditions (see http://www.fda.gov/orphan/designat/recent.htm for a list of drugs that have been approved under the Orphan Drug Act.); (2) The Prescription Drug User Fee Act of 1992, which required manufacturers to pay user fees to the Federal Government for new drug applications and supplements, enabling the FDA to hire additional reviewers to accelerate the review process so that reviews are performed under the user fee category on a shortened timetable than the average review period before the legislation; (3) Section 112 of the Food and Drug Administration Modernization Act of 1997, which allowed for an accelerated drug approval process for agents to treat life-threatening illnesses such as AIDS and cancer if the agent had the potential to address medical needs unmet by currently available drugs. Many of the accelerated drug approval programs rely on efficacy results based on a surrogate marker that is known to be linked to the ultimate indication for the drug. For ex-

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ample, the protease inhibitors were shown to reduce HIV viral load for the treatment of AIDS and were approved based on the accelerated track with confirmatory clinical trials under way that ultimately showed an increased survival. Has the accelerated drug approval process led to an increase in the need to withdraw unsafe medications?14,32,38 Figure 117–2 shows the number of FDA drug approvals for new molecular entities (NME) per year from 1993 to 1999 as well as the median approval time and the FDA review time for drug products for corresponding years. Both the median approval time and review times have decreased during this 6-year period despite an increase in the number of NMEs approved during this time period. The number of safety-based withdrawals of NME drugs is shown in Fig. 117–3 by 5-year approval periods and as percentages of the approved-drug cohort that was withdrawn. This figure suggests that althoughwhile the number of NMEs approved as new drugs in the United States is increasing per year, the percentage of NMEs withdrawn for safety reasons has been relatively stable, with the exception of drugs approved between 1985 and 1989, which showed that 4.4% of the drugs approved in these 4 years were eventually withdrawn. Interestingly, it was during that same time period that terfenadine and astemizole were approved for marketing. However, it is possible that in some cases there may be as much as a 10- to 15-year lag in the postmarketing detection system (ie, MedWatch) for rare or difficult to diagnose ADEs. Time may yet show that the recent drug approval cohorts have not reached their peak for detection. The next several years will ultimately determine whether or not there is an association between the increased rate for drug approval and the rate of safety-related drug withdrawals. Other issues such as gender effects on ADEs also require closer examination. A recent General Accounting Office report dated January 19, 2001 (http://www.gao.gov) has highlighted the fact that 8 of 10 drugs recently withdrawn from the US market posed greater health risks to women than to men.

Figure 117–2. Yearly new molecular entity (NME) US approvals by FDA and median approval and review time for 1993 through 1999. (From www.fda.gov.)

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Figure 117–3. The number and percentage of approved drugs withdrawn from the US market for safety reasons by 5-year periods. (From www. fda.gov.)

THE DRUG DEVELOPMENT PROCESS A schematic overview of the process for drug development of a NME is shown in Fig. 117–4. The process begins with the preclinical evaluation of the candidate drug. During this evaluation, toxicologic testing is performed in more than one animal species as well as other testing including stability of the product, manufacturing methods, purity, and carcinogenicity. Dose-response relationships in animal models and in vitro receptor binding or surrogate marker effects are often determined at this time in the program. Also, this is the time when many manufacturers determine the drug’s metabolism in animal and in vitro human systems. Following this preclinical testing, the sponsor submits an IND application to the FDA for approval to initiate human testing. This application contains all relevant data concerning animal and in vitro toxicology testing, product manufacturing and purity, and a protocol for utilizing the drug in initial human investigation. Within 30 days, the FDA must review the application and either allow the proposed human study to proceed or inform the sponsor that additional data or preclinical work is required before clinical testing of the candidate drug can begin. The clinical study of new medications is divided into four basic phases. Phase 1 clinical testing involves a relatively small number of subjects with the primary aim of determining the safety and toxicity of the drug. Many Phase 1 studies will also determine the human pharmacokinetics of the drug. Phase 1 studies are normally conducted in 20 to 100 healthy volunteer subjects with the notable exception of Phase 1 studies for cancer chemotherapeutic agents, which only enroll patients with cancer.

Phase 2 clinical testing is designed to determine the potential efficacy of the drug product in humans and sometimes explores the range of effective drug dosages. In this phase, approximately 100 to 300 subjects are studied. In Phase 2 clinical trials, subjects generally have the diseases for which the drug is intended or are capable of demonstrating the appropriate, validated, biologic surrogate marker to indicate response to the drug. Phase 3 clinical drug studies usually involve large-scale clinical trials in the actual population for which the drug is intended to be used. Typically, this phase of a drug’s development will involve testing a treatment cohort of several hundred to several thousand patients who have the target disease, depending on both the prevalence of the disease and effectiveness of the drug. The primary goal of Phase 3 studies is to determine the safety and efficacy of the candidate drug in the actual patient population it will be used in, under conditions close to the anticipated medical use. A candidate drug completing Phase 1, 2, and 3 can thus be approved for marketing after study in only 2000 to 4000 patients. In the setting of a fast-track approval or under the Orphan Drug regulations, substantially fewer patients will receive the drug before its approval for marketing. After the FDA approves a drug for marketing, Phase 4 clinical studies are initiated. Phase 4 studies may be marketing-type studies comparing the new drug to a competitor. However, enhancement of safety information is the primary goal of most Phase 4 studies. The methods by which Phase 4 safety studies are conducted are primarily observational and epidemiologic studies. Main sources of data for the postapproval monitoring of the safety of a drug are the spontaneous reports gathered by both the pharmaceutical manufacturer and FDA. The fields of pharmacovigilance and pharmacoepidemiology are typically employed in the conduct of Phase 4 studies.27 Until 1993, the FDA utilized the spontaneous reporting system (SRS) to gather information regarding ADEs occurring in patients using the approved drug. In 1993, this system

Figure 117–4. Schematic representation of new drug development. (From www.fda.gov.)

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was renamed and promoted as the MedWatch system.20 This system relies on spontaneous reports by healthcare professionals or patients regarding the occurrence of deleterious effects associated with the use of a medical product. The primary goals of the MedWatch system are (1) to increase awareness of drug- and deviceinduced disease; (2) to clarify what should (and should not) be reported to the agency; (3) to make it easier to report adverse effects by creating a single system for health professionals to use in reporting adverse events and product problems to the agency; and (4) to provide regular feedback to the health care community about safety issues involving medical products.26 Currently, the MedWatch program is supported by over 140 organizations, representing health professionals and industry, that have agreed to be MedWatch Partners to help achieve these goals. Medical product manufacturers that are regulated by the FDA are required to report adverse events occurring in association with the use of their products. Healthcare professionals are encouraged (but not required) to report ADEs. An adverse event is any undesirable experience associated with the use of a medical product in a patient. The MedWatch system has tried to make reporting by healthcare providers easier. A MedWatch report can be made by either facsimile, telephone, mail, or Internet. Establishing causality for a specific medical product is not required before submission of a MedWatch report. The FDA is primarily interested in the report of a serious adverse event, whether or not a causal relationship is established. An event is serious and should be reported when the patient outcome is one of the following:

1. Death, and the death is suspected to be a direct result of the adverse event. 2. Life-threatening, if the patient was considered to be at substantial risk of dying at the time of the adverse event or the use or continued use of the product would result in the patient’s death. (Examples include gastrointestinal hemorrhage, bone marrow suppression, pacemaker failure, and infusion pump failure that permits uncontrolled free flow and results in excessive drug dosing.) 3. Hospitalization (initial or prolonged) if admission to the hospital or prolongation of a hospital stay resulted from the adverse event. (Examples include anaphylaxis, pseudomembranous colitis, or bleeding causing or prolonging hospitalization.) 4. Disability, if the adverse event resulted in a significant, persistent, or permanent change, impairment, damage, or disruption in the patient’s body function/structure, physical activities, or quality of life. (Examples include cerebrovascular accident caused by drug-induced coagulopathy, toxicity, and peripheral neuropathy.) 5. Congenital anomaly, if there are suspicions that exposure to a medical product before conception or during pregnancy resulted in an adverse effect on the child. (Examples include vaginal cancer in female offspring from diethylstilbestrol during pregnancy or limb malformations in the offspring from thalidomide use during pregnancy.) 6. Requires intervention to prevent permanent impairment or damage if use of a medical product is suspected to result in a condition requiring medical or surgical intervention to preclude permanent impairment or damage to a patient. (Examples include acetaminophen overdose-induced hepatotoxicity requiring treatment with N-acetylcysteine to prevent permanent damage, burns from radiation equipment requiring drug

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therapy, or breakage of an orthopedic screw requiring replacement of hardware to prevent malunion of a fractured long bone.)26 Physician reports are given priority for review by the FDA in the MedWatch system. A well-documented case of a serious adverse event is a significant and useful contribution to the MedWatch system. The medical toxicologist may be the first person to encounter a patient with a serious ADE in the ED or may be one of the first consultants called to see a patient with a suspected serious drug-induced disease. Reports of serious ADEs to the FDA or to the manufacturer can evolve into an epidemiologically detectable signal that can catalyze subsequent, more detailed investigations (examples of cases where this has occurred are provided later in this chapter). Reporting serious ADEs has periodically been encouraged by various healthcare groups in conjunction with the FDA. With the introduction of the MedWatch system and MedWatch partner programs, medical societies and organizations such as the American Medical Association, the American College of Medical Toxicology, and the American Academy of Pediatrics have encouraged their members to report to the MedWatch system. As a requirement for accreditation, the Joint Commission on Accreditation of Healthcare Organizations mandates hospitals to collect, analyze, and report significant and unexpected ADEs to the FDA. The primary limitation of the MedWatch system and, in fact, of most Phase 4 drug studies is the exclusive reliance on spontaneous reporting of adverse events. Significant underreporting is known to occur in such systems. Current estimates are that fewer than 10% of ADEs are reported.15,29,31 The true incidence of the reported ADE is almost never obtainable because the denominator, which is the number of actual exposures to the drug, is rarely accurately known. Despite these limitations, the MedWatch system is capable of detecting significant adverse events. The relatively small number of patients or subjects exposed to the drug before approval (Phases 1–3) is one reason why relatively uncommon ADEs are not detected until the postapproval marketing phase. For example, in order to detect an uncommon adverse event occurring in approximately 1 of 5000 individuals exposed to a drug with 95% probability that the ADE resulted from exposure to that drug, approximately 15,000 patients would have to be exposed to the drug.25 In a balanced (equal numbers of drug and placebo recipients) placebo-controlled clinical trial, 30,000 subjects would need to be enrolled. Premarketing clinical studies (Phase 1, 2, and 3) may not be able to detect rare ADEs, ADEs that are incorrectly diagnosed, or ADEs that result from a drug interaction that may not have been tested in the development program. An example of a rare ADE not detected until postmarketing involves the drug felbamate, which was approved by the FDA in September 1993 and subsequently found to be associated with aplastic anemia during postmarketing surveillance. Felbamate-induced aplastic anemia had not been detected during the drug development program for the agent. By July 1994, nine cases had been reported from an estimated 100,000 patients exposed to felbamate in the United States. Most of the aplastic anemia cases occurred in patients who had taken the drug for less than 1 year. The nine cases represented an approximate 50-fold increase in aplastic anemia over the expected rate with the very low background rate of two to five cases per million per previous year,1,34 allowing the FDA to attribute this rare condition to exposure to felbamate. Attributing a serious ADE to a drug solely from MedWatch reports occurs uncommonly. A primary role of the MedWatch sys-

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tem is to generate a “hypothesis” for a potential association of an ADE with a specific drug. An example of this “hypothesis generation” function of MedWatch is the question of whether phenylpropanolamine (PPA) causes hemorrhagic stroke in patients using nonprescription diet suppressants or cough and cold preparations containing PPA. In the early 1990s, the Spontaneous Reporting System (SRS, now MedWatch) detected a potential association of hemorrhagic stroke and nonprescription use of PPA. An industry-sponsored prospective, case-controlled study resulted, to determine if such an association existed. The multicenter study demonstrated that an association did exist, especially for women ages 18 to 49. The Nonprescription Drug Advisory Committee (NDAC) of FDA reviewed this study and the associated MedWatch data in the fall of 2000 and decided that the evidence supported such an association. Consequently, the idea of removing PPA from the market was considered and then implemented. Although the entire process of signal identification from MedWatch to presentation of results from the prospective epidemiologic study required nearly a decade for PPA, the process demonstrates the value of the hypothesisgenerating ability of the MedWatch system.

ESTABLISHING THE DIAGNOSIS OF DRUG-INDUCED DISEASE The recognition and diagnosis of a drug-induced disease, or an ADE, is an essential skill for practitioners, including medical toxicologists and clinical pharmacologists. The diagnosis of an ADE is typically made as a result of a systematic medical evaluation. One approach to making the diagnosis of drug-induced disease involves consideration of six related questions concerning the patient’s clinical presentation, as shown in Table 117–1. The first question concerns the timing of the onset of the adverse event in relationship to the reported exposure to the drug. Perhaps because of publicity or word of mouth, ADEs are sometimes reported to the FDA MedWatch system even when the onset of the adverse event occurs before the first exposure to the suspect drug. A careful reconstruction of the time course of drug exposure and onset of adverse effects is extremely important in assessing causality. The time course differs considerably for different adverse clinical events. An anaphylactic reaction to a drug occurs within minutes of exposure, whereas renal insufficiency caused by a drug is not likely to be clinically detectable for up to several days after the exposure. A drug that causes cancer (a carcinogen) may not produce a clinically detectable effect for decades. Establishing a time course is an essential first step in the process of making the diagnosis of drug-induced disease. TABLE 117–1. Considerations When Establishing the Diagnosis of an Adverse Drug Event (ADE) • Was the timing of the adverse event appropriate relative to the exposure to the drug? • Has the suspected ADE effect been reported before? • Is there evidence of excessive exposure to the drug? • Are there other more likely etiologies reponsible for the suspected ADE? • What is the patient’s response to withdrawal or cessation (dechallenge) of the drug? • What is the patient’s response to rechallenge?

The second question is whether or not this adverse effect has been reported previously for the suspect drug. An adverse drug effect that occurs commonly is likely to be known before the approval of the drug and is therefore usually found on the drug label. For example, respiratory depression and mental status changes were well known before the approval of fentanyl, an opioid agonist. Less common ADEs for drugs that have been on the market for a period of time are sometimes reported in the literature, included in various medical databases, and in some cases will appear in a revised drug label for the medical product. Previous reports linking the observed adverse effect to drug exposure are very helpful to the toxicologist trying to establish a significant level of probability for causality in the setting of an ADE. However, in the setting of a newly approved drug or a previously unreported possible ADE, neither previous reports, the medical literature, nor the drug label will help establish causality. In this setting, the clinician must rely more on what is known of the pharmacology, the pharmacokinetics, and the anticipated pharmacodynamics of the suspect drug as well as the timing of the appearance and observed time course of the adverse event. It is important to put “drug-induced disease” in the differential diagnosis for the patient presenting for medical care. Someone has to be the first to report what is ultimately recognized as an adverse effect for every drug or toxin. Appropriate vigilance for the possibility of a new ADE significantly increases the probability that a finding can be made early after introduction of a new drug to prevent more widespread drug-induced morbidity or mortality. “Is there evidence of excess exposure to the drug?” The majority of ADEs that occur are predictable on the basis of the known pharmacology of the specific drug. Such ADEs are referred to as “type A” ADEs.8 For example, antihistamines such as diphenhydramine are known to cause significant anticholinergic effects. When a patient presents with mental status changes and clinical findings consistent with the anticholinergic toxidrome after significant exposure to an antihistamine-containing product, the observed effects are consistent with an ADE attributable to the antihistamine. Occasionally, proof of drug excess can come from measurement of the drug substance in plasma. In the case of the patient with a history of manic-depressive illness, who exhibits hyperreflexia and tremors, the measurement of an elevated lithium plasma concentration supports the diagnosis of lithium toxicity or an ADE attributable to lithium. In either case, knowing the pharmacology of the drug is important for establishing the diagnosis of an ADE. When an ADE is caused by an allergic mechanism or another mechanism unrelated to dose of the drug, ie, a “type B” ADE, evidence of drug excess usually does not contribute to the diagnosis. In this setting, other factors such as allergy history or pharmacogenetic background are weighed more heavily to support the diagnosis of an ADE. The next issue to address in considering possible causality is whether there are other more likely etiologies that could be responsible for the observed effects. Although it is important to be appropriately vigilant for possible adverse drug effects, it is equally important not to miss an alternative cause for the patient’s condition. There are certain clinical settings in which establishing an ADE becomes a diagnosis by exclusion. For example, in the case of persistent fever, the assignment of the diagnosis “drug fever” should not be made until a complete search for infectious causes has excluded this etiology.

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Another factor to consider in contemplating a diagnosis of ADE is “What is the patient’s response to cessation of a suspect drug (dechallenge)?” In this case, the pharmacokinetics of the agent and the timing of resolution of the specific condition must be carefully considered. In some instances, the resolution of a “type A” ADE closely follows the pharmacokinetics of the suspect agent. For example, in the case of acute ethanol intoxication, central nervous system effects resolve in association with decreasing plasma concentrations of ethanol. However, confounding this approach is the case of a penicillin rash, which may develop within 1or 2 days of starting the medication but may take several days to weeks to completely resolve. In this case of a “type B” ADE, the resolution of the condition (rash) occurs over a much longer time period than would be predicted by the pharmacokinetics of the agent. When a suspected ADE resolves after discontinuation of exposure to the offending agent, along a predictable time course, then the result of this “dechallenge” would support the diagnosis of ADE. Last, the clinician may have the opportunity or need to rechallenge the patient with the suspect agent. If the rechallenge results in the identical response or effect, then this would be considered strong evidence to support a causal relationship for the suspect agent and the adverse event. In the setting of a serious or lifethreatening adverse event, it is too dangerous to perform a rechallenge with the suspect drug, in which case the response to rechallenge will not be known. In this setting, the weight of evidence previously discussed will then be the only factor available to assign the probability of causality.

EXAMPLES OF DRUG WITHDRAWALS FROM THE UNITED STATES MARKET When concern for the safety of a particular drug no longer suggests an acceptable risk–benefit relationship for continued availability of a drug product, the FDA begins a defined process to remove the drug from the market. Table 117–2 contains a compilation of products that have been withdrawn or removed from the market in the United States for reasons of safety or efficacy. The manufacturers have voluntarily withdrawn the majority of the drugs listed in Table 117–2 from the United States market. Only very rarely has the FDA itself actually removed a drug from the market. One example where the FDA did act is the drug phenformin, which was removed by the FDA after due process was completed. More typically, the manufacturer removes the drug from the market after notification by the Food and Drug Administration that regulatory action is being initiated against their product. For several of the products listed in Table 117–2, the pharmaceutical manufacturer filed suit against the Food and Drug Administration to fight or delay the planned regulatory action against the product. The manufacturer’s legal action generally prolongs the time the product remains on the market because the drug usually continues to be sold while the legal proceedings and appeals proceed through the courts. Several of the more recent drug withdrawals in the United States are discussed as examples. Over the last several years, three types of ADE have been of particular concern as a result of unexpected drug safety issues discovered during the postmarketing phase for a drug product. These are (1) prolongation of the QT interval, (2) significant drug-drug

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interactions, and (3) hepatotoxicity. Each of these safety issues is represented below by a recent drug withdrawal.

Prolongation of the QT Interval Three recent drug withdrawals exemplified a serious drug safety issue with an agent found to prolong the QT interval when administered alone or as the result of increasing plasma concentrations of the drug as a result of inhibition of its metabolism by other medications. The three examples in this category are terfenadine (Seldane), astemizole (Hismanal), and cisapride (Propulsid). Clinical studies with terfenadine began in the early 1970s. The investigational new drug application was filed with the Food and Drug Administration in 1972. Clinical studies were completed in the drug development package by 1983, and the new drug application was submitted to the FDA at that time. After 26 months of review, terfenadine was approved for marketing in the United States in 1985. The case presented in the beginning of this chapter was in fact the initial indication of a serious drug-drug interaction and led to a subsequent prospective FDA-funded clinical investigation to establish the interaction. Significant labeling changes, the addition of a “black box” warning in the drug label, and a series of “Dear Doctor” letters highlighting this new safety issue were initiated in 1992. In 1998, the drug was voluntarily withdrawn from the market by the sponsor, coincident with FDA approval of fexofenadine, a noncardiotoxic metabolite of terfenadine, marketed as an extended-release combination with pseudoephedrine (AllegraDTM).11 The terfenadine case pointed out for the first time the potential for noncardiovascular drugs to cause potent or fatal cardiotoxic effects subsequent to a drug-drug interaction. Astemizole (HismanalTM), another antihistamine, was approved by the FDA in 1988. In the late 1980s and early 1990s, postmarketing reports from the FDA Spontaneous Reporting System (SRS) pointed out cardiac-related ADEs similar to those associated with terfenadine. The SRS and other reports again suggested an association between either excessive doses of astemizole or its administration in combination with inhibitors of its metabolism and deleterious cardiac repolarization effects leading to increased risk for cardiac dysrhythmias, particularly torsades de pointes. In the mid 1990s, “Dear Doctor” letters were sent to prescribers in the United States. A significant modification of the drug label to include a “black box” warning for these newly discovered, potentially fatal drug-drug interactions was made. In June 1999, the FDA announced that the sponsor was voluntarily withdrawing astemizole from the market.10 There are substantial parallels between terfenadine and astemizole. Both agents are nonsedating antihistamine compounds that are metabolized by cytochrome P450 (CYP3A) and alter cardiac repolarization to produce prolongation of the QT interval, leading to cardiac dysrhythmias, torsades de pointes, and sudden death. The most recent voluntary drug withdrawal resulting from altered cardiac repolarization and increased risk of cardiac dysrhythmia involved cisapride (PropulsidTM). By December 31, 1999, cisapride was associated with 341 reports of cardiac dysrhythmias including 80 fatalities. The mechanism for the prodysrhythmic effect is less well documented for cisapride than for astemizole and terfenadine, but the drug is believed to alter cardiac repolarization, possibly through a potassium channel mechanism, and inhibition of cisapride metabolism increases the risk for dysrhythmia and death. Administration of cisapride with inhibitors of CYP3A such

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TABLE 117–2.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY List of Drug Products Withdrawn or Removed from the Market for Reasons of Safety and Effectiveness

Name of Drug

Year of Introduction

Month and Year of Withdrawal

Adenosine phosphate

1933

1973 (FDA)

Adrenal cortex

1937

January 1978 (FDA)

Alosetron hydrochloride

February 2000 (FDA)

November 2000

Aminopyrine

1964 (NDA)

October 1977 (NDA)

Astemizole

December 1988 (FDA)

Voluntarily withdrawn June 1999

Azaribine

Benoxaprofen Bithionol

Bromfenac sodium

July 1997 (FDA)

Butamben

Camphorated oil Carbetapentane citrate

Approval of NDA withdrawn November 1972 October 1964

Casein, iodinated Chlorhexidine gluconate

Approval of NDA withdrawn June 1977 Voluntarily withdrawn August 1982 Approval of NDA withdrawn October 1967 Voluntarily withdrawn June 1998 Approval of NDA withdrawn August 1964 1982 (FDA)

1976 (FDA)

Chlormadinone acetate

Early 1984 (FDA)

March 1972 (FDA)

Chloroform

1831?

1976 (FDA)

Cisapride monohydrate

July 1993

July 2000

Cobalt

Dexfenfluramine hydrochloride Diamthazole dihydrochloride Dibromsalan

1967 (FDA)

April 1996 (FDA)

September 1997 July 1977 1975 (FDA)

Reason for Withdrawal Formerly marketed as a component of Adeno for injection, Adco for injection, and other drug products, it was determined to be neither safe nor effective for its intended uses as a vasodilator and an antiinflammatory agent. The low level of corticosteroids found in adrenal cortex injection and adrenal cortex extract were determined to present a substantial risk of undertreatment of serious conditions such as adrenal cortical insufficiency, burns, and hypoglycemia. The FDA determined that adrenal cortex for injection and adrenal cortex extract represented a significant potential hazard and directed the removal of these drug products. Reported cases of intestinal damage resulting from reduced blood flow to the intestine (ischemic colitis) and severely obstructed or ruptured bowels. Aminopyrine caused agranulocytosis, a condition characterized by a decrease in the number of certain white blood cells and lesions on the mucous membrane and skin. Some of the cases of agranulocytosis were fatal. Because of low prescription usage and the availability of other agents with fewer propensities for drug interactions, Janssen Pharmaceutica discontinued this agent from manufacture. The use of azaribine, formerly marketed as Triazure tablets, was associated with very serious thromboembolic events. Formerly marketed as Oraflex tablets, was associated with fatal cholestatic jaundice among other serious adverse reactions. Formerly marketed as an active ingredient in various topical drug products, it was shown to be a potent photosensitizer with the potential to cause serious skin disorders. Formerly marketed as Duract capsules, it was associated with fatal hepatic failure. Formerly marketed as Efocaine, it was associated with severe adverse reactions such as severe tissue slough and transverse myelitis. Products containing camphorated oil were associated with poisoning in infants and young children following unintentional ingestion. Formerly marketed as Candette Cough Jel, it was determined not to be safe because the inexact methods of measuring the gel by consumers were potentially dangerous. Formerly marketed as a component of Neo-Barine, it was associated with thyrotoxic side effects. Formulated for use as a patient preoperative skin preparation. Chlorhexidine gluconate topical tincture 0.5%, formerly marketed as Hibitane, was associated with chemical and thermal burns when used as a patient preoperative skin preparation. Formerly marketed as a component of the combination drug products Estalor-21 and C-Quens tablets, it was associated with the development of mammary tumors in dogs. National Cancer Institute studies demonstrated that chloroform is carcinogenic in animals. Marketed as Propulsid, its primary health risk was torsades de pointes. Propulsid remains minimally available on a patient-by-patient basis for those with severely debilitating conditions. All drug products containing cobalt salts (except radioactive forms of cobalt and its salts and cobalamin and its derivatives). FDA found that cobalt salts were not safe or effective for treatment of iron-deficiency anemia. The toxic effects of cobalt salts include liver damage, claudication, and myocardial damage. Formerly marketed as Redux capsules, it was associated with valvular heart disease. Formerly marketed as Asterol ointment, powder, and tincture, was associated with neurotoxicity. Formerly marketed in a number of drug products, largely antibacterial soaps, as an antimicrobial, preservative, or for other purposes; was, with other halogenated salicylanilides listed in this table, found to be a potent photosensitizer capable of causing disabling skin disorders. (continued )

CHAPTER 117

TABLE 117–2.

ADVERSE DRUG EVENTS

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List of Drug Products Withdrawn or Removed from the Market for Reasons of Safety and Effectiveness (continued)

Name of Drug

Year of Introduction

Month and Year of Withdrawal

Diethylstilbestrol

1941 (FDA)

February 1975 (FDA)

Dihydrostreptomycin sulfate Dipyrone

July 1970 (FDA) June 1977 (FDA)

Encainide hydrochloride

December 1986 (FDA)

December 1991

Fenfluramine hydrochloride Flosequinan

1973

September 1997 (FDA) July 1993

Gelatin

1682?

April 1978 (FDA)

Glycerol, iodinated Gonadotropin, chorionic Grepafloxacin hydrochloride Mepazine

April 1993 (FDA) 1939 (FDA)

July 1972

November 1997

November 1999 May 1970

Metabromsalan

Methamphetamine hydrochloride

1975 (FDA)

1943 (FDA)

March (1973)

Methapyrilene

June 1979

Methopholine

March 1965

Mibefradil dihydrochloride

June 1997

June 1998

Neomycin sulfate

1952 (FDA)

January 1989 (FDA)

Nitrofurazone

1945 (FDA)

December 1974 June 1975

Nomifensine maleate

January 1986 (FDA)

Oxyphenisatin

March 1973

Oxyphenisatin acetate

February 1972

Reason for Withdrawal All oral and parenteral drug products containing 25 mg or more of diethylstilbestrol per unit dose. Diethylstilbestrol, marketed in various tablet and parenteral drug products, was associated with adenocarcinoma of the vagina in the offspring of the patient when used in early pregnancy. Formerly marketed in several parenteral drug products, it was associated with ototoxicity. Formerly marketed as Dimethone tablets and injection, Protemp oral liquid, and other drug products; it was associated with potentially fatal agranulocytosis. Formerly marketed as Enkaid capsules, it was associated with increased death rates in patients who had asymptomatic heart rhythm abnormalities after a recent heart attack. Formerly marketed as Pondimin tablets, it was associated with valvular heart disease. Formerly marketed as Manoplax tablets, it was the subject of a study that indicated the drug had adverse effects on survival and that beneficial effects on the symptoms of heart failure did not last beyond the first 3 months of therapy. After the first 3 months of therapy, patients on the drug had a higher rate of hospitalization than patients taking a placebo. Gelatin for intravenous use, formerly marketed as Knox Special Gelatine Solution Intravenous-6 percent, was found not to be suitable as a plasma expander because the drug caused increased blood viscosity, reduced blood clotting, and prolonged bleeding time. Formerly marketed as lodur Elixir and other drug products, it was found to have carcinogenic potential. Chorionic gonadotropins of animal origins, formerly marketed as Synapoidin Steri-Vial, were shown to produce allergic reactions. Formerly marketed as Raxar, this antibiotic drug was withdrawn because of its primary health risk relating to torsades de pointes. Formerly marketed as Pacatal tablets, and mepazine acetate, formerly marketed as Pacatal for injection, was associated with granulocytopenia, agranulocytosis, paralytic ileus, urinary retention, seizures, hypotension, and jaundice. Formerly marketed in a number of drug products, largely antibacterial soaps, as an antimicrobial, preservative, or for other purposes, was, with other halogenated salicylanilides listed in this table, found to be a potent photosensitizer capable of causing disabling skin disorders. Formerly marketed as Methedrine injection and Drinalfa injection and used as an adjunct treatment for weight reduction, it was found to have a history of serious abuse and a severe risk of dependence. Formerly marketed in many drug products, it was shown to be a potent carcinogen. Formerly marketed as Versidyne tablets, it was associated with ophthalmic changes and corneal opacities in dogs. Formerly marketed as Posicor tablets, it was associated with potentially harmful interactions with other drugs. Mibefradil dihydrochloride reduced the activity of certain liver enzymes that are important in helping the body eliminate many other drugs. Inhibiting these enzymes can cause some of these drugs to accumulate to dangerous levels in the body. Parenteral neomycin sulfate was found to present toxicity problems when used to irrigate wounds and was found not to be acceptable for the treatment of urinary tract infections because of the availability of newer, safer antibiotics that were as effective as, or more effective than, parenteral neomycin sulfate. All drug products containing nitrofurazone (except topical drug products formulated for dermatologic application). Nitrofurazone, formerly marketed in nasal drops, otic drops, and vaginal suppositories, was associated with mammary neoplasia in rats. Formerly marketed as Merital capsules; it was associated with an increased incidence of hemolytic anemia. Oxyphenisatin, formerly marketed in Lavema Compound Solution and Lavema Enema Powder; it was associated with hepatitis and jaundice. Formerly marketed in Dialose Plus capsules, Noloc capsules, and other drug products; it was associated with hepatitis and jaundice. (continued )

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PART D

TABLE 117–2.

List of Drug Products Withdrawn or Removed from the Market for Reasons of Safety and Effectiveness (continued)

Name of Drug

Year of Introduction

Month and Year of Withdrawal

Phenacetin

November 1983

Phenformin hydrochloride Pipamazine

November 1978 (FDA)

Potassium arsenite

July 1969 April 1980 (FDA)

Potassium chloride

Voluntarily withdrawn July 1977 and April 1992

Povidone

1986 (FDA)

April 1978

Reserpine

1953 (FDA)

May 1977

Sparteine sulfate

August 1979

Sulfadimethoxine

March 1966

Sulfathiazole

September 1970

Suprofen

1988 (FDA)

May 1987

Sweet spirits of nitre

1980 (FDA)

Temafloxacin hydrochloride

September 1997

Terfenadine

May 1985 (FDA)

3,3′,4′,5-Tetrachlorosalicylanilide

Tetracycline

Ticrynafen Tribromsalan

February 1998 (FDA)

1975 (FDA)

1953 (FDA)

May 1996 1975 (FDA)

Reason for Withdrawal Formerly marketed in A.P.C. with Butalbital tablets and capsules and other drug products, was associated with a high potential for harm to the kidneys and the possibility of hemolytic anemia and methemoglobinemia resulting from abuse. Formerly marketed as D.B.I. tablets, Meltrol-50 capsules, and other drug products; it was associated with lactic acidosis. Formerly marketed as Mornidine tablets and injection; it was associated with hepatic lesions. Formerly marketed as Fowler’s Solution (oral); it was toxic and highly carcinogenic. All solid oral dosage form drug products containing potassium chloride that supply 100 mg or more of potassium per dosage unit (except for controlledrelease dosage forms and those products formulated for preparation of solution before ingestion). Concentrated solid oral dosage forms of potassium salt were associated with small bowel lesions. All intravenous drug products containing povidone. Povidone, marketed as Polyvinylpyrrolidone in Normal Saline, was found to be unsafe for use as a plasma expander in the emergency treatment of shock because povidone accumulates in the body and may cause storage disease with the formation of granulomas. Povidone also interferes with blood coagulation, hemostasis, and blood typing and crossmatching. All oral dosage form drug products containing more than 1 mg of reserpine. Reserpine, marketed as Reserpoid tablets, Rau-Sed tablets, and other drug products for the treatment of hypertension and psychiatric disorders, were associated with a greater frequency and severity of adverse effects in strengths greater than 1 mg. Formerly marketed as Spartocin injection and Tocosamine sterile solution, it was found to have unpredictable effects and was associated with tetanic uterine contractions and obstetric complications. Formerly marketed in Madricidin capsules, it was associated with Stevens-Johnson syndrome and fatalities. All drug products containing sulfathiazole (except those formulated for vaginal use). Sulfathiazole, formerly marketed in Tresamide tablets and several other brands of tablets, was associated with renal complications, rash, fever, blood dyscrasias, and liver damage. All drug products containing suprofen (except ophthalmic solutions). Suprofen, formerly marketed as Suprol capsules, was associated with flank pain syndrome. Also known as spirit of nitre, spirit of nitrous ether, and ethyl nitrite spirit; it was associated with methemoglobinemia in infants. Formerly marketed as Omniflox tablets, it was associated with hypoglycemia in elderly patients as well as a constellation of multisystem organ involvement characterized by hemolytic anemia, frequently associated with renal failure, markedly abnormal liver tests, and coagulopathy. Formerly marketed in Seldane and Seldane-D tablets, it was associated with serious heart problems when used concurrently with certain drugs, including certain antibiotics and antifungals. Formerly marketed in a number of drug products, largely antibacterial soaps, as an antimicrobial, preservative, or for other purposes; it was, with other halogenated salicylanilides listed in this table, found to be a potent photosensitizer capable of causing disabling skin disorders. All liquid oral drug products formulated for pediatric use containing tetracycline in a concentration greater than 25 mg/mL. Concentrated tetracycline was associated with temporary inhibition of bone growth, permanent staining of the teeth, and enamel hypoplasia in children. Formerly marketed as Selacryn tablets, it was associated with liver toxicity. Formerly marketed in a number of drug products, largely antibacterial soaps, as an antimicrobial, preservative, or for other purposes; it was, with other halogenated salicylanilides listed in this table, found to be a potent photosensitizer capable of causing disabling skin disorders. (continued )

CHAPTER 117

TABLE 117–2. Name of Drug

1763

List of Drug Products Withdrawn or Removed from the Market for Reasons of Safety and Effectiveness (continued) Year of Introduction

Trichloroethane

Troglitazone

ADVERSE DRUG EVENTS

Month and Year of Withdrawal 1977 (FDA)

January 1997

March 2000

Urethane

March 1977

Vinyl chloride

1974 (FDA)

Zirconium

1977 (FDA)

Zomepirac sodium

March 1983

as clarithromycin results in prolongation of the QTc (QT interval corrected for heart rate) interval on the surface electrocardiogram.33 Despite several modifications in the drug label to enhance the warnings for the product, reports of significant cardiotoxicity continued. In March 2000, the manufacturer agreed to stop marketing this agent as of July 2000.9 Unlike the voluntary withdrawals of astemizole and terfenadine, the sponsor was able to retain the ability to make cisapride available to patients who meet specific clinical eligibility criteria for a limited-access protocol. It is unclear at this point whether or not this agent will eventually be completely withdrawn from the US market.

Reason for Withdrawal All aerosol drug products intended for inhalation containing trichloroethane. Trichloroethane is potentially toxic to the cardiovascular system and was associated with deaths from misuse or abuse. Formerly marketed as Rezulin, a widely used diabetic drug; it was withdrawn because of its apparent cause of liver failure. Urethane (also known as urethan and ethyl carbamate), formerly marketed as an inactive ingredient in Profenil injection, was determined to be carcinogenic. All aerosol drug products containing vinyl chloride. The inhalation of vinyl chloride is associated with acute toxicity manifested by dizziness, headache, disorientation, and unconsciousness. Formerly used in several aerosol drug products as an antiperspirant, it was associated with human skin granulomas and toxic effects in the lungs and other internal organs of test animals. Formerly marketed as Zomax tablets, it was associated with fatal and near-fatal anaphylactoid reactions.

ing changes and issued a public warning for these potential drug interactions within 5 months of its initial approval. In addition, the sponsor distributed a letter to healthcare professionals warning of drug-drug interactions. In the face of a growing and significant list of drug-drug interactions, and a 3-year international study demonstrating no clinical benefit of mibefradil over placebo for congestive heart failure, the FDA initiated regulatory action. In an unprecedented step for a drug with numerous drug interactions, the FDA then requested that it be withdrawn from the market approximately 1 year after it was approved. The FDA felt that the diversity of drug-drug interactions could not be addressed by standard drug label instructions and additional public warnings.

Clinically Significant Drug-Drug Interactions The cases of terfenadine, astemizole, and cisapride emphasize both the potential for a drug to alter cardiac repolarization as an ADE and also the importance of understanding the metabolism of a drug and the potential consequences of an alteration of the metabolism of that drug. An example of a drug recently withdrawn from the US market because of postmarketing discovery of a plethora of drug-drug interactions is mibefradil (PosicorTM). Mibefradil is a calcium channel blocker chemically unlike other available calcium channel blockers. The drug was approved by the FDA for the treatment of patients with hypertension and chronic stable angina. Clinical research in the United States drug development program began in 1992 with filing of the investigational new drug application with the FDA. The 4-year clinical program concluded with submission of the new drug application in 1996. After 15 months of review, the FDA approved mibefradil for marketing in 1997. At the time mibefradil was approved, information regarding its inhibition of hepatic enzymes of the P-450 system were known and printed on the drug label. The initial labeling for mibefradil specifically listed three drug-drug interactions: astemizole, cisapride, and terfenadine. Inhibition of CYP3A by mibefradil was known to cause accumulation of parent (unmetabolized) drug in the case of these three drugs, leading to an increased risk for cardiac dysrhythmias. During the 1 year that mibefradil was marketed, information began to accumulate regarding drug-drug interactions with many other agents as well. As the in vitro and in vivo drug interaction data continued to accumulate for mibefradil, the FDA made label-

Drugs That Cause Hepatotoxicity Another category of ADE of concern recently is those agents that cause hepatotoxicity. In June, 1998, the manufacturer of the nonsteroidal antiinflammatory drug (NSAID) bromfenac sodium (DuractTM) withdrew this agent from the US market. Clinical trials with bromfenac began in the United States in 1984 with filing of the investigational new drug application. The new drug application was submitted for review to the FDA in 1994 and after 28 months of review was approved in 1997. The drug was introduced into the United States market later that same year but withdrawn approximately 11 months later after postmarketing discovery of significant hepatotoxicity. Although no cases of serious liver injury had apparently been reported during premarketing clinical trials, after introduction to the market a higher incidence of liver enzyme elevation was found in patients who were being treated with the agent. Postapproval exposure of patients to bromfenac was generally for longer time periods than those for which subjects in the clinical trials were treated. Because of a preapproval concern by the FDA that long-term exposure to bromfenac could cause hepatotoxicity, bromfenac labeling specified that the product was to be used for 10 days or less. This dosing limitation appeared to be in conflict with the initial approved drug indication for treatment of a chronic condition (eg, osteoarthritis). Information concerning elevated liver enzymes was actually included in the original product labeling. The postmarketing surveillance of this product identified rare cases of hepatitis and liver failure, including some patients who required liver transplantation, among those using the drug for

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more than the 10 days specified on the label. In February 1998, approximately 6 months after approval for marketing, the FDA amended the drug label for bromfenac sodium with a special “black box” warning indicating that the drug should not be taken for more than 10 days and emphasizing the risk of severe hepatitis and liver failure. The label change was done in conjunction with a required “Dear Doctor” letter to prescribers informing them of this labeling change. Nonetheless, severe injury and death from longterm use of bromfenac sodium continued to be reported, and ultimately, the sponsor agreed to voluntarily withdraw bromfenac sodium from the market. The withdrawal of bromfenac sodium raised several important questions concerning interpretation of “safety laboratories,” such as liver enzymes during the drug development program, and also raised questions concerning the effectiveness of drug labeling. Another example of a drug recently withdrawn for safety concerns related to hepatotoxicity is the oral hypoglycemic agent troglitazone (RezulinTM). Although it was approved in the mid1990s, severe liver toxicity was detected by postmarketing surveillance for troglitazone beginning in 1997. Increasingly serious labeling changes and warnings to prescribers recommending close monitoring of liver function tests in patients taking troglitazone were issued over the next 2 years. In March 1999, an FDA advisory committee reviewed the status of troglitazone and its risk of liver toxicity and recommended continued marketing of this drug in patients with type II diabetes who were not well controlled by other drugs. When two newer agents for type II diabetes, rosiglitazone and pioglitazone, became available, the FDA concluded that the risk profile for troglitazone was significantly worse than these newer agents and then asked the manufacturer of troglitazone to remove the drug from the market.16 Analogous to the example with mibefradil, this FDA-initiated drug withdrawal was based on a change in the risk-benefit profile for the specific agent in light of new safety information discovered during the postapproval phase for the drug. One voluntary withdrawal of two separate drugs used in combination serves as an example of the discovery and publicizing of an unusual adverse event occurring years after individual drug approval but after a significant increase in the prescription use of the combination product. The drug fenfluramine was approved in 1973 after an FDA review period of 75 months. Clinical investigation of a similar agent, dexfenfluramine, began in 1991 in the United States with approval of its IND. The new drug application for this product was filed in 1993, and after 35 months of review the drug was approved for marketing in 1996. A significant increase in prescription use of a combination product of fenfluramine with phentermine (referred to as “fen-phen”) began to occur in the 1990s when clinical data suggested that this drug combination was effective in a weight loss program.35–37 Dexfenfluramine was approved for weight loss as a single agent for up to 1 year of use. Use of the fen-phen drug combination, however, was never fully approved by the FDA and was therefore considered an “off-label usage” of the product. The number of prescriptions for the drug combination soared in the mid-1990s. In July 1997, research from the Mayo Clinic reported 24 cases7 of an unusual form of cardiac valvular disease causing aortic and mitral regurgitation in patients using the fen-phen combination. The publicity surrounding the potential linkage of this drug combination to an unusual adverse event led to a significant increase in reports of possible adverse events associated with this drug combination. The FDA issued a public health advisory and initiated fur-

ther epidemiologic studies in order to ascertain its prevalence. The FDA also encouraged echocardiographic studies of valvular diseases in patients taking fenfluramine or dexfenfluramine either alone or in combination with phentermine. Although at the onset neither the FDA, the product manufacturers, nor the medical community expected valvular lesions to be associated with either fenfluramine or dexfenfluramine, the epidemiologic evidence suggested a possible association, leading the FDA to conclude that these agents should be removed from the US market. The potential association of valvular heart disease with these agents is an example of the use of a case-control study to explore a possible causal relationship between drug exposure and an ADE. In this case, it is unclear what the strength of the MedWatch signal was for the possible association of cardiac valvular disease with exposure to the fen-phen combination. If the association between cardiac valvular lesions and exposure to the drug combination or components of the combination is ultimately proven to be true, however, this would serve as an example of elucidation of a rare, unexpected ADE as the result of a dramatic increase in the number of exposed patients utilizing a product.

ADVERSE DRUG EVENTS CAUSED BY MEDICAL ERRORS Medical therapy results in unintended injury to an estimated 1.3 million people in the United States annually.23 The incidence of adverse drug events (ADEs) has been studied within both the inpatient and outpatient settings. Primarily because of the availability of data, the inpatient setting is more extensively studied. Depending on the method utilized for detection of ADEs, studies have reported an ADE rate of between 2.0 and 6.5 per 100 medical and 100 surgical admissions in certain inpatient settings.3,6 When the upper rate of 6.5% is extrapolated to all hospitalized patients in the United States, the estimated cost incurred as a result of ADEs is a staggering $5.6 million per year for a single 700-bed teaching hospital.4 Half of this $5.6 million, or $2.8 million, was considered a result of preventable ADEs.4 A preventable ADE is one that would not have happened if an error in prescription, dispensing, or drug administration had not occurred. The method for data acquisition can influence the observed rate for studies examining ADEs.30 Automated, computer-based systems generally do not detect as many errors as are found by manual review of hospital charts by a healthcare professional. The number of medications being administered to an inpatient correlates with the potential for the occurrence of ADEs.2 The risk for medication-related errors in the pediatric population has also been studied.22 A rate of nearly five medication errors for every 1000 medication orders is reported in the pediatric inpatient setting.13 The financial impact of all ADEs occurring in the inpatient setting is estimated at approximately $2 billion per year in the United States.4,5 In these estimates, costs that are included are those resulting from an increased hospital length of stay and increased patient morbidity. Costs not included in the estimate are the costs to the healthcare system for malpractice claims or the costs to the patient or healthcare systems incurred after discharge from the hospital. The costs of outpatient drug-induced patient morbidity are also estimated to be considerable in the United States.19 Preventable adverse medical events (not just ADEs) are estimated to be the eighth leading cause of death in the United States.

CHAPTER 117

If this extrapolation is accurate, then deaths from preventable adverse medical events exceed deaths from motor vehicle crashes or AIDS in the United States. A significant number of preventable ADEs result from medical errors. A recent Institute of Medicine report has drawn attention to the large number of medical errors occurring in the United States. In the setting of a tertiary-care teaching hospital, the overall medication error rate was estimated to be 3.13 errors for each 1000 orders written for inpatients. More than one-half of these errors were judged to be significant.24 Medication-related errors are a large and important subset of overall medical errors in that the vast majority of medication-related errors are preventable. The incidence of medication-related errors as a cause of death may be increasing in the United States.21 Recommendations of the Institute of Medicine report include the following: 1. The Congress should create a Center for Patient Safety within the agency of Health Care Research and Quality to set national goals for patient safety, to investigate causes and seek remedies for errors, and to educate. 2. A nationwide mandatory reporting system should be established to provide for the collection of standardized information about adverse events that result in death or serious harm. 3. The development of a voluntary reporting effort should be encouraged by the Center for Patient Safety. 4. The Congress should pass legislation to extend peer review protection to data related to patient safety and quality improvement that are collected and analyzed by healthcare organizations for internal use or shared with others solely for the purposes of improving safety and quality. 5. Performance standards and expectations for healthcare organizations should focus greater attention on patient safety. 6. Performance standards and expectations for health professionals should focus greater attention on patient safety. 7. The Food and Drug Administration should increase attention to the safe use of drugs in both pre- and postmarketing processes through the following actions: developing standards for the design of drug packaging and labeling that will maximize safety in use; requiring pharmaceutical companies to test (using FDA-approved methods) proposed drug names to identify and remedy potential sound-alike and look-alike confusion with existing drug names; and working with physicians, pharmacists, consumers, and others to establish appropriate responses to problems identified through postmarketing surveillance, especially for concerns that are perceived to require immediate response to protect safety of patients. 8. Healthcare organizations and the professionals that affiliate with them should make continuously improved patient safety a declared and serious aim by establishing patient safety programs with defined executive responsibility. 9. Healthcare organizations should implement proven medication safety practices. The committee writing the Institute of Medicine report stated that they recognized that no single activity or recommendation would provide a solution to the medical error problem; however, they suggested that a combination of the activities proposed in the recommendations will provide a roadmap or starting point for a safer healthcare system.21

ADVERSE DRUG EVENTS

1765

THE ROLE OF THE CLINICAL TOXICOLOGIST IN THE DETECTION AND PREVENTION OF ADVERSE DRUG EVENTS Clinical toxicologists include healthcare professionals, such as physicians, pharmacists, and nurses, with a focus on the recognition and treatment of drug- and/or toxin-induced disease. Medical toxicologists are physicians who have recieved subspeciality training in clinical toxicology. Clinical paharmacists are generally Doctors of Pharmacy (PharmD) with comparable advanced training. Clinical toxicologists occupy an important role in ADE detection and prevention. There are at least three main areas in which the clinical toxicologist can have significant beneficial impact. These areas include patient care, education, and administrative functions. In patient care, it is common for the medical toxicologist to be the first medical specialist called to see a patient with a potential ADE. As a result, clinical toxicology occupies an important position as sentinel for drug-induced disease. Maintenance of clinical skills and appropriate continuing education is essential, especially in the area of newly approved therapeutic agents or newly recognized ADEs caused by older approved therapeutic agents. Maintenance of a current knowledge base in the area of therapeutics enhances the ability of the clinical toxicologist to diagnose drug-induced disease. Perhaps more than any other medical specialty, clinical toxicologists are likely to include a thorough medication history that also includes nonprescription products, herbal products, and so-called nutraceutical dietary supplements. As stated previously, obtaining a history for drug exposure is an essential component in attributing an observed adverse medical event to a specific drug product. The clinical toxicologist’s involvement in the clinical arena, especially in settings where the initial diagnosis of ADEs can be made, serves to provide an important role model: the clinical toxicologist is an educator in the specialty to promote the detection and prevention of ADEs. Medical toxicologists occupy many different roles in clinical practice in the United States. An obvious role for the medical toxicologist is as educator in the academic setting of a medical school and affiliated teaching hospitals. Here, the academic toxicologist can champion the inclusion of education in therapeutics in the curriculum for medical school students and residents-in-training and take an active role in the implementation of the instruction. Assuring that the curriculum in therapeutics includes recognition and prevention of ADEs and medical errors that lead to ADEs could have a significant beneficial impact on the ultimate outcome of the education process toward reduction of preventable ADEs. In addition to making sure that quality information is presented in the curriculum for trainees, the medical toxicologist can often create a special teaching opportunity for this type of education by establishing an elective experience or in some instances a required clinical experience in the curriculum for training in therapeutics. Participation in a quality learning experience can significantly impact on the graduates’ knowledge of and attitudes toward therapeutics and risk reduction in the practice of medicine. Although the Institute of Medicine report discussed earlier did not focus on education initiatives in its main recommendations for reduction of medical errors in United States, it seems logical that education be considered one of the major tools to prevent medical errors with therapeutic agents. Education can intervene at the point of initiation by adding emphasis on therapeutics during the education

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process for writers of the prescription. Surveys of medical errors involving therapeutic agents show that a lack of specific drug knowledge is a common cause of preventable medical errors involving medication.22 In the private practice setting, the medical toxicologist sometimes has an opportunity to educate fellows in training in the medical specialty as well as peers who call on them for consultations. In these settings, a consistent approach to the patient that includes the listing of drug-induced disease, drug excess, or potential drugdrug interactions to explain an unexpected drug response can provide an example for one’s medical colleagues. The administrative functions that the clinical toxicologist can perform could also beneficially impact on enhancing detection and prevention of ADEs. The main administrative functions that fall into this category include the reporting of ADEs and hospital or health organization committee service (for example, the pharmacy and therapeutics committee). ADEs are known to be significantly underreported in the United States.15,29,31 Reporting ADEs at the local (hospital) and national level (MedWatch) has been a priority and has been made less difficult administratively. Despite efforts to encourage filing of ADE reports, the overall reporting rates do not appear to have changed significantly. A well-documented, complete report to MedWatch made by a healthcare professional is given priority review by the Food and Drug Administration. The MedWatch system encourages reporting of serious adverse events by all practitioners. Because the clinical toxicologist is likely to encounter a significant number of drug-induced disease cases from a diagnostic standpoint, practitioners of the specialty can make a significant impact on ADE reporting. Clinical toxicologists and their trainees should always submit an adverse event report locally for appropriate cases they encounter. Hospitals generally do not mandate or request that the reported event be “serious” as a requirement. The FDA’s MedWatch system asks that reported events be serious in nature. Manual review of reports and database checks are performed by FDA, and duplicative reporting is accounted for when noted. In addition to reporting of the ADE, the clinical toxicologist should promote publication of case reports of all new adverse events or adverse events occurring with newly approved products. Such publication often stimulates appropriate reporting of ADEs from other practitioners. Service on hospital or healthcare organization committees is another important opportunity for clinical toxicologists to impact on the drug-induced disease problem. Whenever possible, clinical toxicologists should participate in the local hospital pharmacy and therapeutics committee. Often these committees have ADE-monitoring subcommittees where the expertise of the medical toxicologist in diagnosing drug-induced disease could prove beneficial to the organization. These committees systematically analyze trends in ADEs and occasionally recommend various interventions for the medical pharmacy, or nursing staff to reduce the potential risk for ADEs. These interventions include a targeted educational program, system modifications to reduce error risk, or limitation of a specific drug usage by certain components of the organization. Another committee where the toxicologist can have an impact on ADEs and medical error prevention is the quality assurance committee of the hospital or healthcare organization. Careful analysis of medical errors or ADE reports brought to the quality assurance committee can often reveal significant trends that are sometimes amenable to educational initiatives or systematic improvements in process. Again, the medical toxicologist can play an important

role on the committee as a practitioner of clinical medicine with specialized expertise in the potentially harmful effects of drugs.

SUMMARY Drug-induced disease is common in both inpatient and outpatient settings in the practice of medicine. The resulting ADEs have a significant impact on patient mortality and morbidity in addition to producing a significant burden on the healthcare system. ADEs caused by newly approved drugs and ADEs resulting from a previously unrecognized association with therapeutic agents with a long marketing history continue to be a significant cause of mortality and morbidity. The medical toxicology specialty is well positioned to have a beneficial impact toward recognition and prevention of ADEs and medical errors. Early recognition of druginduced disease by the medical toxicologist can benefit the individual patient in many cases and may lead to prevention of further patient harm by prompt ADE reporting to local authorities and, if appropriate, to the FDA. The rapidly expanding number of approved therapeutic agents requires that the medical toxicologist and other practitioners have a strong continuing education commitment to reduce the risk for ADEs and medication errors. Local and national-level involvement by the specialty of medical toxicology to design and implement programs and activities aimed at decreasing the medical error rate and the occurrence of preventable ADEs should benefit patients and, by extension, society.

REFERENCES 1. Alter BP: Bone marrow failure disorders. Mt Sinai J Med 1991; 58:521–534. 2. Bates DW, Cullen DJ, Laird NM, et al: Incidence of adverse drug events and potential adverse drug events: Implications for prevention. JAMA 1995;274:29–34. 3. Bates DW, Leape LL, Petrychi S: Incidence and prevention of adverse drug events in hospitalized adults. J Gen Intern Med 1993;8:289–294. 4. Bates DW, Spell N, Cullen DJ, et al: The costs of adverse drug events in hospitalized patients. JAMA 1997;277:307–311. 5. Classen DC, Pestonik SL, Evans R, et al: Adverse drug events in hospitalized patients: Excess length of stay, extra costs and attributable mortality. JAMA 1997;277:301–306. 6. Classen DC, Pestonik SL, Stanley L, et al: Computerized surveillance of adverse drug events in hospital patients. JAMA 1991;266: 2847–2851. 7. Connolly HM, Crary JL, McGoon MD, et al: Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337: 581–588. 8. Edwards IR, Aronson JK: Adverse drug reactions: Definitions, diagnosis and management. Lancet 2000;356:1255–1259. 9. FDA Talk Paper: “Janssen pharmaceutical stops marketing cisapride in the US,” March 23, 2000. 10. FDA Talk Paper: “Janssen pharmaceutical announces the withdrawal of Hismanal from the market,” June 21, 1999.z 11. FDA Talk Paper: “FDA approves Allegra-D manufactured to withdraw Seldane from marketplace,” December 29, 1997. 12. FDA Talk Paper: “FDA Proposes to Withdraw Seldane Approval,” January 13, 1997. 13. Folli HL, Poole RL, Benitz WE, et al: Medication error prevention by clinical pharmacies in two children’s hospitals. Pediatrics 1987;79: 718–722. 14. Friedman MA, Woodcock J, Lumpkin MM, et al: The safety of newly approved medicines. Do recent market removals mean there is a problem? JAMA 1999;281:1728–1734.

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15. Griffin JP, Weber JC: Voluntary systems of adverse reaction reporting. Part II. Adverse Drug React Acute Poisoning Rev 1986;5:23–55. 16. HHS News, P00–8, “Rezulin to be Withdrawn from the Market,” March 21, 2000. 17. Honig PK, Woosley RL, Zamani K, et al: Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992;52:231–238. 18. Honig PK, Wortham DC, Zamani K, et al: Terfenadine-ketoconazole interaction study, pharmacokinetic and electrocardiographic consequences. JAMA 1993;269:1513–1518. 19. Johnson JA, Bootman JL: Drug-related morbidity and mortality: A cost-of-illness model. Arch Intern Med 1995;155:1949–1956. 20. Kessler DA: Introducing MEDWatch: a new approach to reporting medications and device adverse effects and product problems. JAMA 1993;269:2765–2768. 21. Kohn LT, Corrigan JM, Donaldson MS: To Err Is Human: Building a Safer Health System. Washington, DC, Committee on Quality of Health Care in America, Institute of Medicine, 2000. 22. Koren G, Haslam R: Pediatric medication errors: predicting and preventing tenfold disasters. J Clin Pharmacol 1994;34:1043–1045. 23. Leape LL, Bates DW, Cullen DJ: Systems analysis of adverse drug events. JAMA 1995;274:35–43. 24. Lesar TS, Briceland L, Stein DS: Factors related to errors in medication prescribing. JAMA 1997;277:312–317. 25. Lewis JA: Post-marketing surveillance: how many patients? Trends Pharmacol Sci 1981;2:93. 26. MedWatch Web site: http://www.fda.gov/medwatch/partner.htm. 27. Meyboom RHB, Egberts ACG, Gribnau FWJ, Hekster YA: Pharmacovigilance in perspective. Drug Safety 1999;21:429–447. 28. Monahan BP, Ferguson CL, Killeavy ES, et al: Torsades de pointes occurring in association with terfenadine use. JAMA 1990;264: 2788–2790.

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29. Moride Y, Harambaru F, Requejo AA, Bejaud B: Underreporting of adverse drug reactions in general practice. Br J Clin Pharmacol 1997; 43:177–181. 30. O’Neill RT: Some FDA perspectives on data monitoring in clinical trials in drug development. Stat Med (England) 1993;12:601–608; discussions 609–614. 31. Rogers AS, Israel E, Smith CR, et al: Physician knowledge, attitudes and behavior related to reporting adverse drug events. Arch Intern Med 1988;148:1596–1600. 32. Schwartz J: Is FDA too quick to clear drugs? Growing recalls, sideeffect risks raise questions. Washington Post, A01, March 23, 1999. 33. van Haarst AD, van’t Klooster GA, van Gerven JM, et al: The influence of cisapride and clarithromycin on QT intervals in healthy volunteers Clin Pharmacol Ther 1998;64:542–546. 34. Wallace Laboratories: Express telegram to physicians. Cranbury, NJ: Wallace Laboratories, August 1, 1994. 35. Weintraub M, Sundaresan PR, Madan M, et al: Long-term weight control study (weeks 0–34): The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther 1992;51:586–594. 36. Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study (weeks 34–104): An open-label study of continuous fenfluramine plus phentermine versus targeted intermittent medication as adjuncts to behavior modification, caloric restriction, and exercise. Clin Pharmacol Ther 1992;51:595–601. 37. Weintraub M. Long-term weight control: The National Heart, Lung, and Blood Institute–funded multimodal intervention study. Clin Pharmacol Ther 1992;51:581–585. 38. Wood AJJ: The safety of new medicines: The importance of asking the right questions. JAMA 1999;281:1753.

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118 RISK MANAGEMENT AND LEGAL PRINCIPLES Walter LeStrange / Kevin Porter

The use of emergency services has increased dramatically since the early 1970s, and along with it the number of toxicologic emergencies has increased steadily and continues to rise today. This chapter is concerned primarily with the medical-legal management of patients who present to an emergency department (ED) with an organic impairment, that is, a relatively recent deterioration in the level of cognitive or behavioral function caused by the effects of drugs or alcohol. A secondary component of this chapter addresses the legal dilemmas associated with the social and ethical issues that emergency practitioners routinely face. Patients who are experiencing toxicologic emergencies require immediate care yet are often unable to give consent because their impaired consciousness prevents them from making decisions. Treating patients who present with an acute organic impairment manifested by confusion and irrational, or even dangerous, behavior is extremely difficult. Emergency physicians must recognize the medical-legal problems created when the impaired patient refuses treatment or admission to the hospital and insists on leaving against medical advice. No clear guidelines are available to the physician confronted with such a toxicologic emergency. There is no nationally recognized standard of law relating to these issues; instead, the relevant laws vary from state to state. The emergency physician must become familiar with the legal requirements of informed consent and the essential management necessary to avoid liability for negligence and abandonment. Of particular concern are the risk management and liability issues that relate to the patient who attempts to leave the ED while impaired. The legal requirements of informed consent in emergency settings, the duty to treat, medical malpractice, battery, and negligence are examined here, and guidelines based on generally accepted common law principles, as well as New York State case law and statutes, are suggested for developing appropriate patient care plans and departmental policies.

INFORMED CONSENT A patient who understands the risks and benefits of medical treatment is afforded a legally enforceable right to accept or refuse any treatment that is proposed, by reference to constitutionally protected rights of privacy and control of one’s body. When a determination is made that a patient is capable of consenting to or refusing treatment, the law requires that adequate information be disclosed to patients so that they may comprehend (1) the potential risks and benefits associated with receiving the treatment recommended, in order to make an informed consent to treatment; (2) the potential risks of not receiving treatment, in order to make an informed refusal; and (3) possible alternative treatments and their potential risks. Personal autonomy and self-determination are the two basic principles that provide the foundation for the modern doctrine of informed consent, which requires the practitioner “to

disclose to the patient such alternatives thereto and the reasonably foreseeable risks and benefits involved as a reasonable medical, dental, or pediatric practitioner under similar circumstances would have disclosed, in a manner permitting the patient to make a knowledgeable evaluation.”18 An early landmark case in the evolution of the doctrine of informed consent to treatment is Schloendorff v Society of New York Hospital (1914),21 which upheld the right of individuals to selfdetermination and, therefore, the right to consent to or refuse any proposed treatment. The “emergency doctrine” was first enunciated in the Schloendorff decision to address aspects of the doctrine of informed consent that are problematic when patients are deemed not capable of participating in the consent process. Justice Cardozo’s decision in Schloendorff stated: Every human being of adult years and sound mind has a right to determine what shall be done with his own body and a surgeon who performs an operation without his patient’s consent commits an assault, for which he is liable in damages, except in cases of emergency where the patient is unconscious and where it is necessary to operate before consent can be obtained.21 In the matter of Storar (1981), the Court of Appeals held the right of a competent individual to refuse medical assistance as a matter of law in New York.6 Section 2504 of the New York State Public Health Law gives physicians the authority to treat patients without consent if “the person is in immediate need of medical attention and an attempt to secure consent would result in delay of treatment which would increase the risk to the person’s life or health.”17 As currently formulated, Section 2504 is interpreted to apply under special circumstances. Exceptions to idealized informed consent and the right to refuse treatment include the cases of minors and victims of emergencies for whom delays in treatment while consent is being obtained would seriously compromise the patient’s clinical condition.1 The New York State Public Health Law provides basic guidelines describing the extent of disclosure requirements for a patient. However, disclosure of pertinent information is frequently not possible in the provision of emergency care to the organically impaired patient who has limited or no decision-making capacity. Often the physician’s well-intended efforts to communicate treatment information to the impaired patient prove ineffectual and present the practitioner with a medical-legal dilemma. The physician is unable to discuss in a legally meaningful way the implication of the proposed treatment with the impaired patient; however, there is a duty to treat patients who present with the potential for permanent disability or life-threatening conditions. In these situations, consent on the part of the impaired patient is considered to be implied, and emergency treatment should be provided. Support for this view of implied consent is a general tenet of tort law.16 Im-

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plied consent is manifest by patient action and determined by the emergency nature of the patient’s condition and capacity to consent.

PATIENT REFUSAL AND IMPLIED CONSENT Patient 1 A 34-year-old man was brought to the ED alert and oriented after ingesting 40 to 50 aspirin tablets (325 mg each). He was fully cognizant of the physician’s intent to treat him and initially refused treatment. However, very soon after arrival, his level of consciousness deteriorated and the physician initiated emergency management, including the use of restraints to allow orogastric lavage to be performed with limited patient resistance.

This case raises two important issues. First, the practitioner must question whether or not the patient, although “alert and oriented,” is initially capable of making a decision for himself. Given the history of abnormal behavior manifested by an apparent deliberate overdose ingestion, a reasonable argument could be made that the patient’s judgment is so impaired that his initial refusal of treatment should not be honored. This conclusion must be supported by specific documentation in the medical record of the nature of the ingestion, specific statements suggesting suicidal ideations or attempts (if any), and the patient’s statements and behavior. Where available, a written psychiatric consultation should be obtained. If psychiatric consultation is not immediately available, the emergency physician should use whatever mental health resources are available (eg, social worker) to assist in evaluating the suicidal intention of the patient. Second, this case illustrates how the doctrine of implied consent can be applied to a difficult clinical situation. Patients who present with an altered consciousness are presumed under law to have consented to necessary treatment. The law further assumes that the patient would have consented to the indicated treatment if conscious and able to communicate with his physician. The 34year-old man in this case developed an altered level of consciousness and required immediate intervention, potentially to save his life. By using the legal assumptions in the doctrine of implied consent, the emergency physician is able lawfully to intervene on the patient’s behalf without any consequential risk of potential liability for assault and battery. Documentation describing the patient’s altered level of consciousness would be particularly critical in support of the physician’s determination that the patient’s condition was emergent and justified the physician’s invocation of a specific duty to treat the patient that arises under the law of implied consent. If the facts of this case are altered slightly, a more complex ethical and legal problem may confront the physician. Assume that the same patient was witnessed to have ingested these pills, remains fully cognizant with no observable deterioration, adamantly refuses any medical intervention, and desires to leave the ED. What course of action should the emergency physician follow? The ethical issue is whether a person has the right to commit suicide under any and all circumstances. The legal issue is whether, after you determine that in a particular situation the patient should not be allowed to commit suicide, you have the legal right to intervene. Under such circumstances, a strong argument can neverthe-

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less be made mandating immediate patient care intervention. The medical record should document any statements or actions by the patient suggesting impaired judgment. Further, an accurate and detailed description of this attempt at suicide should be recorded, and the source of this information (family, police, friends) noted in the ED record. If the patient persists in his refusal to accept intervention, the application of physical restraints may be necessary and should be considered, with these actions performed in a timely manner. Such a patient could also benefit from psychiatric consultation, and the hospital chaplain might be utilized as an additional resource in this situation. After restraints are applied correctly (Chap. 115), all appropriate medical interventions can be initiated. To obtain maximal legal protection, the emergency physician must document the reasons for intervention in the specific factual manner described.

FORCIBLE RESTRAINT OF THE IMPAIRED PATIENT Patient 2 A 31-year-old woman who reportedly injected heroin was brought to the ED by emergency medical service (EMS) and became apneic within a few seconds of arrival. On administration of 2 mg of naloxone IV, the patient regained consciousness and demanded immediate release. The patient was fully alert and oriented, with no evidence of hypoxia or other clinical signs to suggest impaired judgment at this particular time. Routine evaluation of the patient’s belongings revealed a small glassine envelope of white powder.

The right of a hospital to retain and physically restrain a person who has an altered level of consciousness for evaluation and emergency intervention is generally well supported by states and case law.4 This case represents a frequent problem that arises when a patient is brought to an ED in an obviously incapacitated or dangerously unstable clinical condition as a result of ingestion of pharmacologic or toxicologic agents and who, after partial recovery, demands to be released from the hospital. In most states, legal precedents for such a situation have yet to be formally established by either written statutes or reported case law. However, reasonably clear guidelines for the management of such impaired patients have evolved from legal precedents governing appropriate medical assessment, from risk management considerations, and from the predictability of patient injury in the event of premature discharge. A staff decision to allow a treated or partially treated patient with a drug overdose who subsequently becomes alert to return to the community must be based on a medical assessment encompassing a number of factors. The initial concern is the patient’s capacity to comprehend. Before the patient can be permitted to leave the hospital, a determination would have to be made that the patient is capable of understanding the information presented and has neither a medical nor a psychiatric problem preventing her from making a voluntary decision. In the case of patient 2, such an assessment cannot be limited to an evaluation of the patient’s statements at the time she is oriented and “apparently capable” only because of the administration of naloxone. In a situation such as this, patients may appear to be alert, demand to be released from the ED, and may even be willing

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to sign the leaving “Against Medical Advice” (“AMA”) or refusal of medical assistance (RMA) waiver that is included as part of many ED records. Under these circumstances, it must be determined whether the ED staff has a legal duty to prevent such an individual from leaving before the patient’s toxic metabolic condition is resolved. Common ED practice and sound legal principles suggest that both the hospital and its staff have a duty to prevent such a person from leaving if the duration of the effect of the involved drugs or toxins is characteristically longer than that expected of the antidote. Patient 2 was brought to the ED in a comatose state after the injection of heroin. Naloxone treatment rendered her temporarily awake and alert. She should not be allowed to leave on demand because the emergency physician can predict with reasonable medical certainty that recurrence of coma or apnea will happen to the patient in the near future. (see Antidotes in Depth: Opioid Antagonists). In other words, if this patient is permitted to leave, her life or health will be placed at significant risk. Such a person could collapse while driving an automobile or lose consciousness in a location where no medical attention is available. A physician who makes a judgment that such an event is probable or likely has a duty to inform the individual of the life-threatening nature of the condition and then to retain, with physical restraints if necessary, the patient in the hospital until “medically cleared.” Liability in this situation is further reduced when the chart substantiates the medical judgment that was the basis for the decision to use restraints and to retain the patient. Such documentation should specifically note the likely relapse of the patient into a symptomatic state and should further state that such an occurrence could place the patient and others in a life-threatening situation. When such documentation is clearly entered on the medical record, legal challenge to the decision to restrain the patient has very limited chance of success. Sound risk management principles support treatment and detainment rather than premature release of the patient. Conversely, prematurely releasing a seriously intoxicated patient exposes both the physician and the hospital to a claim of negligence on the grounds of failure to foresee a likely and harmful event.

RISK MANAGEMENT CONSIDERATION AND DOCUMENTATION Patient 3 6:05 PM. A 28-year-old woman was brought to the ED by the police. The police believed she might be a “bodypacker” (an individual who swallows drugs to avoid arrest and prosecution). 6:10 PM. The triage nurse helped the patient onto a stretcher and brought her to the treatment area. The physician was summoned to see the patient. Her vital signs at that time were: blood pressure 130/70 mm Hg; pulse 78 beats/min; respiratory rate 24 breaths/ min; temperature 36.7°C (98°F). As the physician initiated the examination, the patient became combative and uncooperative. The physician verbally ordered that the patient be restrained. The patient was given 40% oxygen via face mask, cardiac monitoring was begun, and an intravenous line was started with D5W at 125 mL/h; a bolus of 100 mL of D50W and 100 mg of thiamine were then administered IV. Orogastric lavage was then performed, and 50 g of activated charcoal were administered.

7:10 PM. The patient’s vital signs were: blood pressure 120/70 mm Hg; pulse 82 beats/min; respiratory rate 24 breaths/min. The patient was noted to be stable and transferred to the observation unit. Oxygen and cardiac monitoring were discontinued. No further orders were written, and the patient remained restrained. 11:15 PM. The vital signs were blood pressure 110/60 mm Hg; pulse 92 beats/min; respiratory rate 18 breaths/min. A nurse’s note stated that the patient was resting comfortably. 11:50 PM. The initial physician completed his shift and was replaced at midnight by another physician. The first physician informed his replacement that the patient was stable and resting in the holding area. 4:20 AM. The patient was found unresponsive, with agonal respirations. She was hypotensive and had no palpable radial pulse. She felt very hot to the touch and had a rectal temperature of 108°F (42.2°C). Resuscitative efforts were initiated but unsuccessful. 4:50 AM. The patient was pronounced dead.

Several important risk management questions frequently arise in medical malpractice litigation involving the ED. To prove that a case constitutes medical malpractice, a plaintiff’s attorney must show clear and convincing evidence of a departure from good practice by the physician. The attorney must further demonstrate that the negligent act or omission by the physician proximately caused the patient’s injury. Courts have held that where “there is substantial probability that the [defendant physician’s] negligent conduct caused the resulting injury, that sufficient evidence has been developed against [the] physician.”25 The problem issues covered by an improperly documented ED record are numerous, but they can be minimized if the practitioner is cognizant of risk management principles. When the attorney for the patient (plaintiff’s attorney) introduces evidence to prove a case, the central document in the medical malpractice trial is likely to be the ED record. Thus, every entry in that record is scrutinized with great care by both parties (plaintiff and defendants), and the importance of completing it with knowledge of risk management implications should be a concern for all emergency physicians. The emergency physician is required to write a medical record that will amply support the basis for the medical judgments exercised. When a physician chooses to write only a summary statement on the ED record without noting supporting clinical data or patient history, claims alleging failure to diagnose will be extremely difficult, if not impossible, to defend. One of the basic elements of the defense in a medical malpractice case is that the physician’s judgment was appropriate, given the clinical facts and the patient’s history available at that time. Therefore, emergency physicians who do not record supporting clinical data and history deprive themselves of a strong “medical judgment” defense. Inappropriate entries or markings on the medical record can weaken the defense in a liability case. For example, in attempting to correct an error in entering a PO2 value, if the emergency physician or nurse totally obliterates the number, an attorney representing a patient may suggest to the jury that the obliteration was done intentionally to conceal clinical data harmful to the position of the defense. If a physician must correct a prior entry made on the ED record, the preferable method is to draw a single line through the value or word to be changed and insert the correct information directly above and to initial the correction. Dating the correction also precludes potential difficult questions in a courtroom setting. By following these suggestions, the emergency physician avoids

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any accusations that he or she intentionally concealed an error in judgment (Fig. 118–1). A frequent claim is that the patient was abandoned or improperly monitored. For patient 3, although the chart appears to document repeated vital signs at appropriate intervals, no temperature is included after the first set until the patient is moribund; nor is any mention made again of the continued use of restraints, the patient’s continued need for these restraints, or any adverse effects developing from the use of the restraints. Quality assurance reviews of ED records very often demonstrate inadequate charting by physicians and nurses monitoring patients who remain on the ED for prolonged periods of time (longer than 8 hours). Under any circumstances, a lapse of documentation of the patient’s clinical condition for 4 hours or more after the initial physician and nursing assessment creates a potential risk management problem. In a lawsuit the plaintiff’s attorney would undoubtedly use such a record to develop the theory that no care whatsoever was given to the patient during this time interval and that the patient was abandoned. Monitoring notations in the patient’s record are considered inadequate when they offer no insight into the patient’s clinical status. Thus, any monitoring note for a patient who must be retained in the ED for a lengthy period of evaluation, observation, or until an inpatient bed becomes available must include specific clinical data and observations (laboratory results, radiographic findings, hemodynamic changes, and infusion of medications and solutions). All of these deficiencies would undoubtedly be noticed and highlighted at trial by a plaintiff’s expert, who frequently is a physician board-certified in emergency medicine and/or medical toxicology. Any documentation supporting the restraint of an impaired patient against his will must include a clinical description to support such a forcible impediment to the patient’s right to liberty and freedom of movement. Such a clinical description should specifically describe any manifestation of agitation and uncooperative behavior. The record should refer to the specific uncooperative acts of the patient and, most importantly, should comment on the difficulties in providing care to the patient because of the patient’s actions. If such documentation is present, a theory of negligence against the emergency physician for inappropriate restraints would be virtually impossible to sustain. Physicians who order restraints for patients in the ED need to exercise extreme caution in the language used to describe such patients. A judgmental physician’s note stating that a patient is “a chronic drunk and obnoxious” could undermine the support for the use of restraints. Poorly written physician notes can become an issue in a medical malpractice action, with the plaintiff’s attorney focusing on the derogatory nature of such a statement and suggest-

Figure 118–1. Examples of the preferred and an unacceptable procedures for correcting an error in the medical record.

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ing a less-than-caring attitude by the doctor toward the patient. A plaintiff’s appeal criticizing the ethical and social consciousness of the physician could very likely be seized on by a jury and result in a punitive verdict against the physician. As a general rule, all healthcare professionals should depict a compassionate and professional manner by describing patient behavior and life styles in objective and concrete terms. An alternative and more appropriate description of a patient comparable to the one above would note that the patient had a “history of alcohol abuse and was uncooperative and combative.” To summarize, a well-documented ED record consistent with the accepted risk management principles set forth is the best course for the emergency physician managing a difficult overdose situation where legal principles may appear to present problems in providing proper medical management.

BLOOD ALCOHOL AND EVIDENCE COLLECTION Patient 4 A 41-year-old male automobile driver was brought to the ED from a motor vehicle crash in which two other motorists were killed. The patient had no physical injuries and was brought to the hospital because he refused an alcohol breath analysis at the scene. On arrival, he was alert and oriented, responded appropriately to all commands, and demonstrated a normal gait and motor function. The police officers who accompanied the patient informed the ED staff that he was suspected of driving while intoxicated and might be charged with vehicular homicide. The officers then requested that the emergency physician draw a blood specimen to determine blood alcohol concentration. The patient refused to allow ED staff to draw blood for an alcohol determination.

(1) Can blood be drawn against a patient’s will? (2) If the blood is drawn under these circumstances, can the physician be accused by the patient of assault and battery? (3) Do law officers have the right to demand that ED staff obtain specimens against a patient’s will? (4) Could a specimen for blood alcohol concentration be obtained from an obtunded patient, ie, without consent? What are the legal implications? (5) When a specimen is obtained for legal proceedings, what is the appropriate chain for evidence collection? Several of the questions raised by this case involve constitutional issues of significant magnitude. Defendants in criminal trials have claimed that a compulsory blood test obtained under circumstances similar to those above violates the Fifth Amendment privilege against self-incrimination and infringes on the constitutionally protected concerns for human dignity and privacy, as expressed in the Fourth Amendment. However, in 1966, in Schmerber v California,22 in a case involving “an apparently inebriated driver,” the Supreme Court of the United States ruled that blood may be taken from a patient against his or her will if done in the context of a lawful arrest. The decision in Schmerber is extremely important in that it recognizes society’s judgment that blood tests do not constitute an unduly extensive imposition on an individual’s personal privacy and bodily integrity. In explaining its decision, the Court stated:

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In the case of a conscious individual, a chemical test can be administered since he is deemed to have given his consent when he used the highway. It is not necessary that a person be given the opportunity to revoke his consent. The only reason the opportunity is given is to eliminate the need for the use of force by police officers if an individual in a drunken state should refuse to submit to the test.23 In order to ensure compliance with constitutional standards set forth in Schmerber, the states have tailored laws and regulations governing the seizure of blood for the purpose of blood alcohol testing, broadly requiring that the procedure be (1) done in a reasonable, medically approved manner, (2) be incident to a lawful arrest, and (3) be based on the belief that the arrestee is intoxicated. State laws and regulations governing chemical testing for drunk driving generally reflect the strong public interest in protecting the public from potentially dangerous drunk drivers while providing a measure of protection for the physical well-being of the suspected drunk driver. Generally, under state implied consent laws, a person is deemed to have given consent to a chemical test by operating a motor vehicle on a public thoroughfare.24 However, a conscious person is usually given an opportunity to withdraw his or her consent to obtaining a blood sample to avoid the dangerous and volatile situation that can arise with the need for the use of physical force by the police in order to obtain a blood sample.13 Numerous states, including New York and California, allow a patient to refuse a blood alcohol test in circumstances similar to those involving patient 4. However, in order to protect the public from the dangers of drunk drivers, such a refusal to submit to a blood test would probably result in a suspension of the person’s driving privileges. In New York State, for example, the person would be informed by the arresting police officer that his license to drive will be immediately suspended if he refuses to undergo a blood alcohol test, and, in fact, if the person still refuses to submit to the test after being so warned, his license is immediately suspended. The person is then entitled to a hearing concerning the suspension of his license within a period of 15 days and could face revocation of his license for a minimum of 6 months.24 Perhaps the most serious consequence of refusing to submit to a blood test is that such refusal is admissible at a subsequent criminal trial as evidence of consciousness of guilt.12 This statutory approach is similar to the law in many states including California.24 Notwithstanding the relatively standardized approach followed in New York and California, it is critically important that the ED staff be familiar with the specific requirements of the law in the state where the crash takes place. For example, Illinois and Texas both authorize a blood test on an individual such as patient 4 regardless of the patient’s expressed will or refusal. Illinois law governing the administration of blood alcohol tests contains a statutory approach substantially similar to that of New York. However, in a case where a law enforcement officer has probable cause to believe that the individual is under the influence of alcohol and that a motor vehicle driven by, or in actual physical control of, the individual has caused the death of another or injuries to another consisting of severe bleeding wounds, distorted extremities, or injuries requiring an injured party to be carried from the scene, the law enforcement official is authorized to order an involuntary blood test be performed on that individual responsible.15 Texas law governing the administration of blood alcohol

tests is very similar to that of Illinois. Texas authorizes an involuntary blood test to be performed on an individual in a case where a law enforcement officer has probable cause to believe that the individual was driving while intoxicated, was involved in a vehicular crash as a result of driving while intoxicated, and that a person has died or will die as a direct result of the accident.24 Although state laws clearly reflect the interest in protecting people from the danger of death or injury inflicted by drunk drivers, procedural requirements governing the actual withdrawal of blood are concerned with the physical well-being of the person suspected of drunk driving and with adherence to a “chain of evidence” approach. As a general rule, the healthcare professional personally supervising the blood drawing should first make a medical judgment that drawing blood does not put the person at risk.11 In determining whether to comply with the request of a law officer to draw blood for legal purposes, the staff should also consider the possibility of being held amenable to suit. In most states, if the patient consented to a blood test or was unable to refuse consent, any action alleging assault and battery would be unsuccessful. Furthermore, states have statutory provisions that protect those who are authorized to collect blood from liability under these circumstances. In Illinois, “a person authorized to collect blood . . . cannot be held civilly liable for damages when the person, in good faith, withdraws blood . . . for evidentiary purposes under this Code, upon the request of a law enforcement officer, unless the act is performed in a willful and wanton matter.”24 Willful and wanton within the meaning of this section is described in the code as “a course of action that shows an actual or deliberate intention to cause harm or which, if not intentional, shows an utter indifference to or conscious disregard for the health or safety of another.”24 At least one court in Illinois has held that a staff member’s forcible restraint of a patient’s arm was not willful and wanton.20 In Texas, a person authorized to collect a blood sample or the hospital where the blood sample is taken cannot be held liable for damages for complying with the request of a police officer to take a blood sample if the sample was taken according to recognized medical procedures. However, Texas law does not relieve a person from liability for negligence in the taking of a blood sample.24 In New York, a person entitled to draw blood for the purposes of determining the alcohol content therein cannot be sued or held liable for any act or omission while drawing blood at the request of a police officer. However, a patient who may have a cause of action for an act or omission in the course of having his or her blood withdrawn may maintain an action and recover against the state, and the state can then bring an action against the person entitled to draw blood or the hospital employing such person in order to recover the amount awarded the patient.24 In California, the legislature has recognized two conditions that specifically exempt persons from blood tests under the implied consent law and that must be addressed by anyone entitled to draw blood for such testing. The California Vehicle Code specifically provides that persons afflicted with hemophilia or using a prescribed anticoagulant for a heart condition are exempt from a blood test,24 although this is not a medical standard, as blood drawing is performed routinely to assess the success of anticoagulation. Finally, anyone entitled to draw blood for legal reasons should be familiar with and comply with statutory guidelines and/or regulations describing the specific procedures to be followed in the

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withdrawal of blood from a patient suspected of driving while intoxicated. Generally, to admit the results of a blood test into evidence, the prosecution must show that the blood sample was (1) tested by a scientific method acceptable in state court, (2) actually drawn from the suspect, and (3) handled throughout utilizing a proper chain of custody. Compliance with respective state laws and/or state administrative regulations will not only protect against an allegation that the specimen was obtained in a manner deviant from recognized medical procedures but will also further the interests of justice by ensuring the admissibility of a specimen in a later criminal proceeding. In New York, the Vehicle and Traffic Law Section and the New York Code of Rules and Regulations govern methods and procedures for the collection of blood samples. In New York State, only a physician, RN, or RPA may withdraw blood for blood alcohol analysis, or, if acting under the direction and supervision of a physician, a medical laboratory technician, medical technologist, an employee of a clinical laboratory including a phlebotomist, medical laboratory technician, or medical technologist who is competent and acting under the general supervision of a lab director and the personal supervision and direction of a physician. The physician need not physically be present but must authorize the taking of a sample.14 The New York Code of Rules and Regulations also prohibits the use of alcohol or phenol as an antiseptic on the area of skin from which the blood is to be withdrawn and describes the type of equipment that is to be used: either a sterile dry needle into a vacuum container containing a solid anticoagulant or a sterile dry needle and syringe, and the sample must be deposited into a clean container containing a solid anticoagulant, which container shall then be capped or stoppered and identified.23 Similarly, the Illinois Vehicle Code and regulations promulgated by the Illinois Department of Public Health, set forth in the Illinois Administrative Code, provide procedural steps for the withdrawal of blood samples for chemical analysis of alcohol or drug content.5 The Code provides that the blood sample should be collected in the presence of the arresting officer by a physician authorized to practice medicine, a registered nurse, or other qualified person trained in venipuncture and acting under the direction of a licensed physician. The Code also describes the appropriate equipment to be used in the collection of blood samples. Specifically, the Code calls for the collection of two tubes of blood and provides that the skin in the area in which the blood is to be collected should not be cleaned with alcohol or another volatile organic substance.5 In addition to providing a procedure for the withdrawal of blood, the Illinois Administrative Code contains protocol for the labeling of the blood samples and delivery to a laboratory certified by the Department of Health. The Illinois Vehicle Code and Illinois Administrative Code also call for the blood to be tested to determine the concentration of alcohol and/or drugs present by a laboratory method acceptable in a court of law. In Texas, under the Transportation Code, when a person submits to a blood test at the request of a law enforcement officer, only a physician, qualified technician, chemist, registered professional nurse, or licensed vocational nurse may withdraw blood for the purpose of determining alcoholic content, and the specimen must be obtained in a sanitary place.24 In California, the California Vehicle Code specifically provides a list of persons authorized to withdraw blood, and the California Code of Regulations outlines the specific procedures for the taking of a blood specimen.24

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Because the situations described above inevitably occur in EDs everywhere, all emergency physicians should review with hospital counsel the local state laws and regulations governing blood alcohol testing at the request of a law enforcement official, particularly when beginning a new position in a different hospital or state. The laws and regulations vary from state to state and are the subject of frequent restructuring and amendment. The examples provided in this discussion are aimed at illustrating the source of law and some of the approaches to blood alcohol testing in the case of a person suspected of drunk driving.

EVIDENCE COLLECTION Once the blood specimen is obtained, another significant medicallegal task confronts the staff: compliance with the chain of evidence, which can eliminate the risk of nonadmissability of a specimen in a later criminal proceeding. In cases where laboratory results are likely to be used in a court of law regarding criminal conduct, it is essential to establish the appropriate chain of evidence and to process the laboratory specimens in a meticulous fashion. This result may or may not support a charge of driving while intoxicated. First, the specimen must be obtained in full view of a witness. Second, if the hospital laboratory is used to analyze the specimen, the laboratory should be alerted that the specimen is likely to become evidence in a criminal trial. Accordingly, every processing step for that specimen, beginning with the act of collection, each individual test done on the specimen, and transport to and from the laboratory must be documented with the name of the person performing the task. The “chain of evidence” requires that each step in the processing and transport of the specimen be documented without a break in the custody of the specimen. These same requirements apply to specimens for analyses (such as toxicologic testing) sent to an outside laboratory. To ensure the chain of custody from the hospital to the outside laboratory, at the minimum, prudent practice would suggest sending the specimens in a clearly labeled package and obtaining a receipt from the laboratory. Some practitioners have questioned the legality of blood alcohol concentrations when these tests are drawn for another purpose. For example, in a seriously traumatized victim a blood alcohol concentration may be drawn to diagnose or exclude a cause of an altered level of consciousness and altered level of perception. In these cases, the legality of the laboratory value obtained can be questioned. It should be noted that the entire medical record can be introduced as evidence if it is deemed relevant by the court. However, without a chain of evidence, an attorney can challenge the validity of a blood alcohol concentration. Furthermore, the outside laboratory should be called before delivery of the specimen and instructed to document each step in the performance of the required test. Usually, the police department will sign for and assume responsibility for all such specimens taken to an outside laboratory.

DISCHARGING PATIENTS WITH ELEVATED BLOOD ALCOHOL LEVELS Currently in most jurisdictions the legal limit of a blood alcohol concentration (BAC) is 80 mg/dL. Because some number is required to provide an objective standard for the law, this guideline

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may be appropriate to assess legal blood alcohol concentrations, but it is not accurate to determine clinical intoxication or impairment. Patients who chronically abuse alcohol may have baseline alcohol concentrations several times the legal level, yet do not appear to be clinically impaired or intoxicated. Although such patients would be considered legally intoxicated, they do not act this way. Blood alcohol concentrations alone should not be used as the criterion for delaying discharge of such patients from the ED. However, if the patient is known to be operating a motor vehicle, assistance should be obtained from family, friend, or taxi to limit the patient’s use of the motor vehicle. The decision to discharge a patient with a high BAC who is clinically unimpaired should be based on sound clinical grounds. To minimize the liability associated with this decision, the physician should carefully document the patient’s condition. The patient’s motor function and ability to reason should be tested, and the results documented. A detailed discharge summary must document results that reflect the patient’s competency. It is also advised that the physician counsel and caution the patient regarding the health implications of the elevated blood alcohol concentration and risk to self and others in the operation of any type of motor vehicle and document that this advice was given. The physician should initiate the social and psychological support necessary for the patient to seek alcohol detoxification. Following these recommendations minimizes the legal liability of the emergency physician and hospital: the potential for any litigation to be successful is significantly reduced on the grounds of comparative negligence.

report of prehospital personnel should be incorporated into the triage notes. In situations similar to that of patient 5, careful assessment and documentation of mental status is critical because the history offered (IDU) and the clinical findings (odor of alcohol) are highly suggestive of acute and chronic substance abuse. The final component of triage is assessing and recording vital signs. Vital signs should be documented in the appropriate area of the chart, and the time should be noted accordingly. For patients not immediately triaged to a patient care area, vital signs must be retaken at fixed intervals. At these times, patients should also be reassessed, and any change in the clinical condition should be noted. If any deterioration or suspicion of significant changes in the patient’s condition occurs, the patient may need to be recategorized and “up-triaged.” Patients may also improve, and recategorization may occur for this reason as well. A three-category triage system classifies patients as emergent (any life-threatening condition, must be evaluated immediately); urgent (less acute, not life-threatening but may become life-threatening); or nonurgent (no immediate threat) in order to determine the priority of care (Chap. 115).8 Occasionally, the triage professional needs to provide treatment to the emergent patient (eg, oxygen therapy, hemorrhage control, insertion of an airway). In this instance, documentation of emergency interventions and their outcome is required. Careful documentation of immediate interventions provides important information essential to ongoing emergency care and may also be valuable in the defense of a civil lawsuit.

RISK MANAGEMENT CONSIDERATIONS FOR PATIENT TRIAGE, DISCHARGE, AND TRANSFER

Reducing the Legal Risks Associated with Patient Discharge

Patient 5 A 26-year-old male injection drug user (IDU) was brought to the ED after falling in the street and bumping his head. The odor of alcohol was noted on the patient’s breath. He was alert and oriented and denied any loss of consciousness. The patient was evaluated by the triage nurse and then by an emergency physician. A complete physical examination, including a detailed neurologic examination, was performed. The entire examination was normal, and the patient was released.

Essential Components of Triage That Minimize Potential Risk Management Problems Beginning with the initial contact at triage, medical personnel must be extremely observant in evaluating the victim of a head injury. This task is more difficult and more important if the patient has potentially abused illicit drugs, alcohol, or medications. The assessment should be initiated by obtaining a past medical history, including medical problems, allergies, and immunizations. The history of alcohol or substance abuse (acute and chronic) should also be obtained to determine the potential impact on the patient’s clinical presentation, particularly neurologic findings. The chief complaint should be solicited and documented in the patient’s words. A subjective interpretation of a patient’s complaints, particularly in this setting, should be avoided; similarly, a presumptive diagnosis should not be made. Sound medical and legal principles governing triage establish that the nurse and physician must objectively describe findings based on observations and assessment. If the patient was brought by ambulance, the

Detailed criteria for release from an ED serve to protect patients from injury following premature discharge and also to reduce the health care provider’s risk of liability. Such criteria are particularly important for a patient whose mental status might be impaired from alcohol or drug abuse. Sample criteria include giving the patient and/or family members written discharge instructions. Advise the patient to return to the ED if any abnormal symptoms appear or reappear and describe any activities to perform and/or avoid at home (eg, rest, elevation, and ice). Verbal instructions should include followup information regarding prescriptions (eg, adverse effects, impact on driving, medicating schedule) and emphasize the goal of sobriety and desirability of detoxification. Documentation that such written and verbal instructions were given to the patient and that the patient understood them is essential. The patient’s signature, with date and time, should be obtained to indicate that the patient received discharge instructions. However, in cases of head injury and/or intoxication, if discharge is recommended, and the patient is accompanied by family or friends the accompanying individuals should also sign the chart, indicating that instructions were understood. The chart should clearly state the relationship of the family member or friend to the patient. Finally, in any situation in which the ED staff suspect that drugs were utilized, social services, substance use counseling, and/or psychiatric consultation is useful and strongly recommended. Whether the intoxication was a conscious intentional act or unintentional, psychiatric consultation is indicated to ensure safe risk management practices. By doing this, the emergency physician will obtain another objective professional assessment of

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the patient’s ability to make basic decisions about his or her care and to plan for future behavior modification.

Telephone Contact with a Poison Information Specialist

Potential Legal Liabilities Associated with Patient Transfer and Refusal to Treat

As a general rule, any physician who decides to treat a patient enters into a physician–patient relationship that creates well-established legal duties. Courts have ruled that the physician–patient encounter need not be a face-to-face interaction to have legal consequences. For example, the absence of physical contact between a physician and patient as in the practice of radiology and pathology does not preclude a patient from asserting that a duty of care exists.2 More particularly, and quite relevant to the practice of a poison center, a New York State court ruled that an initial telephone call from a patient to a physician can be sufficient basis to hold that physician responsible for inappropriate advice or a significant error in judgment.10 Given the legal precedents previously stated, it is eminently clear that patient contact with a poison information specialist is a sufficient foundation for a subsequent legal action if inappropriate advice was given. In this case, a medical toxicologist could criticize the advice given to the parents. In particular, the recommendation apparently failed to include a directive to seek immediate emergency assistance. The advice to give the child syrup of ipecac was appropriate, but the failure to recommend emergency transport rendered the totality of the advice given substandard and less than the applicable duty of care.

“Patient dumping” increased dramatically as a phenomenon in the 1980s. Patient dumping occurs when a hospital that is capable of providing emergency medical care to a particular patient turns the individual away because of the patient’s inability to pay. Congress enacted the Consolidated Omnibus Budget Reconciliation Act (COBRA), which encompassed the Emergency Medicine Treatment and Active Labor Act (EMTALA), in 1985. This statute was intended to create significant penalties for hospitals and physicians who discharge patients solely for financial reasons. The statute also focuses on patient transfers from EDs to other institutions. It states that “if an individual patient has an emergency medical condition that has not been stabilized, it is unlawful to transfer the patient unless a number of conditions are met.” These conditions are as follows: 1. The physician must certify in writing the professional opinion that the anticipated medical benefits of transfer outweigh the risks. 2. If capable, the patient must consent to the transfer. 3. The sending hospital must assure adequate medical treatment during the transfer to minimize the risks to the patient or fetus. 4. The receiving facility must be notified before the transfer, agree to accept the patient, and have the capability to treat the patient. 5. Adequate medical information, such as a copy of the medical records and/or a well-prepared interinstitutional transfer form, must accompany the patient. Sanctions under EMTALA can be severe. A physician who authorizes an inappropriate transfer is subject to fines of up to $50,000 for each violation. If such an action is found to be “gross and flagrant,” the physician could be excluded from the Medicare and state Medicaid programs. An institution held responsible for a pattern of inappropriate transfers could be suspended or terminated from the Medicare program for violating any EMTALA requirement.7 Therefore, the guidelines concerning documentation of triage decisions, discharge, and transfer must be followed without any deviation to ensure that the acts of an individual will not lead to any institutional or individual liability.

LEGAL CONSIDERATIONS FOR POISON CENTERS AND INFORMATION SPECIALISTS Patient 6 The local poison center received a call from concerned parents regarding the acute ingestion of a full bottle of liquid acetaminophen by their child. The parents were advised by an information specialist to administer 30 mL of syrup of ipecac to induce vomiting. Three days later the baby lapsed into coma, and the parents called the 911 emergency number. An ambulance arrived and transported the child to the local hospital. The child suffered irreversible liver damage. Action was subsequently brought against the local poison center, alleging inappropriate advice and failure to recommend transport to a hospital.

Standards of Care Applicable to Poison Information Specialists Any discussion of the standard of care to which a poison information specialist should be held would be misleading without mentioning several operational aspects of most poison centers. The specialists are required to have rapid and accurate access to a standard information resource system, such as Poisindex, a computerized information source that is updated quarterly and contains both basic information and recommendations to deal with most encountered toxic exposures. Advice that differs significantly from an existing protocol or standard of care will be subject to critical review in a civil lawsuit. If a patient were to bring an action, the negligence theory against the poison center might rely particularly on deviations from the standard recommendations. It would be inaccurate to suggest, however, that the duty of care owed by a poison information specialist can be measured only by how closely the advice given compares with the standard resources. Frequently, a specialist may encounter situations that cannot be managed in accordance with an information system alone, and the poison information specialist should seek counsel from a doctor of pharmacy or physician consultant working with the poison center. If this were to occur, any subsequent legal proceeding would also review carefully the content of the input given by the consultant as to its accuracy and appropriateness to the underlying toxicologic problem.

Practices of Regional Poison Centers that Can Reduce Potential Liabilities Clearly there are some inherent risks of potential liability for a poison center. To minimize such risk and the risk of civil actions against a poison center, quality assurance and risk management programs should be a regular function. Usually regional poison centers practice this routinely. Daily physician audits or monitoring of the advice given by poison information specialists should be

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done. Such interactions enhance care and ensure patient safety for the individual and establish a higher general standard. The medical toxicologists and clinical pharmacists responsible for supervising the poison information specialist must be able to adequately assess the competence and capabilities of the staff and to make recommendations, take corrective actions, and provide suggestions for improvement to involved members. Both individual case audits and departmental committee review of complicated toxic ingestions should be addressed, evaluating the quality of poison information specialist documentation. The medical toxicologist must assess the adequacy of the patient history obtained and should pay particular attention to the written documentation of advice given. In the event of a lawsuit, the most likely area of dispute will be what was actually said to the patient. In a case similar to that of patient 6, a patient might be told by the poison center to seek immediate emergency help from a physician or ambulance service but choose not to follow this advice, with poor outcome or disastrous consequences. The failure of the poison information specialist to document such advice meticulously could lead to a significant credibility issue in subsequent litigation. If the patient’s lawyer knew that such specific documentation were lacking, then a likely claim in the lawsuit would be that the advice was not actually given.

IMPLICATIONS OF LIVING WILLS, DO-NOT-RESUSCITATE ORDERS, ADVANCED DIRECTIVES, AND PHYSICIAN-ASSISTED SUICIDE FOR PATIENTS WITH DRUG OVERDOSE OR TOXIC INGESTION Patient 7 A 75-year-old unresponsive man was brought to the ED by EMS. He reportedly had ingested a large quantity of phenobarbital. The patient was well known to the medical center staff and had been previously diagnosed as having metastatic prostate cancer. The ED staff suspected that the patient had completed a living will and explicitly requested that no advanced life support and resuscitation be utilized. On arrival in the ED, the patient was hypotensive with a blood pressure of 80/40 mm Hg, a pulse of 80 with normal sinus rhythm, a respiratory rate of 4 breaths/min, and a rectal temperature of 96°F (35.6°C). Naloxone, dextrose, and thiamine were immediately administered with no response; an endotracheal tube was then inserted, and ventilation with 100% oxygen was provided. Orogastric lavage was performed, and activated charcoal was instilled before removal of the lavage hose. Despite the administration of 2 L of lactated Ringer solution, his systolic blood pressure remained at 80 mm Hg, and a dopamine infusion was started. Neurologic examination at the time revealed fixed and dilated pupils with absent corneal and oculocephalic reflexes. The patient was transferred to the MICU for further management.

(1) Should this patient be resuscitated? (2) What is the implication of a living will for a patient who has intentionally ingested a drug overdose? Advanced directives, a living will, or a healthcare proxy (a document that transfers to an agent the right to make lifeand-death decisions for an impaired patient) are considered to be

legally binding when a patient presents with symptoms from a naturally occurring disease process. It is not the intent of any state to use these documents to assist a patient who has attempted to commit suicide. (Revisions of state law have been established in Oregon.) Such a view would be considered violative of public policy. A decision in this instance cannot be made simply by reference to the patient’s intentions as individually expressed in a living will or by the designated agent in the healthcare proxy. The regulatory authorities in most states (living will and healthcare proxy statutes are regulated by state health departments) would probably indicate that the patient should be resuscitated in this situation because of society’s position that a physician should not assist in a suicide attempt. In view of the current debate in the medical, legal, and ethical literature with regard to euthanasia in controlled and stateapproved circumstances, the approach to this hypothetical case may very well be different in different locations in the future. This area of law and ethics is evolving at a rapid and variable pace throughout the individual states. The issues regarding physician-assisted suicide and the circumstances under which it is permissible were left ambiguous by a 1997 United States Supreme Court decision. Ethicists have taken strong positions on both sides of this controversial issue, and a clear understanding of the controlling law in this area remains to be elucidated. Accordingly, this is an issue that ED practitioners will have to monitor closely as individual state governments and health departments create regulations. One of the arguments asserted by those in the medical community supporting physician-assisted suicide is that patients experiencing extreme suffering with no possible amelioration by medical means are a protected class and should be granted equal protection under the constitution. Whether or not this view will prevail is highly uncertain at this time. EDs should routinely incorporate discussions of these issues into their educational programs.

INTOXICATION AND PATIENT CONFIDENTIALITY Patient 8 A 52-year-old man was seen by his general practitioner during his lunch hour for the complaint of recurring headaches. The patient was the local school bus driver in a small rural community. The physician believed that the patient was intoxicated and noted the odor of alcohol on his breath. The patient was well known and respected throughout the community. The physician confronted the patient with his suspicion, and the patient adamantly denied alcohol use. The physician requested permission to draw blood tests, including a blood alcohol level. The patient refused and threatened to sue the physician if he reported his suspicions.

(1) Would the release of information regarding the physician’s suspicions constitute a violation of patient confidentiality? (2) Do the facts of this case present a public policy exception to the patient’s rights of confidentiality in light of the general societal need to protect the safety of passengers and children? This case presents a dilemma that occasionally confronts every practitioner. As a first point it must be emphasized that any release of patient information to an individual or agency not involved in the patient’s care (school authority or supervisors) would clearly be a technical violation of the normal patient confidentiality re-

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quirements. However, the facts in any particular case may create an exception to the normal rules governing the release of patient information. In this case, a convincing and compelling argument could be made that public policy mandates practitioners to advise school authorities of the bus driver’s potentially intoxicated condition. This position could be taken in the interest of preserving life and safety of children who might ride on his bus at a time when he became impaired. If the bus driver chooses to bring a lawsuit against the practitioner and hospital on the grounds that he had lost his job because of the unauthorized release of medical information, such a case could be well defended with the public policy arguments just given. There is little likelihood of success of such a lawsuit. These principles would apply to any scenario involving an individual who is responsible for public safety (eg, train conductor, airline pilot, police officer). A more complicated situation arises if the patient does not appear to be intoxicated but the physician smells the odor of alcohol on the patient’s breath. In this case the physician may be less willing to report his or her suspicion because of the seriousness of the accusation and the degree of uncertainty regarding the extent of alcohol use. Despite this dilemma, the highest ethical standards suggest that the physician has a duty to protect society and to report any suspicions to the appropriate authority.

IMPLICATIONS FOR EMANCIPATED MINORS, CHILD ABUSE AND NEGLECT, AND THE UNBORN FETUS Patient 9 A 17-year-old woman presented to the ED for altered mental status. Physical examination revealed an obviously pregnant young woman with a blood pressure of 150/100 mm Hg, pulse of 140 beats/min, respiratory rate of 30 breaths/min, and rectal temperature of 101°F (38.3°C). Her skin was diaphoretic, and her pupils were 6 to 7 mm and reactive to light. The remainder of her evaluation was unremarkable except for a 28-week size uterus with strong fetal heart tones. After receiving 20 mg of Valium IV, the patient’s vital signs normalized, and she admitted to frequent crack cocaine use. She had no prenatal care and was not married. Her 2year-old child was brought in from home by the police for evaluation. The ED received a telephone call from the patient’s grandmother (the legal guardian) inquiring about her condition. The patient indicated that she did not want her grandmother to know about her admission or pregnancy.

(1) Can the physician accept the patient’s wishes not to inform the grandmother of her medical condition? (2) Is the patient an emancipated minor capable of making her own consent for treatment? (3) What is the responsibility of the ED staff when confronted with a patient who refuses to obtain needed social service help for his or her child? (4) Can the hospital and the ED staff compel this patient to go for routine prenatal care in the obstetric clinic? Many states have guidelines that protect the confidentiality of adolescent patients seeking obstetric and gynecologic healthcare. Despite the wishes of this young patient to keep her status confidential, a delicate balance must be considered when the emer-

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gency physician is confronted with an impaired adolescent who is pregnant or who is the mother of a small child. In the case above, societal concerns and sound hospital policy suggest that the grandmother should be fully informed of the patient’s medical condition. There are several reasons for this conclusion, and one controlling factor in this decision is the state’s interest in insuring the protection of a small child. When balanced against this overriding ethical concern, the patient’s desire for confidentiality cannot be met. The legal doctrine of emancipated minor varies somewhat in different states, but the general definition is consistent and quite similar throughout the United States: If an adolescent patient lives apart from her parental home and is pregnant, then such a grouping of factual elements would constitute emancipated minor status in virtually all states. If this patient was not impaired by cocaine or some other drug or substance of abuse, then she would have a legal right to make decisions about her healthcare in all respects. However, her ingestion of crack cocaine permitted the ED staff to treat her despite her protestations because of her present inability to fully comprehend the implications of her actions. As noted in Chap. 114, the patient’s impairment must be documented as to specific clinical symptoms. Statutes in all states require the ED staff (often as a mandated reporter) to inform the designated state authorities when child abuse or neglect is suspected. The 2-year-old in the above case should not be permitted to leave the ED under the care of this young patient/mother because the expanded definition of neglect in most state statutes would preclude disposition at this stage of care. The appropriate course of action for the ED staff includes the provision of maximum support for this potentially imperiled child. A social worker should assist with an assessment of the home situation. It is often beneficial if the social worker (a child abuse specialist) speaks to the state authorities in addition to the ED staff. In this example, a possible resolution that is minimally disruptive to the child’s well-being might be placement with the grandmother. This should be done only with the approval if the state child abuse authority. If the hospital and ED staff seek to compel this patient obtain outpatient care in the obstetric clinic, some form of court intervention would have to be sought. As a rule, the courts have been reluctant to compel care of the fetus on the grounds of abuse and neglect despite behavior by the mother harmful to the prospects for the child. However, a case plan that includes close followup of the adolescent mother’s condition by an in-hospital child abuse interdisciplinary team in conjunction with a child welfare agency that has jurisdictional responsibility for the adolescent’s care is probably the optimal method to achieve a coordinated solution to this difficult ethical and medical problem. There are times when a court order is not effective and a more appropriate solution may be the intervention of a child welfare agency.

HEALTH INSURANCE AS A BARRIER TO DRUG AND ALCOHOL SCREENING IN TRAUMA PATIENTS Patient 10 A 25-year-old unrestrained man was involved in a motor vehicle crash and was ejected from the automobile. He was brought to the ED via EMS immobilized and intubated. He had signs of head trauma, was responsive to verbal commands, had no sen-

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sory or motor response from the neck down, and had minimal shoulder shrug. Radiographs revealed a C5–6 fracture. It is likely that the patient has suffered a permanent spinal injury and will require long term hospitalization and rehabilitative care.

This crash occurred in a state where insurance companies are not required to reimburse claims when alcohol or drugs are involved. By statute a majority of US states do not consider the insurer liable for any loss sustained or contracted in consequence of an insured person who is intoxicated or under the influence of any controlled substance unless prescribed by a physician.9,19 In the past year, this hospital has had three claims for extensive hospitalization and numerous procedures denied for trauma patients on these grounds. The ED did not have a policy requiring blood and alcohol levels on all trauma patients, and therefore the ED physician followed the administrator’s advice and did not obtain the indicated blood alcohol levels. Studies repeatedly demonstrate that 40 to 50% of all patients admitted to level I trauma centers have positive blood alcohol levels at the time of injury. No-fault insurance has a maximum allowable coverage in the range of $50,000.00. For this patient, it is likely that $50,000.00 would be exhausted in the first month of care, and then the patient’s standard health insurance would be applied to the extended hospital stay. (1) Does insurance law allow insurance companies to refuse benefits to trauma patients who are legally intoxicated or have ingested an illegal substance? (2) What are the legal and ethical implications for physicians if they adhere to administrative directives and fail to take blood alcohol levels when clinically indicated? (3) If the medical record has been subpoenaed, can the patient cite “patient confidentiality” and avoid a release of his medical record? Because most states permit insurance companies to refuse benefits to trauma patients for injuries that involve the patient’s use of alcohol or controlled substances, concerns about the effect of screening for alcohol and narcotics on insurance coverage are valid.19 Thus, the trauma victim who presents in the ED not only may pose a challenge in terms of medical management but also may create an administrative dilemma that encompasses legal, ethical, and professional concerns. Such policies can influence institutional and physician behavior and lead to administrative directives or mandates requiring that the emergency physician not take a blood alcohol level even though such a test is clinically indicated. Further, although federal confidentiality regulations protect clinical records of patients participating in drug and alcohol abuse programs, there are no such barriers to disclosure in the case of the ED patient who is both impaired and a trauma victim. Information about acute and chronic alcohol use is gathered as a part of the history taken at the time of the ED admission, and it is appropriate for the ED staff to seek such information to determine its effect on treatment and outcome. Under such conditions, the information obtained would be exempt from the special federally created laws regarding patient confidentiality. In regard to this legal and ethical dilemma for the practitioner, several comments may help the emergency physician provide appropriate care to this patient. The ED physician’s first duty is to the patient and not to a vague, off-the-record administrative directive that does not have a basis in institutional policy and procedure. Further, such a policy would not be deemed consistent with good and accepted department medical practice, nor would it be

sanctioned by applicable law. An emergency physician who chooses not to draw a clinically indicated blood alcohol level to protect hospital reimbursement would likely be deemed unethical by the state licensing board. Additionally, if such a fact pattern were presented under a theory of medical malpractice, it is likely that a plaintiff’s attorney would have little difficulty in obtaining an expert with board certification in emergency medicine or medical toxicology who would criticize such action. A number of questionable or illegal “creative” administrative procedures have been offered to prevent disqualification of impaired trauma patients from insurance coverage. One such administrative mechanism involves obtaining blood alcohol levels on a “John Doe” basis, allowing the practitioner to utilize the clinical data without recording a level in the patient’s record. This is a dangerous practice for a number of reasons. A subsequent provider of care in the same hospital may not be aware of the “John Doe” practice and therefore may not take into consideration the elevated blood alcohol in the subsequent care and treatment. Further, any attempt to obtain reimbursement for treatment could subject the hospital and perhaps the physicians involved to charges of fraud and/or filing of a false claim. For these reasons, such a procedure cannot be recommended.

THE JEHOVAH’S WITNESS REFUSAL TO ACCEPT TREATMENT A comprehensive review of medical-legal issues must always include a discussion of the care of the patient who is also a Jehovah’s Witness. Although religious and legal issues rarely are relevant in toxicologic emergencies, the rights of a patient who is also a Jehovah’s Witness is a subject worthy of a detailed discussion. This analysis may allow for a thoughtful review of toxicologic issues. The most common problems involving a patient who is a Jehovah’s Witness is the patient’s refusal to receive transfusions of any blood or blood products regardless of the indications. Three variations of this scenario have been discussed in legal briefs: 1. A conscious patient who understands the risks and benefits of medical treatment requires emergency transfusions. The patient refuses all transfusions and risks death as a consequence. 2. An unconscious patient arrives in an ED and requires emergency blood transfusions to sustain life. Family members accompanying the patient inform the staff that the patient is a Jehovah’s Witness, and they refuse to consent to any blood transfusions. 3. The parents of a child requiring emergency transfusions to sustain life refuse to allow blood to be given to their child on the grounds of religious beliefs. A serious legal and ethical dilemma occurs when an individual who understands the risks and benefits of medical treatment refuses the treatment necessary to save his or her life. Numerous case decisions have involved this issue. The courts generally agree that a competent individual has a constitutional right to refuse medical treatment. Refusal to accept life-saving treatments, or in this case blood transfusions, is supported by the fact that every individual is entitled to bodily integrity and privacy. In fact, in the landmark case of Fosmire v Nicoleau, New York’s highest court,

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the State Court of Appeals, ruled definitively that the state’s interest in preserving an individual’s life cannot override the individual’s right to refuse life-saving medical treatments.3 This constitutional right is not specific to any particular religious belief. The courts have had to struggle with the question of how to deal with the parent of a small child who is refusing blood transfusions for himself or herself. In such cases, the court has generally decided that the rights of the parent (patient) must be protected even though the individual has responsibility for minors or children. In most cases, the individual’s right to refuse treatment is protected under the First Amendment if it is linked to a religious objection or, in the absence of a religious objection, may be linked to the fundamental right of privacy for everyone. One of the most difficult situations created by patients who are Jehovah’s Witnesses arises when the patient is unconscious and requires emergency blood transfusions, and accompanying family members refuse to sign consent for transfusions. Under these circumstances the physician must immediately determine whether the patient’s illness is emergent (life threatening), urgent, or nonurgent (not life threatening). In emergent cases, particularly when there is inadequate time to make a detailed assessment, the physician has a duty to treat the patient immediately. This premise is the same as the principle of implied consent discussed with respect to patient 7. Immediate action rarely creates any significant liability, whereas delays and deliberations followed by negative outcomes can carry enormous liability. If the case is not emergent, the emergency physician should verify the family’s request, provided that this delay will not jeopardize the patient’s condition. The family should be given an opportunity to provide clear and convincing evidence that the patient would have refused transfusions or other medical interventions. The most difficult situation of all arises in cases of minors or children whose competent guardian or parent refuses to allow medical treatment for the child. In such a case, virtually all states invoke the parens patriae doctrine, which permits the state to protect its citizens who are unable to protect themselves. This doctrine has been upheld in many cases by not allowing Jehovah’s Witness patients to refuse the transfusion of blood products into their children. The emergency physician must be mindful of several communication issues when administering transfusions to a child in such circumstances: The parents or guardians must be told that a transfusion is anticipated and that the hospital will proceed on the basis of state law. A progress note must be entered into the chart documenting the time of transfusion, the medical necessity of the transfusion, and the details of conversation(s) with the parents; obtaining a court order to administer blood transfusions to a child in a life-threatening circumstance is not required and therefore must not delay emergency treatment. An emergency physician who is confronted with a life-threatening refusal of blood products by a patient who is also a Jehovah’s Witness should work very closely with the risk management staff of the hospital. Legal advice should always be sought when possible to ensure that all risk management concerns are addressed.

SUMMARY The risk management and legal issues of an active emergency department have implications for many patients. The ability of providers to function responsibly is dependent on an understand-

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ing of these ever-evolving principles. Those patients whose consciousness is abnormal because of a toxin represent an acute complex medicolegal emergency. A well-organized hospital is dependent on a close working relationship among the legal, risk management, and medical personnel. Only in this manner can they learn, cooperate, and meet the needs of the ever-evolving clinical dilemmas they confront.

ACKNOWLEDGMENT To Mr. Frank Sanotoro, who assisted in the research for parts of this chapter.

REFERENCES 1. Borak J, Veilleux S: Informed consent in emergency settings. Ann Emerg Med 1984;13:731–735. 2. Capuano v Jacobs, 33A.D., 2d. 743, 305 N.Y. State, 2d 837 (1960). 3. Fosmire v Nicoleau, A.D., 2d. 876, 551 N.Y. State (1990). 4. Gonzalez v State, 110 A.D., 2d. 810, 488 N.Y. 2d. 231, 67 N.Y. 2d. 647 (1985). 5. Illinois Administrative Code 77, Chapter 1, subchapter f, Section 510.110. 6. In the Matter of Storar, 52 N.Y. 2d 363, 377 (1981). 7. Krugh T: Medical COBRA: The federal anti-dumping act. For the Defense 1992;June:14–16. 8. New York City Health and Hospitals Corporation, Bellevue Hospital Center: Policy and Procedure Manual for Emergency Services, 1993. 9. New York Insurance Law §3216 (d) (2) (K); California Insurance Code §10369.12; 215 Illinois Consolidated Statutes 5/357.25. 10. O’Neil v Montefiore Hospital, 11A.D., 2d 132, 202 N.Y. State, 2d 436 (1960). 11. People v Ebner, 195 A.D.2d 1006, 600 N.Y.S.2d 569 (4th Dept 1993); but see People v Moser, 70 N.Y.2d 476, 522 N.Y.S.2d 497, 517 N.E.2d 212 (1987). 12. People v Ferrara, 158 Misc. 2d 671, 602 N.Y. (Richmond Cty 1993); People v Rosado, 158 Misc. 2d 50, 600 N.Y.S. 2d 624 (Bronx Cty 1993). 13. In New York, People v Kates, 53 N.Y.2d 590, 444 N.Y.S.2d 446, 428 N.E.2d 852 (1981); In California, see Hughey v Department of Motor Vehicles, 1 Cal.Rptr.2d 115, 235 Cal.App.3d 752 (App. 3 Dist. 1991). 14. People v Olmstead, 649 N.Y.S.2d 624 (4th Dep’t 1996). 15. People v Ruppel, 303 I11. App.3d 885,237 I11. Dec. 21, 708 N.E.2d 824 (4 Dist. 1999); 625 ILCS 5/11–501.2 (c) (2) (3). 16. Prosser WL: The Law of Torts. St Paul, West, 1984. 17. Public Health Law Section 2504(4). McKinney’s Consolidated Laws of New York Annotated book 44, public health law sections 2100–3399. St. Paul, West, 1985. 18. Public Health Law, Section 2805 (d) (1). McKinney’s Consolidated Laws of New York Annotated, book 44, public health saw sections 2100–3399. St. Paul, West, 1985. 19. Rivara FP, Tollefson S, Tesh E, Gentilello LM, Screening trauma patients for alcohol problems: are insurance companies barriers? J Trauma 2000;48:115–118. 20. Ruppel v Ramseyer, 33 F.Supp. 720 (C.D.I11. 1999) 21. Schloendorff v Society of New York Hospital, 211 N.Y. 125, 105 N.E. 92, 93 (1914). 22. Schmerber v California, 384 US 757, 16L ed 2d. 908, 86 Sct 1826 (1966). 23. Title 10 of the New York Code of Rules and Regulations Section 59.2. 24. In New York, under the Vehicle and Traffic Law, “any person who operates a motor vehicle is considered to have consented to a chemical test of breath, blood, urine or saliva for the purpose of determining alcoholic and/or drug content, provided that such test is administered

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at the direction of a police officer.” N.Y. Vehicle and Traffic Law §1194 (McKinney’s Consolidated Laws of New York, Annotated, book 62A, vehicle and traffic law sections 600ff St. Paul, West, 1996). In Illinois, under the Illinois Vehicle Code, “Any person who drives or is actual physical control of a motor vehicle upon the public highways of this State shall be deemed to have given consent . . . to a chemical test or tests of blood, breath, or urine for the purposes of determining the content of alcohol . . .” 625 ILCS 5/11–501.1. In Texas, under the Transportation Code, “if a person is arrested for an offense arising out of acts alleged to have been committed while the person was operating a motor vehicle in a public place . . . while intoxicated,

the person is deemed to have consented . . . to submit to the taking of one or more specimens of the person’s breath or blood for analysis to determine the alcohol concentration. . .Tex. Transportation Code Ann. § 724 (Vernon 1991). In California, under the Vehicle Code, “any person who drives a motor vehicle is deemed to have given his or her consent to chemical testing of his or her blood or urine for the purpose of determining the alcoholic content of his or her blood. . .” Cal. Vehicle Code §23612 (West 1996). 25. Vialva v City of New York, 118 A.D., 2d. 701, 499 N.Y. 2d. 977 (2nd Dept. 1986).

CHAPTER

119 POSTMORTEM TOXICOLOGY Rama B. Rao / Mark Flomenbaum

Postmortem toxicology assists in understanding the physiologic and biochemical effects of a xenobiotic at the time of death. A pathologist initiates the first investigative step by collecting specific fluid and tissue samples at autopsy. Several variables may cause quantitative changes in xenobiotic concentrations from the time of death to the time of autopsy. In addition, other artifacts may affect the interpretation of the clinical effects of the xenobiotic identified. The identification and understanding of xenobiotic-related deaths has significant public health consequences. The forensic pathologist may be the first to identify and report critical information regarding rare fatal drug reactions, medication errors, or rapidly fatal epidemics associated with illicit drug use. As in the case of occupational and environmental xenobiotic-related fatalities, interventions can be implemented to prevent subsequent morbidity and mortality. In addition, the pathologist describes gross and microscopic autopsy findings that may elucidate mechanisms of xenobiotic toxicity, enhancing knowledge that may affect clinical practice. Using multiple sources of information (Table 119–1), forensic pathologists attempt to establish cause and manner of death. Cause of death is the physiologic agent or event necessary for death to occur. For example, the presence of cyanide in the toxicologic evaluation may be sufficient to establish cardiorespiratory arrest from cyanide poisoning. Manner of death distinguishes natural from nonnatural deaths. Nonnatural deaths, depending on the jurisdiction, can be divided into several categories (Table 119–2). With the identification of cyanide, the manner of death cannot be considered natural. The medical examiner must make the best determination of the manner of death based on available evidence.79,85 The consequences of manner of death are far reaching. Homicide necessitates involvement of law enforcement officials for further investigation. Cases deemed suicide not only impact survivors psychologically but also may nullify life-insurance payments, whereas a case deemed an accident may have a double-indemnity insurance clause. Liability suits in workplace disasters may be similarly affected if illicit drugs are identified in the postmortem specimens of involved workers. Postmortem toxicology can be used in other investigations as well. For example, when carboxyhemoglobin is identified in the human remains of airplane crashes, a cabin fire before descent is more probable than a fire on impact. This type of postmortem analysis is useful in reconstruction of events leading to the crash.5,44,50 Techniques for detecting certain compounds in postmortem tissue were developed in the early 19th century and generally fo-

cused on identifying heavy metals as a cause of death in homicides.34,58,60,75,78,79 As the field of forensic pathology developed, laboratory technology progressed rapidly, allowing for more refined qualitative and quantitative identification of xenobiotics. The interpretation of postmortem xenobiotic concentrations, however, is an evolving field. This chapter reviews factors affecting xenobiotic concentrations identified on autopsy and discusses subsequent models for interpreting postmortem toxicologic reports.31,33,38–40,46,54,62,65

THE TOXICOLOGIC INVESTIGATION Ordinarily, toxicologic samples are collected as part of a complete autopsy. In the hospital, when a death is assumed to be from natural causes, the hospital pathologist may perform an autopsy with consent of the family. The medicolegal autopsy, however, is performed in a medical examiner’s office by a forensic pathologist. These autopsies are done in cases in which the manner of death is either unknown or other than natural. When consent for a complete autopsy is not obtained from the family, and the medical examiner decides that a full autopsy may not be necessary, only fluid samples are obtained for analysis. The sampling of fluid and tissue may be obtained minutes to years after death. The postmortem interval, defined by the state of bodily decomposition, can vary depending on environmental conditions such as ambient temperature, humidity, and immersion under water.51 Samples may be collected during advanced stages of decomposition or even after embalming or in exhumed bodies.4,35,61

DECOMPOSITION AND POSTMORTEM BIOCHEMICAL CHANGES In the first stage of decomposition, autolysis, endogenous enzymes are released, and mechanisms maintaining cellular integrity fail.45 Chemicals move across leaky membranes down relative concentration gradients. Glycolysis continues in red blood cells until glucose is depleted, and lactate is produced. Ultimately, intracellular ions and proteins are released into the blood, and tissue and blood acidemia develops (see Table 119–3).79 The next stage of decomposition, putrefaction, involves digestion of tissue by bacterial organisms. Typically these bacteria originate in the bowel or respiratory system. Later other organisms may be introduced by insects or other external sources. As the pu-

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TABLE 119–1. Artifacts and Information Affecting Postmortem Toxicologic Interpretation Xenobiotic dependent Pharmacokinetic considerations State of absorption/distribution at time of death Postmortem redistribution Postmortem metabolism Pharmacodynamic considerations Expected clinical effects Synergistic interactions Postmortem xenobiotic stability during Putrefaction Preservation Previously published tissue concentrations Decedent dependent Comorbid conditions Tolerance Pharmacogenetic differences Autopsy Dependent Postmortem interval (state of decomposition) Undiagnosed conditions Sample specimens Sample sites Handling and preservation Other Laboratory techniques Evidence at scene Chain of custody

trefactive process progresses, gases may form, causing foul odors and bloating.79 If death occurs in a very warm, dry climate, such as a desert or comparably arid environment, the body may proceed to desiccate so rapidly that putrefactive changes may not occur. The result, mummification, produces a lightweight cadaver with a tight, dry skin enveloping a prominent bony skeleton.79 If the environment is very cold and hypoxic, such as at great depths under water, putrefaction will be slowed. Anoxic decomposition of fatty tissues occurs, forming a white, cheesy material known as adipocere. Another phase of decomposition, anthropophagia, occurs in unprotected postmortem environments where insects or other animals feed on the tissue remnants.79 Most morgue refrigerators achieve low enough temperatures to prevent the postmortem interval from progressing. Another factor that may alter or interfere with the natural decompositional changes is embalming. This process preserves dead tissues and can be performed by a variety of techniques. Typically, blood is drained through large vessel pumps, and a substance is injected intravascularly to perfuse and preserve the face and/or other tissues.

TABLE 119–2.

Categories of Manner of Death Natural Nonnatural Homicide Suicide Accident Therapeutic Complicationa Undetermined

a

Not all jurisdictions recognize therapeutic complication as a manner of death.

TABLE 119–3.

Normal Postmortem Biochemical Changes23,53,79

Increased

Decreased

Stable

Variable

Amino acids Ammonia Ca2+ Epinephrine Hepatic enzymes Insulin (esp. right heart blood) K+ Mg2+

Cl− Glucose Na+ pH T4

BUN/Cr (vitreous) Cholinesterases Cortisol (serum) Proteins (serum) Sulfates

Lipids T3

Intracavitary spaces may be injected with preserving substances, and solid organs may or may not be removed (Table 119–4).36,37

SAMPLES USED FOR TOXICOLOGIC ANALYSIS Ideally, bodies in the early postmortem interval have several commonly used tissues for toxicologic sampling19,30,42,47,64 (Table 119–5).

Blood Intravascular blood is a common source for toxicologic examination. Unlike antemortem specimens that usually report plasma concentrations, cell lysis after death precludes this distinction, and “blood” concentrations are reported. Other sources of blood may be available to the forensic pathologist. Occasionally, extravasated blood identified at autopsy is collected for analysis. In cases where there is a prolonged hospitalization between the exposure and death, antemortem samples may be useful and can be obtained from hospital blood banks or laboratories.

Vitreous Humor Another source commonly used for sampling is the vitreous humor.13,18,20 Because of the relatively avascular nature of the fluid, the vitreous humor is well protected from the early decompositional changes that typically occur in blood. Certain physiologic markers such as renal function and specific electrolyte concentrations can be reliably approximated from vitreous humor samples for up to 3 or 4 days in refrigerated bodies. Potassium concentrations are less reliable. The aqueous content of the vitreous is higher than that of blood and may affect partitioning of certain water-soluble xenobiotics.

TABLE 119–4. Some Historical Constituents of Embalming Fluida Calcium oxalate Ethanol Formalin Glutaraldehyde Isopropanol Metals a

Methanol Methylsalicylate Phenol Quarternary ammonium compounds Sodium benzoate Thyme

Some, like ethanol and metals are banned for use as preservatives.

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TABLE 119–5.

Sampling Sites13,18,20,30,42,79

Routine

Less routine

Uncommon

Bile Blood Brain Liver Stomach contents Urine Vitreous humor

Bone CSF Fat Hair Kidneys Lungs Muscle Nails Skin

Antemortem blood Extravasated blood Extravasated fluid Casket fluid Insect larvae Pupae casings Soil

Urine Urine may be available at autopsy and can reveal renally eliminated substances or their metabolites. Because the bladder serves as a reservoir in which metabolism is unlikely to occur, the drugs and their concentrations obtained at autopsy may reflect antemortem concentrations.

Gastric Contents The contents of the stomach are inspected grossly for color and for presence or absence of pill fragments, food particles, activated charcoal, or other foreign materials. Typically xenobiotic gastric concentrations are reported as milligrams of substance per gram of total gastric contents. Several factors may affect the gastric contents identified on autopsy. Xenobiotic-induced pylorospasm, diminished intestinal motility, or decreased splanchnic blood flow may all decrease gastric emtpying.

Solid Organs and Other Sources Xenobiotic concentrations in solid organs are usually reported as milligrams of substance per kilogram of homogenized tissue. Other sources of sampling such as hair and nails are typically used for thiol-avid agents such as metals. Rarely, tracheal aspirates of gases can be analyzed to confirm inhalational exposures.

Other Samples When the body is embalmed, remaining organs, muscle tissue, or the embalming fluid may be utilized for analysis. Soil samples may be obtained in exhumed bodies. In putrefied and anthropophagized bodies, fluids, and potentially insect parts can be analyzed. Entomotoxicology is the science of examining anthropophagic insects at various stages of development to increase information regarding the decedent’s death.32,49 Entomotoxicologists take samples of the insects and can extrapolate, by stage of life, environmental conditions, and season, the approximate time of death. The species Caliphoridae, or bluebottle fly, is attracted to unprotected remains by a very fine scent that develops within hours of death. The adult fly lays eggs on mucosal surfaces or open wounds in the flesh. Once the eggs hatch, the larvae feed on the decomposing tissue. Larval samples can be examined for the presence of toxins, but these must be collected and preserved immediately, as the larvae can continue to metabolize certain xenobiotics if they are allowed to remain alive. In another phase of life, the larvae undergo pupation, secreting a substance that encloses

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them into pupal casings. These casings are often found in the soil beneath the body. Some toxins have been identified in the casings even after the adult fly has emerged68 (Table 119–6).

INTERPRETATION OF POSTMORTEM TOXICOLOGIC RESULTS Once fluid and tissue samples are collected and analyzed for the presence of xenobiotics, the process of interpreting the results begins. This complex task attempts to account for the clinical effects of a xenobiotic at the time of death. Integration of this information allows the forensic pathologist to establish cause and/or manner of death or assists in deciding if the xenobiotic was contributory to death. Multiple confounding variables can affect the sample concentrations of xenobiotics from the time of death to that of the autopsy (Table 119–1).

Artifacts Relating to the Xenobiotic Postmortem Redistribution Xenobiotic blood concentration may be higher at autopsy than at the time of death if the agent undergoes significant postmortem redistribution.43,84,90 This occurs most often in substances with large volumes of distribution, where postmortem decomposition results in release of intracellular xenobiotic into the extracellular compartment.67 For example, digoxin may be released from tissue into the blood as autolysis progresses, resulting in a higher blood concentration at autopsy than at the time of death. If the potential for postmortem redistribution artifact is not considered, xenobiotic concentrations obtained at autopsy may be misinterpreted as supratherapeutic or toxic, and the cause of death may be inappropriately attributed to the identified agent (see Table 119–7, part A). Less commonly, xenobiotic concentration may fall secondary to postmortem metabolism. For example after death, blood cholinesterases, which are stable in postmortem tissue, continue to degrade cocaine. Unless blood is collected immediately at the time of death in tubes containing enzyme inhibitors such as sodium fluoride, the concentration of cocaine will fall and not accurately reflect the concentration of the drug at the time the decedent expired48,56,82 (see Table 119–7, part B). When information is available regarding postmortem redistribution or metabolism, it should be considered and the toxicologic results should be interpreted accordingly. State of Absorption and Distribution As in the case of the living, the state of absorption, distribution, and other toxicokinetic principles at the time of death affect the sampling concentration. In the case of a xenobiotic with minimal postmortem metabolism or redistribution, the phase of absorption is suggested by the relative quantity of xenobiotic in different fluids and solid organs. For ex-

TABLE 119–6. Xenobiotics Identified in Larvae/ Pupal Casings32,49,68,79 Benzoylecgonine Cocaine Heroin Malathion Mercury Methamphetamine

Morphine Nortriptyline Oxazepam Phenobarbital Triazolam

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TABLE 119–7. Examples of Postmortem Xenobiotic Concentration Changes43,48,56,67,82,84,90 A.

Increased Digoxin because of redistribution Amitriptyline because of it large Vd Ethanol during putrefaction

B.

Decreased Cocaine because of postmortem metabolism Glucose because of postmortem red cell consumption

ample, a high concentration of xenobiotic and pill fragments in the gastric contents, with progressively lower concentrations in the liver, blood, vitreous, and brain, suggests an early phase of absorption. When a xenobiotic is administered orally and the tissue concentration is highest in the liver, the relationship suggests a postabsorption, but predistribution concentration. A concentration found to be highest in the urine suggests that the xenobiotic was in an elimination phase at the time of death. Although this approach has it limitations, it may be important for correlating the state of absorption and the expected clinical course of the xenobiotic. Xenobiotic Stability Xenobiotic stability refers to the ability of an agent to maintain its molecular integrity despite changes in the cellular and chemical environment during storage, the addition of preservatives, or with decomposition.3,10,12,73,80,87–89 Putrefaction causes degradation of some xenobiotics. Xenobiotics resistant to this process are “stable.” One study assessing this potential postmortem artifact analyzed homogenized liver tissue infused with various concentrations of xenobiotics.80 The samples were allowed to putrefy outdoors, and sequential sampling of xenobiotic concentrations was performed. The xenobiotics that decreased in concentration as putrefaction progressed were considered “labile,” whereas samples with a constant concentration were stable (Table 119–8). The authors proposed that the chemical moieties of a xenobiotic determine its stability. For example, labile agents share the molecular configuration of an oxygen-nitrogen bond, thiono groups (C=S, P=S), or aminophenols. Chemical structures enhancing stability include single-bonded sulfur groups, carbon-oxygen and carbon-nitrogen bonds, as well as sulfur-oxygen and hydrogen-nitrogen bonds. Although not explicitly studied in otherwise intact, putrefying bodies, a less stable xenobiotic may be recovered in a lower concentration than the actual concentration at the time of death. This artifact must be considered when information regarding xenobiotic stability is available. Xenobiotic Chemical Interactions In some cases, artifact may result from a chemical interaction with a xenobiotic added during the postmortem period, such as embalming fluid.29 A study of xenobiotic-spiked blood and formalin in test tubes described the formation of amitriptyline through methylation of nortriptyline.22 In this situation the identication of amitriptyline, which was not present at the time of death, would confuse interpretation of the toxicologic findings. Where such chemical interactions are described in the literature, the postmortem xenobiotic concentrations should be interpreted accordingly (Table 119–8). Expected Clinical Effects of the Xenobiotic In order for a fatality to be attributed to a xenobiotic, the expected clinical course of a particular xenobiotic exposure should be consistent with the au-

topsy findings. What are the implications, for example, if a person is found dead 90 minutes after last being seen, and a large concentration of acetaminophen is identified in both the gastric contents and blood? Although suicidal intent (manner) may be supported by this finding, the rapid nature of the death is inconsistent with the clinical course typically associated with acetaminophen overdose. Thus, another cause of death must be sought. Interpretation of postmortem toxicology must also incorporate clinically relevant consequences of xenobiotic interactions. For example, the combined ingestion of phenobarbital and ethanol can cause fatal respiratory depression. Although neither may be fatal by absolute concentrations alone, their clinical synergy potentially alters interpretation of the toxicologic findings.

Artifacts Relating to Autopsy The Role of Autopsy In many xenobiotic-related deaths the findings are nonspecific.86 In some cases, the autopsy reveals confirmatory or supportive findings, such as hepatic necrosis in a decedent with a history of acetaminophen overdose. Large numbers of pills on gross inspection of the stomach may corroborate intent. The autopsy may reveal other findings such as coronary artery narrowing, chronic hypertension, renal abnormalities, or a clinically silent myocardial injury. Such information may be useful to assess the significance and potential impact of a xenobiotic in a patient with previously undiagnosed conditions. In other cases, the absence of a chronic condition may be strongly suggestive of a xenobiotic-related death. For example, a decedent with an autopsy finding of aortic dissection in the absence of chronic hypertensive findings may suggest a xenobiotic-induced hypertensive crisis such as from cocaine. During putrefaction, bacteria cause fermentation of endogenous carbohydrates, resulting in ethanol formation. In decedents without gross evidence of putrefaction, especially those in cool, dry environments, endogenous ethanol production is minimal.14,15 With a more advanced postmortem interval or an environment more conducive to ethanol production, the distinction between endogenous and exogenous sources of ethanol becomes more difficult. Multiple sample sites become useful in making the distinction.81

Antemortem Physiologic Considerations Inherent to the Body The clinical response to a xenobiotic may be affected by acquired and inherited physiologic conditions that are not identified on autopsy. Tolerance, an acquired condition in which higher and higher xenobiotic concentrations are required to produce a given clinical effect, is an important consideration. Respiratory depression and death from methadone, for example, may be easily diagnosed in an opioid-naive individual with a history of methadone exposure and methadone-positive postmortem samples. However, the methadone concentrations in a patient who chronically uses methadone may not produce the same outcome. Unfortunately, there are no biochemical, or histologic markers on autopsy that can be used to predict clinically dangerous xenobiotic concentrations in tolerant individuals. Assessment of tolerance in death, as in life, ultimately depends on other information and the best judgment of the investigator. The other important consideration is ability to metabolize certain agents, particularly through specific hepatic enzyme pathways. Some acquired states of enhanced enzyme induction or

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inhibition may affect the predicted antemortem concentrations of agents such as phenobarbital. Alternatively, there is genetic variability in the expression of certain metabolic enzymes. For example, pharmacogenetic differences in metabolic enzymes, such as CYP2D6, predisposed some individuals to fatal hypotension from the inability to metabolize debrisoquine. Such distinctions are not routinely identifiable on autopsy.24

Handling of the Body After death, the handling of the body can result in the development of artifacts.72,74 In one reported case methanol was detected in the vitreous humor of a decedent, postembalming.9 The methanol was subsequently traced to a spray cleanser that likely settled on the surface of open eyes during washing of the body. In the United States, preservatives containing certain metals are currently banned for use in embalming. When these xenobiotics are added during the postmortem period, they can interfere with the interpretation of metal concentrations present before death. Formalin may also affect stability or quantitative identification of some xenobiotics (Table 119–8). When necessary, an

TABLE 119–8. Xenobiotic Stability and Laboratory Recovery10,12,22,27,73,79,80,87 • Quantitative recovery affected by preservatives As, Pb, Hg, Cu, Ag Cyanide Carbon monoxide Ethchlorvynol Nortriptyline (converted to amitriptyline in fixatives) • Chemical stability in formalin Stable Labile Succinylcholine Phenobarbital Diazepam Phenytoin (30 days)

Desipramine

• Chemical stability in putrefying liver Stable Labile Acetaminophen Amitriptyline Barbiturates Chloroform Clemastine Dextropropoxyphene Diazepam Doxepin Flurazepam Glutethemide Hydrochlorothiazide Imipramine Lorazepam Methaqualone Morphine Nicotine Paraquat Pentachlorophenol Quinine Strychnine Vegetable alkaloids

o,p-Aminophenols Chlordiazepoxide Chlorpromazine Clonazepam Malathion Metronidazole Nitrofurazone Nitrazepam p-Nitrophenol Obidoxime Perphenazine Trifluoperazine

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analysis of embalming fluid used by the mortician can determine the potential for postmortem contamination.16 Similarly, in exhumed bodies, soil samples from above and below the body must be obtained to ensure that the soil contents did not leach into postmortem tissue.

Artifacts Related to Sampling Sites Site-specific differences in postmortem xenobiotic blood concentrations are common.28 For example, blood drawn from femoral vessels may have a low glucose because of postmortem glycolysis, but the glucose concentration of blood removed from the right heart chambers may be high as a result of release of liver glycogen stores. Such differences in xenobiotic sampling are also reported; therefore, the individual interpreting the toxicologic report must know the exact site sampled.17,47 Ideally more than one site is available for comparison. Multiple samples may not routinely be obtained if the history and autopsy strongly suggest a nontoxicologic cause of death. The comparison of concentrations in different sites may reveal important information regarding state of xenobiotic absorption at the time of death, and acute versus chronic exposure.6–8,17,21,25,41,52,56,63,64,66,67,69–71,76,77,81,83 What is the meaning of the xenobiotic concentration if a patient who takes digoxin daily for paroxysmal atrial fibrillation is found dead 1 hour after his last dose? At autopsy the following day, the postmortem right heart blood digoxin concentration was 5.6 ng/mL. This high blood concentration may reflect either the early state of absorption or postmortem redistribution of digoxin. Alternatively, the individual may have suffered death from chronic digoxin toxicity. Sampling another site, such as the vitreous humor, becomes important to make the distinction. The vitreous concentration will likely reflect the chronic concentration of digoxin as it equilibrates with blood over a period of hours after ingestion. If the vitreous humor concentration is 0.9 ng/mL, and the creatinine is 0.8 mg/dL, it is unlikely that chronic digoxin toxicity was responsible for the patient’s death. Other Sample Sites Extravasated intracranial blood is unlikely in most cases to undergo metabolism before or after death. These clots serve as useful samples in patients with a prolonged survival period following an exposure. Furthermore, when compared to intravascular blood, samples from intracranial clots may assist in analyzing the sequence of events preceding death. For example, a woman with a past history of suicide attempts, on fluoxetine, complained of a headache while preparing invitations for her husband‘s surprise party. She was found dead on her bed with an empty bottle of oxycodone. On autopsy, seven oxycodone tablets were found in her stomach. There was evidence of chronic hypertensive disease, never previously diagnosed, and a large intracranial subarachnoid hemorrhage. Although the husband did not believe she was suicidal at the time, the life insurance company refused to disburse funds on the grounds that her death might have been a suicide. Subsequent toxicology of the extravasated, intracranial blood revealed the presence of fluoxetine and undetectable concentrations of oxycodone. With this information the medical examiner was able to certify the cause of death as subarachnoid hemorrhage secondary to chronic hypertensive disease, and the manner of death as natural. The gastric contents were interpreted as an attempt by the patient to relieve the associated headache. The insurance company was subsequently satisfied, and the life insurance policy was honored.

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Blood in the abdominal or thoracic cavities is less useful, as it may be contaminated by bacteria or other substances that may affect xenobiotic stability.

Other Considerations Published therapeutic, toxic, and fatal postmortem concentrations are available to aid in interpretation of postmortem specimens.2,55 The conditions associated with these reported concentrations are not necessarily comparable with those of a particular case under investigation. Thus, these resources are valuable but should be used mainly as guidelines and not absolute values defining fatal toxic concentrations. After postmortem concentrations have been obtained, some authors suggest using the standard formula (Concentration = Dose/Vd) and solving for the dose the patient potentially ingested. This formula applies to antemortem therapeutic dosing regimens following drug absorption and distribution. Comparable conditions may not be present in fatal poisonings. Thus, attempts to define whether a xenobiotic is associated with a therapeutic or intentional overdose should be made within the substantial limitations discussed above.

Other Limitations Although there are generalized standards of practice in forensic investigations, specimen collection and laboratory methodology may vary.1 Some xenobiotic concentrations may be falsely elevated or depressed depending on chosen methodology.57 Laboratory toxicology techniques go beyond the scope of this chapter, but these variables must also be given consideration in postmortem toxicologic interpretations. Just as during life, other limits may include availability of information relating to the scene of death and the handling of specimens through a proper legal chain of custody.

SUMMARY In order to interpret postmortem toxicological reports effectively, it is essential to understand potential biochemical changes and the artifacts that affect postmortem sampling. Unfortunately, there is no single resource that systematically correlates xenobiotic blood and tissue concentrations, as postmortem decomposition and complexity vary. Hence, postmortem toxicology is an evolving field that may only permit the most likely truth associated with the xenobiotic identified and the circumstances in question.11,26,59 Research and development will depend on the collaboration among the physicians caring for the patients at the time of death, as well as forensic pathologists, and medical toxicologists.

REFERENCES 1. Andollo W: Quality assurance in postmortem toxicology. In: Karch SB, ed: Drug Abuse Handbook. Boca Raton, CRC Press, 1998, pp. 953–969. 2. Baselt RC, ed: Disposition of Toxic Drugs and Chemicals in Man, 5th ed. Foster City, Chemical Toxicology Institute, 2000. 3. Battah AH, Hadidi KA: Stability of trihexyphenidyl in stored blood and urine specimens. Int J Legal Med 1998;111:111–114. 4. Berryman HE, Bass WM, Symes SA, Smith OC: Recognition of cemetery remains in the forensic setting. J Forensic Sci 1991;36: 230–237.

5. Blackmore DJ: Aircraft accident toxicology: UK experience 1967–1972. Aerospace Med 1974;45:987–994. 6. Bonnichsen R, Gerrtinger P, Maehly AC: Toxicological data on phenothiazine drugs in autopsy cases. J Legal Med 1970;67:158–169. 7. Briglia EJ, Bidanset JH, Dal Cortivo LA: The distribution of ethanol in postmortem blood specimens. J Forensic Sci 1993;38:1019–1021. 8. Caplan YH, Levine B: Vitreous humor in the evaluation of postmortem blood ethanol concentrations. J Anal Toxicol 1990;14: 305–307. 9. Caughlin J: An unusual source for postmortem findings of methyl ethyl ketone and methanol in two homicide victims. Forensic Sci Int 1994;67:27–31. 10. Chace DH, Goldbaum LR, Lappas NT: Factors affecting the loss of carbon monoxide from stored blood samples. J Anal Toxicol 1986;10: 181–189. 11. Chamberlain RT: Role of the clinical toxicologist in court. Clin Chem 1996;42:1337–1341. 12. Chikasue F, Yashiki T, Kojima T: Cyanide distribution in five fatal cyanide poisonings and the effect of storage conditions on cyanide concentration in tissue. Forensic Sci Int 1988;38:173–183. 13. Choo-Kang E, McKoy C, Escoffery C: Vitreous humor analytes in assessing the postmortem interval and the antemortem clinical status. West Med J 1983;32:23–26. 14. Clark MA, Jones JW: Studies on putrefactive ethanol production. I: Lack of spontaneous ethanol production in intact human bodies. J Anal Toxicol 1982;27:366–371. 15. Coe JI, Sherman RE: Comparative study of postmortem vitreous humor and blood alcohol. J Forensic Sci 1970;15:185–190. 16. Coe JI: Comparative postmortem chemistries of vitreous humor before and after embalming. J Forensic Sci 1976;21:583–586. 17. Coe JI: Postmortem chemistry of blood, cerbrospinal fluid, and vitreous humor. Legal Med Ann 1977;76:55–92. 18. Coe JI: Use of chemical determinations on vitreous humor in forensic pathology. J Forensic Sci 1972;17:541–546. 19. Craig PH: Standard procedures for sampling—a pathologist’s prospective view. Clin Toxicol 1979;15:597–603. 20. Daae LN, Teige B, Svaar H: Determination of glucose in human vitreous humor. J Legal Med 1978;80:287–290. 21. Davis GL: Postmortem alcohol analyses of general aviation pilot fatalities, Armed Forces Institute of Pathology 1962–1967. Aerospace Med 1973;44:80–83. 22. Dettling RJ, Briglia EJ, Dal Cortivo LA, Bidanset JH: The production of amitriptyline from nortriptyline in formaldehyde-containing solutions. J Anal Toxicol 1990;14:325–326. 23. Devgun MS, Dunbar JA: Post-mortem estimation of gamma-glutamyl transferase in vitreous humor and its association with chronic abuse of alcohol and road-traffic deaths. Forensic Sci Int 1985;28:179–180. 24. Druid H, Holmgren P, Carlsson B, Ahlner J: Cytochrome P450 2D6 (CYP2D6) genotyping on postmortem blood as a supplementary tool for interpretation of forensic toxicological results. Forensic Sci Int 1999;99:25–34. 25. Druid H, Holmgren P: A compilation of fatal and control concentrations of drugs in postmortem femoral blood. J Forensic Sci 1997; 42:79–87. 26. Ernst MF, Poklis A, Gantner GE: Evaluation of medicolegal investigators’ suspicions and positive toxicology findings in 100 drug deaths. J Anal Toxicol 1982;27:61–65. 27. Falconer B, Moller M: The determination of carbon monoxide in blood treated with formaldehyde. J Legal Med 1971;68:17–19. 28. Felby S, Olsen J: Comparative studies of postmortem barbiturate and meprobamate in vitreous humor, blood and liver. J Forensic Sci 1969;14:507–514. 29. Fomey RB, Carroll FT, Nordgren IK, et al: Extraction, identification and quantitation of succinylcholine in embalmed tissue. J Anal Toxicol 1982:6:115–119. 30. Forrest AR: Obtaining samples at post mortem examination for toxicological and biochemical analyses. J Clin Pathol 1993;46:292–296.

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31. Garriott JC: Interpretive toxicology. Clin Lab Med 1983;3:367–384. 32. Goff ML, Lord WD: Entomotoxicology. A new area for forensic investigation. Am J Forensic Med Pathol 1994;15:51–57. 33. Goldman P, Ingelfinger JA: Completeness of toxicological analyses. JAMA 1980;243:2030–2031. 34. Goulding R: Poisoning as a fine art. Med Legal J 1978;46:6–17. 35. Grellner W, Glenewinkel F: Exhumations: synopsis of morphologic findings in relation to the postmortem interval. Survey on a 20-year the literature. Forensic Sci Int 1997;90:139–159. 36. Halmai J: Common thyme (Thymus vulgaris) as employed for the embalming. Ther Hungarica 1972;20:162–165. 37. Hanzlick R: Embalming, body preparation, burial, and disinterment. Pathology 1994;15:122–131. 38. Hearn WL, Keran EE, Wei H, Hime G: Site dependent postmortem changes in blood cocaine concentrations. J Forensic Sci 1991;36: 673–684. 39. Hearn WL, Walls HC: Introduction to postmortem toxicology. In: Karch SB, ed: Drug Abuse Handbook. Boca Raton, CRC Press, 1998, pp. 863–873. 40. Hearn WL, Walls HC: Common methods in postmortem toxicology. In: Karch SB, ed: Drug Abuse Handbook. Boca Raton, CRC Press, 1998, pp. 890–926. 41. Hearn WL, Walls HC: Strategies for postmortem toxicological investigation. In: Karch SB, ed: Drug abuse handbook. Boca Raton, CRC Press, 1998, pp. 926–953. 42. Helper BR, Isenschmid DS: Specimen selection, collection, preservation, and security. In: Karch SB, ed: Drug Abuse Handbook. Boca Raton, CRC Press, 1998, pp. 873–889. 43. Hilberg T, Rogde S, Morland J: Postmortem drug redistribution— human cases related to results in experimental animals. J Forensic Sci 1999;44:3–9. 44. Hill IR: Toxicological findings in fatal aircraft accidents in the United Kingdom. Am J Forensic Med Pathol 1986;7:322–326. 45. Iwasa Y, Onaya T: Postmortem changes in the level of calcium pump triphosphatase in rat heart sarcoplasmic reticulum. Forensic Sci Int 1988;39:13–22. 46. Jones GR: Interpretation of postmortem drug levels. In: Karch SB, ed: Drug Abuse Handbook. Boca Raton, CRC Press,1998, pp. 970–985. 47. Jones GR, Pounder DJ: Site dependence of drug concentrations in postmortem blood—a case study. J Anal Toxicol 1987;11:186–190. 48. Karch SB: Introduction to the forensic pathology of cocaine. Am J Forensic Med Pathol 1991;12:126–131. 49. Kintz P, Tracqui A, Ludes B, et al: Fly larvae and their relevance in forensic toxicology. Am J Forensic Med Pathol 1990;11:63–65. 50. Klette K, Levine B, Springate C, Smith ML: Toxicological findings in military aircraft fatalities from 1986–1990. Forensic Sci Int 1992;53: 143–148. 51. Krompecher T: Experimental evaluation of rigor mortis. v. Effect of various temperatures on the evolution of rigor. Forensic Sci Int 1981; 17:19–26. 52. Kunsman GW, Rodriguez R, Rodriguez P: Fluvoxamine distribution in postmortem cases. Am J Forensic Med Pathol 1999;20:78–83. 53. Langford AM, Taylor KK, Pounder DJ: Drug concentration in selected skeletal muscles. J Forensic Sci 1998;43:22–27. 54. Levine BS, Smiith ML, Froede RC: Postmortem forensic toxicology. Clin Lab Med 1990;10:571–589. 55. Lewin JF, Pannell LK, Wilkinson LF: Computer storage of toxicology methods and postmortem drug determinations. Forensic Sci Int 1983; 23:225–232. 56. Logan BK, Smirnow D, Gullberg RG: Lack of predictable site-dependent differences and time-dependent changes in postmortem concentrations of cocaine, benzoylecgonine, and cocaethylene in humans. J Anal Toxicol 1997;20:23–31. 57. Long C, Crifasi J, Maginn D, et al: Comparison of analytical methods in the determination of two venlafaxine fatalities. J Anal Toxicol 1997;21:166–169.

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58. Mellen PF, Bouvieer EC: Nineteenth-century Massachusetts coroner inquests. Am J Forensic Med Pathol 1996;17:207–210. 59. Messite J, Stellman SD: Accuracy of death certificate completion. JAMA 1996;275:794–796. 60. Niyogi SK: Historic development of forensic toxicology in America up to 1978. Am J Forensic Med Pathol 1980;1:249–264. 61. Oxley DW: Examination of the exhumed body and embalming artifacts. Med Legal Bull 1984;33:1–7. 62. Peat MA: Advances in forensic toxicology. Clin Lab Med 1998;18: 263–278. 63. Peclet C, Picotte P, Iobin F: The use of vitreous humor levels of glucose, lactic acid and blood levels of acetone to establish antemortem hyperglycemia in diabetics. Forensic Sci Int 1994:65:1–6 64. Pla A, Hernandez AF, Gil F, et al: A fatal case of oral ingestion of methanol. Distribution in postmortem tissues and fluids including pericardial fluid and vitreous humor. Forensic Sci Int 1991;49: 193–196. 65. Polson CJ, Gee DJ, Knight B: The Essentials of Forensic Medicine, 4th ed. Oxford, Pergamon Press, 1985, pp. 3–39. 66. Pounder DJ, Carson DO, Johnston K, Orihara Y: Electrolyte concentration differences between left and right vitreous humor samples. J Forensic Sci 1998;43:604–607. 67. Pounder DJ, Davies JI: Zopiclone poisoning: tissue distribution and potential for postmortem diffusion. Forensic Sci Int 1994;65:177–183. 68. Pounder DJ: Forensic entomo-toxicology. Forensic Sci Soc 1991;31: 469–472. 69. Prouty RW, Anderson WH: A comparison of postmortem heart blood and femoral blood ethyl alcohol concentrations. J Anal Toxicol 1987; 11:191–197. 70. Prouty RW, Anderson WH: The forensic science implications of site and temporal influences on postmortem blood-drug concentrations. J Forensic Sci 1990;35:243–270. 71. Ritz S, Harding P, Martz W: Measurement of digitalis-glycoside levels in ocular tissues. Int J Legal Med 1992;105:155–159. 72. Rivers RL: Embalming artifacts. J Forensic Sci 1978;23:531–535. 73. Robertson MD, Drummer OR: Stability of nitrobenzodiazepines in postmortem blood. J Forensic Sci 1998;43:5–8. 74. Rohrig TP: Comparison of fentanyl concentrations in unembalmed and embalmed liver samples. J Anal Toxicol 1998;22:253. 75. Rosenfeld L: Alfred Swaine Taylor (1806–1880), pioneer toxicologist—and a slight case of murder. Clin Chem 1985;31:1235–1236. 76. Schonheyder RC, Renriques U: Postmortem blood cultures. Evaluation of separate sampling of blood from the right and left cardiac ventricle. APMIS 1997;105:76–78. 77. Schoning P, Strafuss AC: Analysis of postmortem canine blood, cerebrospinal fluid, and vitreous humor. Am J Vet Res 1981;42: 1447–1449. 78. Smith PW, Lacefield DJ, Crane CR: Toxicological findings in aircraft accident investigation. Aerospace Med 1970;41:760–762. 79. Spitz WU, ed: Spitz’s and Fischers Medicolegal Investigation of Death. Springfield, IL, Charles C Thomas, 1993. 80. Stevens HM: The stability of some drugs and poisons in putrefying human liver tissues. J Forensic Sci Soc 1984;24:577–589. 81. Stone BE, Rooney PA: A study using body fluids to determine blood alcohol. J Anal Toxicol 1984;8:95–96. 82. Tardiff K, Gross E, Wu J, et al: Analysis of cocaine positive fatalities. J Forensic Sci 1989;34:53–63. 83. Vermeulen T: Distribution of paroxetine in three postmortem cases. J Anal Toxicol 1998;22:541–544. 84. Vorpahl TE, Coe JI: Correlation of antemortem and postmortem digoxin levels. J Forensic Sci 1978;23:329–334. 85. Wetli CV: Investigation of drug-related deaths—an overview. Am J Forensic Med Pathol 1984;5:111–120. 86. Winek CL, Wahba WW: The role of trauma in postmortem blood alcohol determination. Forensic Sci Int 1995;74:213–214. 87. Winek CL, Esposito FM, Cinicola DP: The stability of several compounds in formalin fixed tissues and formalin-blood solutions. Forensic Sci Int 1990;44:159–168.

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88. Winek CL, Wahba WW, Rozin L, Winek CL Jr: Determination of ethchlorvinyl in body tissues and fluids after embalmment. Forensic Sci Int 1988;37:161–166. 89. Winek CL, Zaveri NR, Wahba WW: The study of tricyclic antidepressants in formalin fixed human liver and formalin solutions. Forensic Sci Int 1993;61:175–183.

90. Worm K, Dragsholt C, Simonsen K, Kringsholm B: Citalopram concentrations in samples from autopsies and living persons. Int J Legal Med 1998;111:188–190.

CHAPTER

120 PANDRINCIPLES OF EPIDEMIOLOGY R ESEARCH DESIGN

Kevin C. Osterhoudt

In 1963 Reye and Johnson described series of patients with encephalopathy and fatty degeneration of the liver.22,34 Further anecdotal observation of similar patients allowed the development of a hypothesis that aspirin may be an etiologic factor in Reye syndrome.13 Given such a common exposure as salicylate therapy and such a rare disease as Reye syndrome, how would researchers investigate whether an association between salicylate and Reye syndrome truly exists? In 1976 a case series suggested that enteral erythromycin given to neonates might predispose to infantile hypertrophic pyloric stenosis.35 How might this association be confirmed given that pyloric stenosis typically occurs in approximately one of every 500 infants, but intake of erythromycin is unusual among this group? Gastric emptying has a long tradition as a method of gastrointestinal decontamination to treat patients after acute oral overdose. Hyperbaric oxygen therapy (HBO) is considered as a therapy to prevent delayed neurologic sequelae from carbon monoxide (CO) poisoning. How can it be determined if these treatments actually offer a patient benefit? Advances in clinical medicine are usually achieved through a typical scientific method. First, astute clinicians make interesting observations. These observations lead to the generation of hypotheses. Research questions are analyzed with epidemiologic investigation, and initial studies are examined with methodologic scrutiny. Initial analytic techniques are improved, and confirmatory studies are performed. Ultimately, models relating cause to effect are formulated. The field of medical toxicology is rapidly transitioning from a descriptive discipline to one of rigorous scientific exploration. New associations between toxins and diseases are being explored every year. Recent high-profile associations include those between silicone breast implants and connective tissue diseases, and insecticide exposure and childhood cancer. An understanding of basic principles of research design and epidemiology is required to interpret published studies and to lay the groundwork for future investigation in toxicology.

EPIDEMIOLOGIC TECHNIQUES AVAILABLE TO INVESTIGATE CLINICAL PROBLEMS Different study formats are listed in Table 120–1.

Observational Design: Descriptive A staggering array of poisons and venoms are able to injure people, necessitating reliance of toxicologists on good descriptive

data regarding toxic outcomes. The Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers now has a database of over 27 million human poison exposure cases.24 Descriptive case reporting serves a valuable purpose in describing the characteristics of a medical condition or procedure and remains a fundamental tool of epidemiologic investigation. A case report is a clinical description of a single patient or procedure with respect to a situation. Case reports are most useful for hypothesis generation. However, single case reports are not generalizable, as the reported situation may be atypical. A number of case reports can be grouped, on the basis of similarities, into a case series. Case series can be used to characterize an illness or syndrome, but without a control group they are severely limited in proving cause and effect. In the now classic paper, Reye described 21 children with encephalopathy and fatty degeneration of the liver that characterized the syndrome that now bears his name.34 Further descriptive data collection suggested that use of aspirin might be associated with Reye syndrome (RS),13 but analytic study would be required to support that hypothesis. Published annual reports of TESS data state that their descriptive data are meant to “identify hazards early, focus prevention education, guide clinical research, and direct training.”24 In these roles, descriptive data are often underappreciated. Cross-sectional studies assess a population for the presence or absence of an exposure and condition simultaneously. Such data often provide estimates of prevalence—the fraction of individuals in a population sharing a characteristic or condition at a point in time. These studies, particularly helpful in public health planning, have been extremely useful in monitoring common environmental exposures, such as childhood lead poisoning, or population-wide drug use, such as occurs with tobacco, marijuana, and alcohol. The United States National Health and Nutrition Examination Survey investigations demonstrated that the percentage of children with blood lead levels >10 µg/dL decreased from 88.2% to 4.4% between 1976 and 1991, with the highest rates of plumbism among African American, low-income, or urban children.4 An analysis of secular trends is a study type that compares changes in illness over time or geography to changes in risk factors. These analyses often lend circumstantial support to a hypothesis; however, because of the ecological nature of their design, individual data on risk factors are not available to allow exclusion of alternative hypotheses also consistent with the data. A prime example of an analysis of secular trends is Arrowsmith’s finding that reports of RS declined between 1980 and 1985, coincident with a fall in sales of, or physician recommendations of, children’s aspirin products.2 This investigation added further confirmation to the etiologic role of aspirin in the development of Reye syndrome but could not exclude alternative hypotheses such as a change in viral epidemic patterns.

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TABLE 120–1.

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY Types of Epidemiologic Study Designsa Experimental Clinical trial Observational: Analytic Cohort Case-control Observational: Descriptive Analysis of secular trends Cross-sectional Case series Case report

a

Study designs are listed in descending order from the design that offers the best epidemiologic evidence for association to that which offers the least.

Observational Design: Analytical Hypotheses generated by theoretical reasoning or anecdotal association require analytic testing. Case-control studies and cohort studies are analytic techniques that utilize observational data, and each technique has its own advantages and disadvantages (Table 120–2). Case-control studies compare affected, treated, or diseased patients (cases) to nonaffected patients (controls) and look for a difference in prior risk factors or exposures (Fig. 120–1A). Because subjects are recruited into the study based on prior presence or absence of a particular outcome, case-control studies are always retrospective in nature. They are especially useful when the outcome being studied is rare, and they enable the investigation of any number of potential etiologies for a single disease. RS is an illness well suited to case-control study. The incidence of RS peaked in the United States in the mid 1970s, and clustered together with viral epidemics of influenza A, influenza B, and varicella. Based on anecdotal observations in a series of patients, a hypothesis was formulated that salicylate may be an etiologic factor in RS.13 Other putative contributory factors were also proposed, including viral infections, aflatoxin, pesticides, antiemetic drugs, and valproate. Exposures to salicylate were common in the 1970s, but the incidence of RS was less than 10 cases per million persons under age of 18 years. In the epidemiologic investigation that served as a foundation for decades of research to follow, seven children diagnosed with RS were compared to 16 control children who were matched on the basis of age, gender, time, and viral symptoms.37 Families were interviewed regarding the types and quantities of medications taken by the children. Salicylates were the only exposure found to be statistically different

TABLE 120–2. Advantages of Case-Control versus Cohort Study Designs Case-control study Smaller sample required when outcome is rare Reduced bias in outcome data Can study many exposures simultaneously Allows estimation of relative risk May obviate need for long followup period Cohort study Provides more robust evidence of association Reduced bias in exposure data Can study many outcomes simultaneously Allows direct calculation of incidence Allows direct calculation of relative risk

Figure 120–1. A. Schematic representation of the case-control study design. Subjects with an outcome or condition of interest are selected, along with control subjects, and then are evaluated for previous exposure to a risk factor of interest. B. Schematic representation of the cohort study design. Subjects are recruited based on the presence or absence of a risk factor or exposure, then followed to see if they develop an outcome.

between cases and controls, and this became the first case-control study to identify increased odds of developing RS after aspirin therapy. Larger subsequent case control studies added confirmatory evidence to the association between salicylate use and RS.15,21,40 Cohort studies compare patients with certain risk factors or exposures to those patients without the exposure, then follow these cohorts to see which subjects develop the outcome of interest (Fig. 120–1B). In this respect, they allow the comparison of incidence (the number of new outcomes occurring within a population initially free of disease over a period of time) between populations who share an exposure and populations who do not. They may be retrospective or prospective and enable the study of any number of outcomes from a single exposure. They are particularly well suited to investigations in which the outcome of interest is relatively common. In circumstances when an outcome of interest is very uncommon, such as the case with RS, the large number of study subjects required might make a cohort study impractical. A suggested association between oral erythromycin administration to newborn infants and increased risk of idiopathic hypertrophic pyloric stenosis, which typically affects up to three individuals per 1000 live births, remained unstudied until a 1999 cohort study. Investigators studied a patient population in which 157 out of 282 infants born at a hospital in a 2-month period were treated with erythromycin prophylaxis because of a pertussis exposure.18 Investigators separated these patients into cohorts based on exposure to erythromycin and looked at the differences of pyloric stenosis rates between the two groups. Neonates treated with erythromycin were found to be at significantly greater risk of pyloric stenosis than untreated controls. Perhaps the most famous and ambitious cohort study was the Framingham Heart Study in which 5209 residents of Framingham, MA, aged 30 to 62 years have been followed for over 50 years. This study provided a useful tool for studying the incidence of lung cancer, stroke, and cardiovascular disease in those exposed to cigarette smoke11 and other toxins.

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Experimental Design Experimental studies are those in which the treatment, risk factor, or exposure of interest can be controlled by the investigator to study differences in outcome between the groups (Fig. 120–2). The prototype is the randomized, blinded, controlled clinical trial. Among epidemiologic study types, these provide the most convincing demonstration of causality. Clinical trials are used to measure the efficacy (the treatment effect within a controlled experimental setting) of treatment regimens and to draw inferences about the effectiveness of a treatment applied to the general population. Unfortunately, interventional studies are the most complex to perform, and several questions must be addressed by investigators before performing a clinical trial (Table 120–3). Human clinical trials have been especially difficult to apply to the practice of toxicology. Indeed, between 1992 and 1996, one author found only three such randomized clinical trials.38 Characteristics of poisoned patients, which hamper attempts at clinical trials, are listed in Table 120–4. Volunteer studies, using nontoxic drugs or subtoxic drug doses, are often used to circumvent many of the problems in controlling human poisoning studies; but it is typically difficult to apply results from these studies to the actual physiology of toxic overdose. Perhaps the best way to demonstrate an etiologic association between salicylate use and RS would be to perform a randomized, double-blinded, controlled clinical trial. Patients with influenza and fever could be randomly treated with salicylate or placebo, and the incidence of RS in both treatment groups could be determined. However, with such a strong association noted from case-control studies, and with suitable alternative antipyretic medications available, such a study would be unethical. As toxicologists strive to find evidence for, or against, the traditions of clinical practice, several important clinical trials have been published. Among them are many important examples and lessons in epidemiologic study design. One trial attempted to evaluate whether or not corticosteroids might be beneficial in preventing esophageal strictures secondary to circumferential caustic injury of the esophagus.1 Because of the inherent difficulty in recruiting eligible patients from a single institution, only 60 patients with esophageal injury were recruited over an 18-year period. These patients were randomized to therapy with or without corticosteroids and followed for the development of stricture. Ten of the 31 patients treated with corticosteroids developed strictures in comparison to 11 of 29 control patients. The authors concluded that there was no apparent benefit from the use of corticosteroids to treat children who have ingested a caustic

TABLE 120–3.

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What is the question of interest? What is the target patient population? How will the safety of subjects be assured? What is a suitable control group? How will outcomes be measured? What difference in outcomes between groups is considered important? What is the analysis plan? How many subjects will be required? How will randomization and blinding be achieved and maintained? How long a followup period will be required? How will loss of study subjects be handled? How will treatment compliance be evaluated?

substance. A second study challenged our notions of gastrointestinal decontamination and randomized 876 acutely poisoned patients with respect to gastric emptying procedures.32 Outcomes measured were clinical course, length of hospital stay, and complications. The investigators concluded that gastric emptying did not provide additional therapeutic benefit beyond that of antidotal activated charcoal. A third representative study demonstrated benefit from hyperbaric oxygen therapy with regard to the prevention of delayed neurologic sequelae after carbon monoxide poisoning.39 Sixty patients with acute carbon monoxide poisoning were randomized to either ambient pressure or hyperbaric oxygen, then followed for the occurrence of neurologic dysfunction. The conclusions of each of the three aforementioned studies have encountered tremendous academic dissection and debate. Certain concerns with the methodology and analysis of these studies are examined later in this chapter to illustrate epidemiologic concepts. Additionally, each of these studies is described in more detail in the relevant chapters of this text (Chap. 87, 5, and 97, respectively).

MEASURES USED TO QUANTIFY THE STRENGTH OF AN EPIDEMIOLOGIC ASSOCIATION The objective of analytic studies is to define and quantify the degree of statistical dependence between an exposure and an outcome. Such associations are ideally represented by the relative risk of developing an outcome if exposed in comparison to being unexposed. Thus, the relative risk can be defined as the incidence of

TABLE 120–4. Difficulties in Applying Clinical Trials to Human Poisoning

Figure 120–2. clinical trial.

Schematic representation of the design of a randomized

It is unethical to intentionally “poison” subjects. Poisoned patients represent a broad spectrum of demographic patterns. A wide variety of poisons exist. Exposures to any single poison are usually limited. A limited number of poisoned patients are available at any one study site. Uncertainty often exists as to type, quantity, and timing of most poison exposures. Poisoning typically results in a relatively short course of illness.

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Figure 120–3. Use of a 2 × 2 table to calculate or estimate relative risk from analytic studies. In cohort studies, study subjects are selected on the basis of exposure. In case-control studies, subjects are selected on the basis of outcome. The letters a, b, c, and d represent the number of subjects either exposed or unexposed to a “risk factor” or treatment, with or without the outcome of interest. The odds ratio estimates the relative risk if the outcome of interest is rare.

outcome in exposed individuals compared to the incidence of outcome in unexposed individuals. The relative risk can be calculated directly from cohort or interventional studies. However, in a casecontrol study, an investigator chooses the numbers of cases and controls to be studied, so true incidence data are not obtained. In case-control studies an odds ratio can be calculated, and the odds ratio will provide an estimate for relative risk in situations where the outcome is rare, such as when the outcome occurs in fewer than 10% of exposed individuals. The calculation of relative risk or odds ratio from analytic studies is demonstrated in Fig. 120–3. A relative risk of 1.0 signifies that an outcome is equally likely to occur whether an individual is exposed or not and implies that no association exists between the exposure and the outcome. A relative risk approaching 0 suggests that an exposure is a marker of protection with regard to the outcome, and a relative risk approaching infinity suggests the exposure predicts a tendency toward the outcome. In the previously described case-control investigation of the link between salicylate use and RS, all of the seven case subjects had used aspirin compared to only 8 of 16 controls.37 The odds ratio calculated from these data approaches infinity and suggests a strong association between exposure and outcome. In the described clinical trial of therapeutic corticosteroids (the “exposure”) in the prevention of esophageal strictures (the “outcome”), 10 of 31 treated patients developed strictures compared to 11 of 29 untreated patients.1 This relative risk calculation approximates 1 and seemingly demonstrates little benefit from corticosteroid therapy.

MEASURES USED TO QUANTIFY THE SIGNIFICANCE OF AN EPIDEMIOLOGIC ASSOCIATION Analytic studies are performed to test hypotheses, typically that an exposure is associated with an outcome. The presence of such association in any given study has a number of possible explanations, as detailed in Table 120–5. The goal of statistical analysis is to determine the degree to which chance can be excluded as the true reason the results of the study were obtained. By convention,

statistical analysis typically tests the null hypothesis—the hypothesis that there is no association between exposure and outcome. Because analytic studies involve only a sample of the total population, they contain two types of inherent error. Type I error, also referred to as alpha (
) error, is the likelihood that an investigator may conclude that an association exists when none truly does. Type II error, or beta () error, is the possibility that an investigator will be unable to find an association when one is really present. The most commonly reported measures of type I error in published toxicologic studies are the p-value and the confidence interval (CI). Statistical significance has customarily, but not necessarily, been defined as having less than a 1 in 20 chance of conducting a false-positive study. Therefore, a type I error of less than 5%, which corresponds to a p-value of less than 0.05, is usually deemed “statistically significant.” Perhaps a more informative description of the significance of an association is provided through the CI. The CI not only provides a test of statistical significance, it also offers information pertaining to the degree (and possible range) of differences observed. In an unbiased study, the 95% CI provides a range between which, if the study could be repeated an infinite number of times, the observed magnitude of effect would lie 95% of the time. One study reported it noteworthy that no toddlers ingesting one or two calcium channel antagonists became seriously ill, but a subsequent analysis of the CI around this small set of data demonstrated

TABLE 120–5. Types of Associations between Exposures and Outcomes That May Be Found with a Clinical Study No Association Artifactual Association Chance Bias Indirect Association Causal Association

The outcome is independent of exposure. The association demonstrated by the study resulted from random error. Systematic error in the study led to the noted association. The association is real, but not truly cause and effect (confounding). The outcome is dependent on the exposure.

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that the true incidence could be as high as 18%.30 A CI around a relative risk or odds ratio is not statistically significant if it includes 1.0, and the narrower the CI the more precise the estimate of the magnitude of effect. The likelihood that a study will find a difference if one truly exists is termed statistical power and relates to the likelihood of a false-negative study (type II error). Power is usually artificially set by an investigator before a study is performed and is typically set at 80% or 90% to practically limit the number of study subjects needed. Considerations applicable to choice of sample size are found in Table 120–6. The sample size of a study is determined by the frequency of the exposure and outcome within the study population, the strength of association deemed clinically relevant, and the amount of error deemed acceptable in the study. Because power is often set relatively low, it is difficult to state that an association does not exist. It is more proper to state that a study was unable to reject the null hypothesis to find an association. In the ongoing controversy regarding the utility of hyperbaric oxygen in the treatment of acute carbon monoxide poisoning, three randomized studies have alleged benefit,9,26,39 and two have not.33, 36 Conventional parameters for statistical significance suggest that, if unbiased, the positive studies met a bigger burden of evidence than did the negative studies.

DIFFERENTIATION BETWEEN CLINICAL SIGNIFICANCE AND STATISTICAL SIGNIFICANCE The finding of a low p-value indicates a statistically high level of confidence that a difference between study groups exists but offers no indication that the difference is clinically important. The interpretation of statistical versus clinical significance is often facilitated through calculation of confidence intervals. Small actual differences between two groups can become statistically significant if large numbers of subjects are studied. Likewise, impressive associations of cause and effect can seem trivial if few subjects are in a study. The clinical significance of an association is left to the judgment of the individual interpreting a study. Ideally, a working definition of clinical significance is developed before a study is performed. In the noted study of corticosteroids and corrosive injury of the esophagus, 64% of control subjects required esophageal replacement versus 40% of treated subjects.1 The investigators’ calcula-

TABLE 120–6.

Considerations in Choice of Sample Size Sample Size

Pros

Cons

Large

Small

• Able to detect associations of small magnitude • Less susceptible to some biases • More robust analysis • More work and more cost

• Less work and less cost

• Might not detect associations of small magnitude • More susceptible to biases associated with patient differences

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tion of the p-value for this comparison is greater than 0.05. Many would interpret a reduction in esophageal replacement by approximately one-third to be potentially clinically important, yet it is unlikely that this study had statistical power to find such an association. Likewise, in a study suggesting no benefit from gastric emptying after acute overdose, when patients presenting within 1 hour of overdose were examined, 15 % of treated patients showed improvement versus 4% of controls.32 Again, statistical significance was not achieved, but the clinical significance of these data is subject to speculation.

METHODOLOGIC PROBLEMS FOUND WITHIN CLINICAL STUDIES Calculation of a p-value or confidence interval does nothing to assess the adequacy of study design. These measures are used to quantify the influence of random error, or chance, on research findings. Clinical research involving patients is particularly susceptible to bias, which can be defined as systematic error in the collection or interpretation of data. Because such error can lead to an inappropriate estimate of the association between an exposure and an outcome, careful evaluation of potential biases affecting a clinical study is of paramount importance. Selection bias refers to error introduced into a study by the manner in which subjects are selected for inclusion in the study. This type of bias is most problematic for retrospective studies in which exposures and outcomes have both occurred at the time of subject recruitment. Selection bias may be introduced into a prospective clinical tudy if the study fails to enroll potential subjects, or if potential subjects refuse to participate, on a systematic basis. Selection bias may even influence the results of clinical trials. In the 1995 trial that found no difference in outcome between acutely poisoned patients treated with gastric emptying and patients from whom gastric emptying was withheld, all patients presenting to the emergency department after acute overdose were enrolled.32 Because most patients with poisoning exposure are likely to do well with minimal support,24 selection of patients on this basis might be expected to bias this study to find no effect. Reasoning suggests that the patients most likely to benefit from gastric emptying are those with life-threatening toxic ingestion presenting within the first hour after overdose. As mentioned previously, subgroup review of the results of this paper suggests clinical benefit within this group of patients, but without conclusive power. Information bias refers to error introduced into a study as a result of systematic differences in the quality of data obtained between exposed and unexposed groups, or between those with and without the outcome of interest. Several distinct types of information bias may exist. Affected and nonaffected individuals may have differential memories with regard to exposures, so recall bias is a concern in retrospective studies. The potential for recall bias is frequently cited as criticism of early retrospective case-control studies of aspirin as an etiologic factor for RS, in which families were asked to recollect their children’s aspirin use history. Critics suggest that the parents of children affected by RS might be more vigorous in their recall of exposures than the parents of unaffected children. Similarly, interviewer bias may occur if study personnel differ in how they solicit, record, or interpret information as a result of knowledge of the subjects’ status with regard to exposures

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or outcomes. Prospective studies may be troubled by loss to followup, especially if subjects are lost from the study for reasons relating to either exposure or outcome (such as when subjects withdraw from a study because they are feeling better, or are “lost” because they die). Misclassification bias occurs when investigators incorrectly categorize subjects with respect to exposure or outcome. In a retrospective study of 378 children regarding the predictability of caustic esophageal injury from clinical signs and symptoms, it was found that 10 of 80 asymptomatic children had significant burns.12 There is a possibility that these “asymptomatic” children were misclassified because of lack of rigorous written documentation of symptoms or signs within the medical charts. Bias is best minimized through careful study design. It is important to precisely define the study question and the population at risk and to carefully define rigorous inclusion and exclusion criteria. The outcome should also be defined precisely. During data acquisition the best way to reduce bias may be to keep study personnel gathering exposure data blinded to outcome, and vice versa. Often, it may also be advisable to keep study subjects unaware of their status within a study to the extent that it is ethical (thus, “double-blinded”—neither investigators nor subjects are aware of the subjects’ status within a study). Use of placebos or “sham treatments” is a way to facilitate blinding. One of the strongest criticisms of a 1995 trial of HBO for the prevention of delayed neurologic syndromes after CO poisoning39 has been the failure to blind patients and investigators to the treatment in question.28 It is inevitable that some degree of potential bias will be present in any clinical study. Such bias should be reviewed in analysis, and estimations of its magnitude and direction (bias toward or away from rejection of the null hypothesis) should be considered. Unlike selection and information biases, which are errors introduced into studies primarily by the investigators or subjects, confounding is a special type of problem that may occur within a study as a result of interrelationships between the exposure of interest and another exposure. Confounding is a bias wherein an observed association is not a product of cause and effect but instead results from linking of the exposure of interest to another associated exposure. Studies pertaining to adverse effects of drugs of abuse are especially prone to confounding by variables such as concomitant caffeine use, alcohol use, tobacco use, nutritional deficiency, and/or psychiatric illness. Analytic studies may restrict characteristics of enrolled subjects or match subject characteristics between comparison groups in an effort to reduce confounding. Accordingly, it has been suggested that future studies on delayed neuropsychiatric syndromes after CO intoxication control for potential confounding from depression and cyanide exposure.25 Randomization is an important method to assure that unsuspected confounding factors are equally distributed between treatment groups within interventional studies. During data analysis, confounding can often be controlled through stratification of data into subgroups or through multivariate analysis techniques.

BIASES INHERENT IN STUDIES USING THE AAPCC DATABASE The Toxic Exposures Surveillance System database of the American Association of Poison Control Centers (AAPCC) is an ambitious effort to catalog and describe the epidemiology of poisoning

in the United States and Canada. These data serve to help identify new poisoning epidemics, focus prevention and education efforts, guide demographic and economic poisoning analyses, and guide implementation of public health policies. It is a desirable goal to use this database in defining the scope of toxicity for particular poisons and as a clinical research tool. In this regard, it is important to understand the biases inherent in the current database. It has been suggested that selection bias might exist within poison center data if poisoning is unrecognized as a cause of illness or if a caregiver has no questions pertaining to the management of a recognized poisoning.16 Indeed, a survey of 170 emergency physicians in Utah found that 53% admitted to utilizing a poison center for symptomatic acute overdoses, and only 10% contacted poison centers for the purposes of reporting cases to the national database.8 Such selection might result in a bias of poison center data toward more severe cases. On the other end of the spectrum, investigation has found selection bias in poison center data suggesting that fatal poisonings may be severely underrepresented.19 Another study of poison center utilization found that one emergency department reported 95% of cyclic antidepressant overdoses, 33% of venomous snakebites, and only 3% of inhalation exposures.17 Knowledge of information bias within TESS data is less well characterized. Phone interviews of callers, many under duress, by poison center personnel is certain to be subject to recall and interviewer bias. A comparison of rural hospital chart data to the TESS database demonstrated deficiencies in poison center reporting and in clinical information transfer to the TESS database.20 Loss to followup remains a problem for many poison centers, and misclassification of poisonings by caregivers inadequately trained in diagnostic toxicology remains an enigma. Despite the large volume of descriptive poisoning data available, it has proven difficult to derive valid, clinically useful conclusions from either the TESS database or from published case reports.5 One suggested means through which to minimize information bias in descriptive toxicology is through the use of improved data collection charts.6 Other researchers have found it useful in clinical studies to transform poison center data collection from a passive to an active process through use of specific research instruments.27 Further efforts are required to reduce and to quantify the impact of selection, interviewer, recall, misclassification, and information biases within poison center data to optimize the value of this important resource.

EVIDENTIARY CRITERIA USED TO LINK CAUSE AND EFFECT As was illustrated in Table 120–5, association of an exposure to an illness does not necessarily equate to cause and effect. In assessing causation it must be determined if bias is present in the selection or measurement of exposure or outcome. If a study is unbiased, the role of chance in the occurrence of the observed association must be explored. If an association is unbiased, unlikely to result from random error, and is not subject to confounding, then assumptions regarding to causation can be derived. Table 120–7 provides a list of evidentiary criteria that are often used to support causation. Many toxicologists deem clinical trials indicating a lack of benefit from gastric emptying, or indicating a therapeutic benefit

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TABLE 120–7.

Criteria Supporting Causation

Study design

Was the association demonstrated in a well-designed study? Does the cause precede the effect? What degree of relative risk was demonstrated in the analysis? Does an increased presence of risk factor correlate to greater or more frequent effect? Does the cause and effect hold true in different studies, locations, and populations? Is the association in accordance with current scientific knowledge? Does the effect occur without the cause in question, or vice versa?

Temporality Strength Dose response Consistency Plausibility Specificity

of hyperbaric oxygen therapy for carbon monoxide intoxication, unconvincing because of the degree of bias present in all relevant published clinical trials. Study design flaws such as bias and confounding are problematic for any epidemiologic study, and after decades of investigation, they still raise skepticism regarding the causative role of salicylate in RS. A wealth of evidence exists to support an etiologic relationship for salicylate with regard to RS. Salicylate administration in the prodromal phase of a viral illness was temporally related to the development of RS. The strength of association, as measured by the odds ratio from case-control studies, was enormous in epidemiologic terms. A study by a US Public Health Service Task Force determined that the adjusted odds ratio for an increased risk for RS if exposed to salicylate in the prodromal illness was 40.21 Because of the rare nature of RS, this measure approximates that salicylate-exposed individuals were at 40 times greater risk of developing RS than those not exposed to salicylate. Concerns of bias in early analytic studies were addressed in further studies,10 and the association between salicylate use and RS was consistent in refined analysis. Data from a number of studies suggested a dose-response correlation between salicylate use and RS.21,37 Finally, the association was consistent throughout different studies performed in different populations. After reviewing the strong epidemiologic evidence linking salicylate use to RS, in 1986 the United States Food and Drug Administration required labeling of aspirin warning of the possible association. Further evidence supporting the results of earlier case-control studies was the observation that the incidence of RS has fallen dramatically in apparent parallel to a decline in salicylate use.3,14 However, in clinical toxicology it is virtually impossible to prove causal relationships beyond any doubt. The goal is to build empiric evidence so that associations can be confirmed or refuted with conviction. To some physicians the link between salicylate therapy and RS remains a matter of debate. A recent review of 49 cases of diagnosed RS in Australia found that most of the cases were able to be reclassified as other medical conditions such as inborn errors of metabolism.29 Advances in medical technology, and a lack of absolute diagnostic criteria that could be applied to all possible RS patients, suggest that significant misclassification bias exists in most of the early RS research. Additionally, it has been suggested that antigenic shift within influenza B and varicella viruses may be an uncontrolled confounding variable in RS research.23 Despite these dissenting views, the overwhelming majority of evidence suggests that the association between salicylate therapy and development of RS is an important one. Of note, aspirin was taken by millions, and yet the peak incidence of RS was

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less than 10 cases per million. It remains unsolved whether salicylate use can cause RS in physiologically normal children with viral illness or, perhaps, whether there exists an unidentified metabolic abnormality that may place a specialized population at risk.

EVALUATION OF DIAGNOSTIC TESTS AND CRITERIA In clinical practice it is often useful to have a test, which may be a laboratory result or clinical paradigm, to help arrive at a diagnosis or predict an outcome. For instance, historical questionnaires, capillary blood lead levels, and venous blood lead levels might all be used to identify children at risk of neurocognitive injury from plumbism.7 However, each of these approaches is likely to have certain disadvantages in terms of effort, cost, discomfort, and/or accuracy. Targeting lead evaluation and therapy at children on the basis of exposure history is expected to be easy and inexpensive, but may not identify some children with significant poisoning; thus, the test may be susceptible to being falsely negative. Capillary blood testing is more costly and uncomfortable and may be susceptible to false-positive test results because of environmental lead dust present on fingertips. The possibility of false-positive or false-negative results must be considered with any diagnostic test (Fig. 120–4). The utility of diagnostic testing is often described in terms of sensitivity, specificity, predictive value of a positive test (PPV),

Figure 120–4. Possible results of diagnostic testing and the statistical characteristics used to describe the utility of diagnostic tests. The letters a, b, c, and d represent the numbers of tested individuals with or without the affliction of interest.

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and predictive value of a negative test (NPV). A cross-sectional design is often utilized to study diagnostic tests, as we seek to determine the prevalence of positive tests among the diseased (sensitivity), and the prevalence of negative tests among the healthy (specificity). A perfect test would be highly sensitive and specific, but this is seldom possible in clinical toxicology. A highly sensitive test is often used in screening programs because they rarely lead to false-negative diagnoses. Specific tests are typically used to “rule-in” a diagnosis, as they rarely yield false-positive results. Whereas sensitivity and specificity are inherent properties of a diagnostic test applied to a given population; the probability of disease, based on the results of a test, is highly dependent on the prevalence of disease within the population being tested. The PPV is the probability of having disease in a patient with a positive test; the NPV is the probability of not having disease when the test result is negative. A number of studies have tried to examine the utility of vomiting, leukocytosis, hyperglycemia, total iron-binding capacity, and radiographic findings in predicting toxicity after acute iron overdose. In a retrospective assessment of 40 patients with oral iron overdose, vomiting was found to predict a serum iron level above 300 µg/dL with a sensitivity of 84%, specificity of 50%, NPV of 44%, and PPV of 87%.31 This suggested that the presence of vomiting should raise concern for iron toxicity but that the lack of vomiting was not particularly reassuring. The calculation of the sensitivity, specificity, PPV, and NPV are illustrated in Fig. 120–4. It is important to remember that these calculations, too, are subject to bias and that these calculations are best presented with confidence intervals.

TABLE 120–8.

SUMMARY

REFERENCES

Clinical toxicology has embraced the vision of incorporating “evidence-based, or literature-based, medicine” into practice. Randomized clinical trials, though a noble goal, are rare and have proven difficult to perform within the discipline. As toxicologists move beyond descriptive data reporting, there remains great potential for scientific advancement in the field of toxicology via observational, hypothesis-testing, clinical research. Clinical investigators are charged with the imperative to perform studies based on sound epidemiologic principles. All studies, by nature of population sampling, are at the mercy of chance, but such random error can be quantified using statistical techniques. Systematic error (bias) can be limited, but not entirely excluded, through careful study design. Clinicians interpreting published toxicologic research need to thoroughly evaluate a study’s research objectives, design, data acquisition, analysis, and conclusions before applying the results to patient care (Table 120–8). Future epidemiologic investigation should allow more valid conclusions to be drawn regarding the associations between exposures and outcomes, or regarding the value of treatments for poisonings, discussed in the preceding chapters of this text. Galen, an influential physician from the second century, remarked of his clinical trial, “All who drink of this remedy recover in a short time, except those whom it does not help, who all die. Therefore, it is obvious that it fails only in incurable cases.” Unfortunately, error in contemporary clinical investigation of poisoning tends to be more insidious than the error in logic in Galen’s conclusion, and skillful scrutiny of published research remains an important endeavor.

1. Anderson KD, Rouse TM, Randolph JG: A controlled trial of corticosteroids in children with corrosive injury of the esophagus. N Engl J Med 1992;323:637–640. 2. Arrowsmith JB, Kennedy DL, Kuritsky JN, et al: National pattern of aspirin use and Reye’s syndrome reporting, United States, 1980 to 1985. Pediatrics 1987;79:858–863. 3. Belay ED, Bresee JS, Holman RC, et al: Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med 1999;340: 1377–1382. 4. Brody DJ, Pirkle JL,Kramer RA, et al: Blood lead levels in the US population: Phase 1 of the third Health and Nutrition Examination Survey (NHANES III, 1988–1991). JAMA 1994;272:277–283. 5. Buckley NA, Smith AJ: Evidence based medicine in toxicology: Where is the evidence? Lancet 1996;347:1167–1169. 6. Buckley NA, Whyte IM, Dawson AH, et al: Preformatted admission charts for poisoning admissions facilitate clinical assessment and research. Ann Emerg Med 1999;34:476–482. 7. Campbell C, Osterhoudt KC: Prevention of childhood lead poisoning. Curr Opin Pediatr 2000;12:428–437. 8. Caravati EM, McElwee NE: Use of clinical toxicology resources by emergency physicians and its impact on poison control centers. Ann Emerg Med 1991;20:147–150. 9. Ducasse JL, Celsis P, Marc-Vergnes JP: Non-comatose patients with acute carbon monoxide poisoning: Hyperbaric or normobaric oxygen. Undersea Hyperbar Med 1995;22:9–15. 10. Forsyth BW, Horwitz RI, Acampora D, et al: New epidemiologic evidence confirming that bias does not explain the aspirin/Reye’s syndrome association. JAMA 1989;261:2517–2524. 11. Freund KM, Belanger AJ, D’Agostino RB, et al: The health risks of smoking. The Framingham Study: 34 years of follow-up. Ann Epidemiol 1993;3:417–424.

Questions to Consider when Evaluating a Study

Research objectives What is the study question? What is the studied population? Study design What type of study was performed? How were subjects recruited and enrolled? Why were subjects excluded? What was the nature of the comparison group? Data accrual How were the data collected? Are the exposures and outcomes clearly defined? Are the observations reliable and reproducible? Was randomization and/or blinding used? Were subjects lost to followup? Analysis Are the results statistically significant? Are the results clinically significant? Are potential confounding variables controlled? Was the study powered to detect important differences? Conclusions Are the conclusions justified by data?

ACKNOWLEDGMENTS The author is grateful to Dennis Durbin, MD, MSCE, for his guidance in the preparation of this chapter. Eddy A. Brenitz, MD, authored this chapter in the previous edition.

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12. Gaudreault P, Parent M, McGuigan MA, et al: Predictability of esophageal injury from signs and symptoms: a study of caustic ingestion in 378 children. Pediatrics 1983;71:767–770. 13. Giles HM: Encephalopathy and fatty degeneration of the viscera. Lancet 1965;1:1075. 14. Hall SM, Lynn R: Reye’s syndrome [letter]. N Engl J Med 1999; 341:845. 15. Halpin TJ, Holtzhauer FJ, Campbell RJ, et al: Reye’s Syndrome and Medication Use. JAMA 1982;248: 687–691. 16. Hamilton RJ, Goldfrank LR: Poison center data and the Pollyanna phenomenon. J Toxicol Clin Toxicol 1998;35:21–23. 17. Harchelroad F, Clark RF, Dean B, et al: Treated vs. reported toxic exposures: discrepancies between a poison control center and a member hospital. Vet Hum Toxicol 1990;32:156–159. 18. Honein MA, Paulozzi LJ, Himelright IM, et al: Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromycin; a case review and cohort study. Lancet 1999;354:2101–2105. 19. Hoppe-Roberts JM, Lloyd LM, Chyka P: Poisoning mortality in the United States: Comparison of national mortality statistics and poison control center reports. Ann Emerg Med 2000;35:440–448. 20. Hoyt BT, Rasmussen R, Giffin S, et al: Poison center data accuracy: A comparison of rural hospital chart data with TESS database. Acad Emerg Med 1999;6:851–855. 21. Hurwitz ES, Barret MJ, Bregman D, et al: Public health service study of Reye’s syndrome and medications: Report of the main study. N Engl J Med 1987;257:1905–1911. 22. Johnson GM, Scurletis TD, Carrol NB: A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. NC Med J 1963;24:464–473. 23. Johnson GM: Reye’s syndrome [letter]: N Engl J Med 1999;341:846. 24. Litovitz TL, Klein-Schwartz W, White S, et al: 1999 Annual Report of the American Association of Poison Control Centers Toxic Exposures Surveillance System. Am J Emerg Med 2000;18:517–574. 25. Martin JD, Osterhoudt KC, Thom SR: Recognition and management of carbon monoxide poisoning in children. Clin Pediatr Emerg Med 2000;1:244–250. 26. Mathieu D, Wattel F, Mathieu-Nolf M, et al: Randomized prospective study comparing the effect of HBO versus 12 hours NBO in non-

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comatose CO poisoned patients. Undersea Hyperbar Med [Suppl] 1996; 23:7. McFee RB, Caraccio TR, Mofensen HC: The granny syndrome and medication access as significant causes of unintentional pediatric poisoning [abstract]. J Toxicol Clin Toxicol 1999;37:593. Olson KR, Seger D: Hyperbaric oxygen for carbon monoxide poisoning: does it really work? Ann Emerg Med 1995;25:535–537. Orlowski JP: Whatever happened to Reye’s syndrome? Did it ever really exist? Crit Care Med 1999;27:1582–1587. Osterhoudt KC, Henretig FM: How much confidence that calcium channel blockers are safe? [letter] Vet Hum Toxicol 1998;40:239. Palatnick W, Tenenbein M: Leukocytosis, hyperglycemia, vomiting, and positive x-rays are not indicatiors of severe iron overdose in adults. Am J Emerg Med 1996;14:454–455. Pond SM, Lewis-Driver DJ, Williams GM, et al: Gastric emptying in acute overdose: A prospective randomised controlled trial. Med J Aust 1995;163:345–349. Raphael JC, Elkharrat D, Jars-Guineestre MC, et al: Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 1989;2:414–419. Reye RDK, Morgan G, Baral J: Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood. Lancet 1963; 2:749–752. San Filippo JA: Infantile hypertrophic pyloric stenosis related to ingestion of erythomycin estolate: a report of five cases. J Pediatr Surg 1976;11:177–180. Scheinkestel CD, Bailey M, Myles PS, et al: Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: A randomised controlled clinical trial. Med J Aust 1999;170:203–210. Starko KM, Ray CG, Dominguez LB, et al: Reye’s syndrome and salicylate use. Pediatrics 1980;66:859–864. Tenenbein M: Good reasons to publish in Clinical Toxicology. J Toxicol Clin Toxicol 1998;36:137–138. Thom SR, Taber RL, Mendiguren II, et al: Delayed neuropsychologic sequelae after carbon monoxide poisoning: Prevention by treatment with hyperbaric oxygen. Ann Emerg Med 1995;25:474–480. Waldman RJ, Hall WN, McGee H, et al: Aspirin as a risk factor in Reye’s syndrome. JAMA 1982;247:3089–3094.

STUDY GUIDE: CASE STUDIES FROM THE TOXICOLOGY CONSULTATION SERVICE CASE STUDIES WITH QUESTIONS Case 1 A 28-year-old man presented to the hospital complaining of uncontrollable twitching of his extremities. He had a long history of uncomplicated intranasal heroin use and denied intravenous (IV) drug use, other substance abuse, or medical or surgical problems. He noted that he had recently changed his supplier of heroin. On examination he was found to be well developed, well nourished, and obviously uncomfortable. His vital signs were: blood pressure, 138/84 mm Hg; pulse, 110 beats/min; respiratory rate, 24 breaths/min; and rectal temperature, 99°F (37.2°C). Physical examination was normal except for the neurologic assessment. He was awake, alert, and fully oriented. His limbs showed irregular and bilateral spontaneous contractions, and their activity increased while he was examined. His mental status remained unchanged during these movements. Strength and sensation were within normal limits, and reflexes were brisk. Chvostek and Trousseau signs were negative. The patient was attached to a cardiac monitor, and an IV line was inserted. Blood was sent for a complete blood count (CBC), serum electrolytes, glucose, calcium, magnesium, and creatine phosphokinase. A urinalysis was also requested. An electrocardiogram (ECG) showed a normal sinus rhythm with normal axis and intervals and a motion artifact. 1. 2. 3. 4.

diagnosis of hepatic failure with an encephalopathy. His treatment consisted of lactulose, dextrose infusion, dietary control, and Nacetylcysteine. Despite aggressive care, his bilirubin continued to rise, his coagulopathy worsened, and his mental status deteriorated. The patient was evaluated for possible liver transplantation but was thought to be a poor candidate because of his history of alcoholism and the fact that he was positive for hepatitis B surface antigen. The patient died. His postmortem evaluation was thought to be consistent with fulminant isoniazid (INH) hepatotoxicity in the presence of alcoholic and viral liver disease (Fig. CS–1). 1. What is the incidence of INH hepatitis? What are the risk factors? 2. Is the metabolism of INH related to the risk of hepatotoxicity? 3. Can toxin-induced hepatitis be differentiated from viral and other causes of hepatic injury? 4. Why did this patient receive N-acetylcysteine? 5. How frequently should patients receiving INH be evaluated to prevent severe hepatotoxicity?

Case 3

What is the differential diagnosis of this patient’s disorder? What is the most likely toxin? How are the clinical effects of this toxin manifested? How should the patient with this clinical presentation be evaluated and treated?

A 16-year-old girl with a history of epilepsy who had recently become pregnant ingested a large quantity of unknown medications in a suicide attempt. She was brought to the hospital in status epilepticus. Although the patient was given a benzodiazepine, she continued to seize. A 15 mg/kg loading dose of phenytoin was given, but intermittent seizures persisted. A continuous infusion of a short-acting barbiturate was initiated, and her motor activity normalized. A bedside electroencephalogram (EEG) revealed electrical evidence of seizure activity, although no overt motor activity was noted concomitantly. Hypotension developed over a period of several hours and continued despite the administration of vasopressor agents. The patient died.

Case 2 1. What is the differential diagnosis of drug-induced seizures? 2. What is the mechanism by which this particular toxin produces status epilepticus? 3. How should the patient in this case have been managed? 4. What antidotes, if any, should be used in the management of a patient with status epilepticus?

A 39-year-old man presented to the hospital complaining of feeling weak and tired and noted that his skin and eyes had turned yellow. He had a history of hepatitis B and alcohol abuse but was otherwise well until about 7 months earlier, when he was found to be Purified Protein Derivative-positive and to have an abnormal chest radiograph. At that time he was started on isoniazid, rifampin, and pyrazinamide for what was presumed to be active tuberculosis. About 4 weeks before presentation he began to notice a change in skin color and stopped his medications. He presented to the emergency department (ED) with worsening symptoms and progressive weakness. Physical examination was notable for scleral and dermal icterus, lethargy with intact orientation, and asterixis. Laboratory analysis showed an aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 166 and 518 IU/L, respectively, a total bilirubin of 21 mg/dL, a prothrombin time (PT) of 21.7 seconds, and a glucose of 62 mg/dL. He was admitted to the hospital with a

Case 4

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A 20-month-old girl unintentionally ingested an unknown amount of a home hair permanent product. She presented to the ED with several episodes of vomiting. Physical examination revealed a child in apparent good health; she was crying and intermittently vomiting. Vital signs were normal, as was the remainder of the examination. The patient had no oropharyngeal lesions on direct inspection. An IV line was inserted, and the patient received a 10 mL/kg bolus of 0.9% sodium chloride solution followed by a mainte-

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Figure CS–2 Radiographs of the remaining 9 of 12 candies revealed their heavy-metal content. The lack of uniform distribution of radiopaque material was highly suggestive of a handmade preparation. (Courtesy of the Medical Toxicology Fellowship of the New York City Poison Control Center.)

Figure CS–1 Postmortem histology of the patient’s liver demonstrating fulminant hepatic failure with a nearly complete loss of hepatic architecture. Additional evidence for alcoholic liver disease and chronic viral hepatitis was noted.

nance infusion. A CBC and serum electrolytes were sent and later returned as normal. Chest and abdominal radiographs were unremarkable. Her vomiting stopped, and she was able to eat and drink normally. Although fluid resuscitation was given, her creatinine rose from 0.6 to 1.2 mg/dL on the second day and to 1.9 mg/dL on day 3. No other abnormalities were noted. 1. What agents are commonly found in hair care products? 2. What are the toxicities of these agents? 3. Is any other therapy required? Are there any specific antidotes?

Case 5 A 26-year-old woman received an anonymous box of candy in the mail. She ate a single piece, gave another piece to a friend, and two other people shared a third piece of candy. Within the first 24 hours of the ingestion, two patients experienced some gastrointestinal upset and had a few loose bowel movements, one patient noted constipation, and the other patient had no gastrointestinal complaints. All four patients noted pleuritic chest pain. At about 24 hours after ingestion all four patients developed numbness of the hands and feet, which progressed in severity over the next day such that the painful paresthesias limited walking in two patients. These symptoms were most pronounced in the two patients who ingested whole candies. Their pain became so severe as to confine

them to strict bed rest, requiring continuous infusion of morphine for pain control. Physical examination and laboratory evaluation, including CBC and differential, electrolytes, blood, urea, nitrogen (BUN), and glucose, were all unremarkable. Urinalysis showed trace proteinuria in the two most severely ill patients. The ECG demonstrated a sinus tachycardia with U waves and nonspecific Twave morphology. Because of the atypical nature of both the patient’s complaints and the candies (e.g. their weight and shape) a radiograph was obtained (Fig. CS-2). On the fifth day after ingestion, hypertension and tachycardia developed in the two more severely affected patients. Hair loss was noted on the sixth day and progressed to total alopecia during the second to third week. 1. What is the differential diagnosis of this illness, and what clinical findings suggest a specific toxin? 2. How does this toxin produce its toxicity? 3. What are the clinical stages of this poisoning? 4. Once considered, how is the diagnosis confirmed? 5. What are the treatment options for this poisoning?

Case 6 A 25-year-old presented to the ED complaining of a pruritic rash most prominent on his arms and legs. The patient knew of no allergies and had never had a similar rash. The rash began earlier in the day and was not associated with the introduction of any new medications, soaps, or foods. The patient stated that he had just returned from a two-day family camping trip during which time he went swimming in a lake. Examination of the rash revealed linear vesicles on an erythematous and mildly edematous base with marked excoriation. The rash was most prominent on his distal upper and lower extremities but was also present on his left neck and left buttock. 1. 2. 3. 4.

What is the differential diagnosis of this patient’s rash? What is phytophotodermatitis? What is allergic contact dermatitis? What is the therapy?

CASE STUDIES FROM THE TOXICOLOGY CONSULTATION SERVICE

Case 7 A 79-year-old man was brought to the hospital complaining of malaise, anorexia, nausea, urinary frequency, shortness of breath, and worsening lethargy, all of 5 days’ duration. He had a history of coronary artery disease and diabetes mellitus and was being treated with a
-adrenergic antagonist, a diuretic, a nitrate, and an oral hypoglycemic agent. The patient was well until about 1 week before the hospitalization, when he developed the onset of a cough and sore throat. A private physician was consulted, and an antibiotic was prescribed, but the patient never took the medicine. The patient was ill-appearing and in obvious discomfort. His vital signs were: blood pressure, 90/50 mm Hg; pulse, 44 beats/ min; respiration, deep at 26 breaths/min; and temperature, 94°F (34.4°C). The only positive findings on examination included right upper quadrant tenderness with guarding, decreased bowel sounds, and stool that tested trace positive for occult blood. Laboratory data were as follows: ABG on a nasal cannula at 2 L/min; pH, 7.04; PCO2, 15 mm Hg; PO2, 115 mm Hg. The sodium was 132 mEq/L; potassium, 7.8 mEq/L; chloride, 91 mEq/L; bicarbonate, 6 mEq/L; BUN, 116 mg/dL; creatinine, 4.9 mg/dL; and glucose, 193 mg/dL. Urine analysis was trace positive for ketones, but without glucose. Adjunctive laboratory studies were performed. A urine ferric chloride test was negative, and no urinary crystals or fluorescence was noted. Similarly, the serum calcium was normal. A serum lactate was determined to be 10.7 mEq/L. A repeat lactate concentration, drawn about 1 hour later, was 17.2 mEq/L. Because of the abdominal pain, guaiac-positive stools, hypotension, and lactic acidosis in an elderly diabetic, the diagnosis of ischemic bowel was considered. A minilaparotomy was performed, and a visual inspection of the bowel as well as chemical analysis of the peritoneal fluid were thought to be normal. 1. 2. 3. 4.

What are the acid–base abnormalities? What is the differential diagnosis? How can the differential diagnosis be narrowed clinically? What therapy is required?

Case 8 A 22-year-old man ate pizza and presented to the emergency department with tonic-clonic movements of all of his extremities that were described by the primary care provider as status epilepticus. The patient was awake throughout these periods. Initial vital signs were: blood pressure, 130/80 mm Hg; pulse, 105 beats/min; respirations, 20/min; rectal temperature 102.5°F (39.2°C). Physical examination was notable for pupils that were 4 mm in size, equal, round, and reactive to light. Skin was diaphoretic. Auscultation of the chest, heart, and abdomen was normal. Neurologic examination revealed an anxious man who was oriented to time, place, and person. Coarse uncontrollable movements of all extremities were noted. Reflexes were brisk and symmetric, and plantar flexion was present. The patient was treated with diazepam, phenobarbital, and phenytoin, after which he was noted to be stuporous, but with normal muscle tone. The only history available from friends was that the patient had had a “cold” recently. 1. What is the differential diagnosis of tonic-clonic movements in a patient with a normal mental status?

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2. What is the experimental and physiologic basis for this patient’s movement disorder? 3. What therapies are indicated for this patient?

Case 9 A 91-year-old woman with a history of glaucoma treated with acetazolamide and atrial fibrillation controlled with digoxin complained of chest pain, left-sided headache, and palpitations during dinner. Later that night, the family noted that she was confused and called an ambulance. On arrival at the hospital the patient was found to be lethargic and disoriented and afebrile. Her vital signs were: blood pressure, 128/78 mm Hg; pulse, 110 beats/min and irregular; respiratory rate, 20 breaths/min. She was noted to be diaphoretic and to have a right-sided facial droop, right-sided hemiparesis, and bilateral plantar extension. 1. What emergent therapy is required? 2. What are the risks of failing to identify this clinical problem? 3. How are these patients best managed?

Case 10 A 5-week-old child was admitted to the hospital for evaluation of neonatal sepsis. Following blood and urine cultures and a lumbar puncture, the child was started on an antibiotic regimen that included intravenous gentamicin. The child inadvertently received 10 times the recommended dose of IV gentamicin. 1. What are the most common calculation errors that occur in neonates? 2. How can these errors be prevented? 3. What toxicity can be expected from this error? 4. Are any special treatments indicated for patients with aminoglycoside toxicity?

Case 11 A 42-year-old woman with a history of IV drug use was admitted to the hospital with seizures and coma secondary to end-stage renal failure. Her admission laboratory studies were remarkable for a BUN of 140 mg/dL; creatinine, 10.8 mg/dL; potassium, 7.9 mEq/L; and bicarbonate, 4 mEq/L. ECG demonstrated severe hyperkalemic changes (Fig. CS–3). Immediate therapy consisted of intravenous calcium, insulin and dextrose, and sodium bicarbonate. The patient was intubated and given diazepam for her seizures. Peritoneal dialysis (PD) was begun because of poor vascular access.

Figure CS–3 Electrocardiographic (ECG) findings of hyperkalemia. The initial ECG shows tall peaked T waves, a prolonged QRS complex, ST segment depression, a prolonged PR interval, and flattening of the P wave. As toxicity progresses, the P wave is lost, and the QRS complex widens. Ultimately, a sine-wave pattern can develop.

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After 24 to 48 hours of PD she was extubated as her electrolyte status began to improve (BUN, 98 mg/dL; creatinine, 6.1 mg/dL; potassium, 4.0 mEq/L). Inadvertently, she was then dialyzed with 2 L of Uromatic (an irrigation solution containing 1.5 g of glycine/100 mL, used for urologic procedures) instead of standard PD solution. Subsequently, the patient had several more seizures, which were controlled with diazepam.

1. What toxicity would be expected from this agent? 2. What therapy is required?

Case 12 A 10-year-old boy suffered a midshaft femur fracture. Before external fixation he was given 30 mL of 2% lidocaine for a femoral block and another 10 mL with epinephrine subcutaneously for insertion of a tibial pin. He weighed 30 kg. Within 20 to 25 minutes he developed seizures, which did not respond to intravenous diazepam (5 mg) or to intravenous lorazepam (5 mg). General anesthesia was induced with IV methohexital, and the child was intubated. During induction of anesthesia the seizures stopped. The child subsequently had a transient episode of hypotension that responded rapidly to a fluid challenge. His ECG was within normal limits. Over the course of the next several hours he began to have spontaneous movements, then withdrew to pain, and slowly regained a normal mental status. The boy was extubated about 8 hours later and had a complete neurologic recovery.

1. 2. 3. 4.

What is the differential diagnosis? What are the clinical consequences of this type of poisoning? What is the treatment of this poisoning? Is there a role in this case for the laboratory determination of serum drug levels?

Figure CS–4 Rhythm strip from the patient demonstrating a regular widecomplex dysrhythmia felt to be consistent with ventricular tachycardia.

Case 14 A 62-year-old Asian man was bitten on the thumb by an unknown animal while playing Frisbee on a cool October morning in Central Park (New York City). He presented to the ED 2 hours later complaining of pain and swelling of his hand. The patient’s entire hand and distal forearm were swollen, tender, tense, and warm. He had pain on passive extension of his fingers, normal sensation in his fingers, and both an adequate radial pulse and capillary refill. There were two “fang” marks noted at the bite site, both of which oozed serosanguineous fluid. Two hours later, the swelling progressed to his shoulder. 1. Is this patient’s history consistent with the available epidemiologic data? 2. What are the complications of snake envenomation? 3. How should the patient be assessed for a compartment syndrome?

Case 13

Case 15

A 40-year-old man was found unresponsive in his car. The paramedics noted that he was apneic, with a sweet smell on his breath, as they intubated him. When he arrived in the ED the patient was hypotensive with a palpable blood pressure of 80 mm Hg and a tachycardia of 140 beats/min, with no spontaneous respirations and a rectal temperature of 97.6°F (36.4°C). His pupils were dilated to 6 mm and were sluggishly reactive to light. Neurologic examination showed deep coma with intact corneal reflexes. The blood pressure failed to respond to an IV bolus of fluid, and the patient was started on dopamine. Almost immediately after the dopamine infusion was started he had a run of ventricular tachycardia (Fig. CS–4) that responded to electrical cardioversion. The rate of his dopamine drip was reduced. Following 2 to 3 hours of fluid resuscitation, his blood pressure returned to normal, and the dopamine infusion was discontinued. Eighteen hours later he was awake and alert. Abnormal liver enzymes were noted.

An 84-year-old woman made a stew with milkweed (Asclepias speciosa) and presented to the hospital with vomiting. After questioning she noted that the milkweed appeared to differ from the usual plants she ate. Her vital signs were: blood pressure, 160/70 mm Hg; pulse, 80 beats/min; respiratory rate, 14 breaths/ min; and temperature, 98°F (36.7°C). The remainder of her physical examination was unremarkable. CBC, serum electrolytes, BUN, and glucose were all within normal limits, and an ECG showed normal sinus rhythm with normal intervals. The initial impression was that the patient had ingested a gastrointestinal irritant or was suffering from bacterial food poisoning. Intravenous rehydration was initiated, and the patient was given a dose of 60 g of oral activated charcoal. She vomited several more times. Over the next 12 hours she developed first-degree heart block (PR interval of 0.26 seconds) and a bradycardia of 50 beats/min, which fell to 20 beats/min during emesis.

1. Do these findings suggest an overdose? If so, of what? 2. What are the mechanisms responsible for the cardiovascular and hepatic toxicities in this patient? 3. What tests could help confirm the diagnosis? 4. What specific treatment issues should be considered?

1. What group of toxins is the most likely cause of this patient’s poisoning? 2. What are the clinical manifestations produced by these poisons? 3. Are any routine laboratory tests useful to assist with this diagnosis?

CASE STUDIES FROM THE TOXICOLOGY CONSULTATION SERVICE 4. What other evaluations will assist in establishing this diagnosis? 5. What treatment is indicated?

Case 16 An 18-year-old healthy female student who was taking part in a physiology laboratory experiment ingested about 1 L of a “buffered saline solution.” Immediately thereafter she complained of headache and nausea and had a syncopal episode. Emergency medical services was contacted, and the patient was brought to the ED. On arrival, her vital signs were: blood pressure, 150/90 mm Hg; pulse, 110 beats/min; respiratory rate, 22 breaths/min; and rectal temperature, 98.6°F (37.0°C). Her physical examination was reported as unremarkable. She was evaluated for syncope, given the diagnosis of psychosomatic illness, and discharged. Twenty-four hours later she presented to a second hospital complaining of shortness of breath and was found to have congestive heart failure. She was transferred to the intensive care unit of a third institution and died 12 hours later. 1. What substances are commonly available in laboratories that could cause these symptoms? 2. By what mechanism does the implicated toxin produce its toxicity? 3. What therapy is required? 4. Are there any special risks to the medical personnel caring for the patient?

Case 17 A 49-year-old woman was referred to the ED by her private physician for evaluation of abnormal laboratory findings. The patient was recently diagnosed with gout after having presented with pain in her left great toe. At that time she was given colchicine, with total relief of her symptoms. On return home, her physician obtained the following laboratory studies: uric acid, 18 mg/dL; BUN, 100 mg/dL; creatinine, 2.8 mg/dL; and serum bicarbonate, 34 mEq/L. Her physician told her to stop the colchicine, drink water, and go to the hospital. In the ED, the woman was described as thin, in no distress, and appearing slightly dehydrated. Her mouth and mucous membranes were dry. Her vital signs were: blood pressure, 114/70 mm Hg; pulse, 64 beats/min; respiration, 18 breaths/min; and rectal temperature, 98.0°F (36.7°C). With orthostatic testing her blood pressure fell to 100/60 mm Hg, and her pulse rose to 88 beats/min. 1. What is the acid–base abnormality, and what are the most common causes? 2. What toxins cause gout or arthritic symptoms? 3. What other adverse effects are associated with this class of toxin? 4. What therapy is required?

Case 18 A 45-year-old woman presented to the hospital complaining of persistent right great toe pain, abdominal pain, malaise, nausea, vomiting, and 25 episodes of diarrhea over the previous day. She had a history of gout, for which she had been given colchicine (0.6 mg) in the past with relief. Beginning almost 3 days before presentation, she began to take her colchicine for recurrent great

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toe pain. She took two tablets every 1 to 2 hours for a total of 50 to 60 mg, without relief. On presentation she was concerned that she was having so much abdominal discomfort that she was unable to take her colchicine. Her past medical history was remarkable for asthma, gout, hypertension, and renal insufficiency. Her vital signs were: blood pressure, 170/80 mm Hg; pulse, 86 beats/min; respirations, 12 breaths/min; and temperature, 100.4°F (38.0°C). There were no orthostatic changes in her vital signs. The remainder of the examination was unremarkable. 1. What is colchicine, and why is it used? 2. What are the signs and symptoms of colchicine toxicity? 3. What immediate therapy is required? 4. What other therapies are available or under investigation?

Case 19 A 27-year-old man was found unresponsive at the international airport. When emergency medical services arrived, they found a well-developed man in respiratory distress. His vital signs were: blood pressure, 90 mm Hg by palpation; pulse, 78 beats/min; and respirations, 4 breaths/min. His skin was cool and moist, and his pupils were pinpoint. The medics administered high-flow oxygen, started an IV line, and gave 2 mg of naloxone, 50 g of dextrose, and 100 mg of thiamine IV with a transient response. Another 2 mg of naloxone was given IV en route to the hospital, again with some improvement in mental status and respirations. On arrival at the ED the patient was lethargic but arousable to deep stimulation. His vital signs were: blood pressure, 110/70 mm Hg; pulse, 84 beats/min; respiratory rate, 6 breaths/min; and rectal temperature, 97.0°F (36.1°C). A pulse oximeter read 100% saturation on high-flow oxygen. His skin was cool, and the only abnormal finding on physical examination was the persistence of pinpoint pupils. 1. What happened? 2. What immediate diagnostic and therapeutic interventions are required? 3. How can the diagnosis be established? 4. What is the role of gastrointestinal decontamination?

Case 20 A 49-year-old unresponsive woman was brought to the ED. She had been smoking crack cocaine the day before admission. When her mother found her disoriented and having profuse diarrhea, she called an ambulance. On arrival in the ED the woman was unresponsive, with no palpable blood pressure or pulse, spontaneous respirations of 8 breaths/min, and a rectal temperature of 99.0°F (37.2°C). She was immediately intubated, given 100% oxygen, and placed on a cardiac monitor, which showed a sinus tachycardia at 140 beats/ min. Two large-bore IV lines were inserted, and lactated Ringer’s solution was infused wide open. After several liters of fluid her blood pressure rose to 100 mm Hg by palpation. After resuscitation she regained her mental status and complained of diffuse abdominal pain. Physical examination was notable for a distended abdomen with decreased bowel sounds and stool that was positive for occult blood. Radiographs demonstrated dilated loops of bowel.

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1. What are the gastrointestinal manifestations of cocaine use? 2. What therapy is required? 3. What other toxins are associated with bowel ischemia or infarction?

Case 21 A 47-year-old man with a history of schizophrenia presented to the emergency department complaining of thirst. On examination he was noted to be diaphoretic, tachycardic (120 beats/min), tachypneic (28 breaths/min) with hyperpnea, with a temperature of 100.3°F (37.9°C) and a blood pressure of 100/80 mm Hg. When asked about medication use, the patient stated that he has been taking several aspirin tablets per day for the last several days. 1. 2. 3. 4.

What is the differential diagnosis? What toxicologic syndrome is present? What diagnostic tests are useful? What therapy is indicated?

Case 22 A 60-year-old woman with a history of inflammatory bowel disease, lower gastrointestinal bleeding, and multiple lower extremity deep venous thromboses was admitted to the hospital with increased swelling of her right leg. A computed tomography (CT) scan showed a clot extending above her Greenfield filter. A second filter was inserted, and the patient was started on warfarin. A few days later, a large lesion was noted on her thigh and was said to resemble a burn. Later the lesion became necrotic and required extensive debridement. 1. What is the mechanism of action of warfarin? 2. What is the purple toe syndrome? 3. What is the skin lesion?

Case 23 A 36-year-old man came to the hospital complaining of eye pain and blurry vision after an unintentional splash of hydrofluoric acid (HF) into his right eye while at work. The patient was a healthy man who was employed by a construction company. His job was to clean the rust from some equipment. Although he knew he was supposed to wear safety glasses, an apron, and gloves while working with the acid, he was in a hurry and forgot his glasses. Immediately after the event, he flushed his eye for 20 minutes with tepid water. The pain persisted, and when he noted difficulty seeing, he came to the hospital. He denied any other exposure to HF. Physical examination revealed an uncomfortable man with normal vital signs. Visual acuity was 20/20 in his left eye but only 20/100 in his right eye. His right lid was slightly reddened and swollen, there was a moderate degree of blepharospam, and his conjunctivae were injected but without chemosis. A topical anesthetic was administered to allow a more complete examination. When his pain and spasm resolved, a slit lamp examination was performed and demonstrated multiple shallow punctate areas of fluorescein uptake without other abnormalities. 1. What is HF, and what is it used for? 2. What is the treatment for HF burns of the skin? 3. What is the treatment for HF burns of the eye?

Case 24 A 34-year-old recently discharged male Marine officer arrived at the ED via EMS in coma 3 hours after ingesting a bottle of pills and ethanol in a suicide attempt. He was unresponsive, and his vital signs were normal except for a heart rate of 110/min. Physical examination revealed mydriasis, a nonfocal neurologic exam, and absence of an identifiable toxicologic syndrome. His pulse oximeter was 99%, and his fingerstick glucose was 110 mg/dL. Laboratory testing, including serum chemistry and arterial blood gas analysis, was normal except for an ethanol level of 120 mg/dL. An electrocardiogram exhibited sinus tachycardia with a QRS duration of 110 milliseconds. Three hours following admission, the patient fully awakened and stated that he could neither see nor hear, although he seemed only minimally concerned by this predicament. Repeat ocular examination revealed that he had no light perception, and his pupils were 6 to 7 mm in diameter with minimal reactivity to light. Examination of his globe, extraocular movements, and retina were normal; opticokinetic nystagmus was absent. Auditory testing confirmed that he was unable to hear. 1. 2. 3. 4.

What are the toxicologic causes of blindness? What are the toxicologic causes of hearing loss? What is the most likely cause in this patient? What therapeutic approach is appropriate?

Case 25a A 10-year-old boy was brought to the hospital complaining of dysphagia and epigastric pain. He had essentially no past medical history other than a severe pollen allergy. On further review he revealed that he was recently started on Claritin. Physical examination revealed a well-developed boy who was somewhat uncomfortable. Vital signs were remarkable only for a slight tachycardia. Examination of the oropharynx was normal. Endoscopy revealed circular small erosions of his distal esophagus and stomach. The patient was treated with antacids and a clear liquid diet, and his symptoms resolved.

Case 25b A 56-year-old woman presented to the hospital complaining of the inability to straighten her head, her eyes, and her tongue. She had a history of asthma, for which she normally took an inhaled
-adrenergic agonist alone. She was well until about 1 week earlier, when she was hospitalized for an exacerbation of her asthma. During her admission she received a parenteral antibiotic and corticosteroids. No other medications were given. After 4 days in the hospital, she was discharged on her inhaled
agonist and a prednisone taper. The emergency department staff recognized that she had a dystonic reaction and gave her 50 mg of diphenhydramine intravenously over about 1 minute. Within 5 minutes all of her symptoms resolved, and she felt well. 1. What do these two cases have in common? 2. How did these atypical reactions occur? 3. Why do these events happen? How can they be prevented?

Case 26 A healthy suburban husband and wife presented to the hospital complaining of severe gastrointestinal distress. The couple and

CASE STUDIES FROM THE TOXICOLOGY CONSULTATION SERVICE their two children had no significant medical problems and no history of occupational or environmental exposure to toxins. All members of the family were well until the day of admission, when the wife prepared a meal that consisted of some meat and wild mushrooms that she had picked from a neighbor’s lawn. Although all four members of the family shared the meal, only the husband and wife ate the mushrooms. Everyone thought that the meal tasted fine and had no complaints until about 5 or 6 hours later, when the husband and wife began to experience nausea and vomiting, followed shortly thereafter by severe watery diarrhea. The children remained asymptomatic. When these symptoms became intolerable, they sought medical care. On presentation to the hospital, both adults appeared ill and had vomiting and diarrhea. Their vital signs were notable for a resting tachycardia and orthostatic hypotension. They were afebrile and had otherwise normal physical examinations. Intravenous antiemetics were administered and hydration was begun. 1. 2. 3. 4.

What is the differential diagnosis for this illness? How is the diagnosis confirmed? What is the pathophysiology of this poisoning? What treatment is indicated?

Case 27 A 41-year-old man with a history of alcohol and Xanax abuse ran out of his Xanax and began medicating himself with a chemical that he had saved from a chemistry laboratory some 20 years earlier. The patient presented to the hospital 1 month later with confusion and hallucinations. His initial vital signs were: blood pressure, 120/70 mm Hg; heart rate, 120 beats/min; respirations, 18 breaths/min; temperature, 98.6°F (37°C). His pupils were small and reactive, his skin was normal and without diaphoresis, and his bowel sounds were normal. Initial laboratory values were reported as: sodium 144 mEq/L, potassium 4.6 mEq/L, chloride “interfering substance,” bicarbonate 31 mEq/L, BUN 7 mg/dL, Cr 1.0 mg/dL, Glu 114 mg/dL. The patient was admitted to psychiatry with a diagnosis of psychosis. During a 3-day admission on psychiatry, the patient’s condition deteriorated. He became comatose and required intubation. At that time, his laboratory values were: sodium 144 mEq/L, potassium 4.2 mEq/L, chloride 161 mEq/L, bicarbonate 26 mEq/L, BUN 12 mg/dL, Cr 1.1 mg/dL, Glu 164 mg/dL. 1. What general differential diagnosis should be considered? 2. What is the differential diagnosis of a low or negative anion gap? 3. What is the cause of the patient’s dramatically elevated chloride? 4. What is the treatment for this patient?

Case 28 Three male co-workers at a dye manufacturing plant inadvertently mixed two chemicals. One employee, not wearing his respirator, was immediately overcome and collapsed. A second employee removed his respirator to call for help and also succumbed. The third employee fled the area to seek help, leaving his respirator in place. The two collapsed employees were safely evacuated by appropriately protected rescuers. EMS arrived and intubated both patients, who were apneic. A weak carotid pulse of 110 to 120 beats/min was obtained in both patients, and an ECG monitor

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recorded a sinus tachycardia en route to the emergency department. On arrival in the emergency department, the physical examinations of both patients were remarkably similar. Vital signs on one patient revealed a blood pressure of 170/108 mm Hg, heart rate of 120 beats/min, mechanical ventilation on an FIO2 100% at 24/min, and a temperature of 99°F. Head and neck were atraumatic with 3-mm pupils and pink mucous membranes. Heart and lung examination was significant for clear breath sounds without wheezing or rales. The skin color was normal, without cutaneous burns, and was well perfused. A carboxyhemoglobin level was 4%, and arterial blood gas (ABG) on 100% was pH 7.37; PCO2, 32 mm Hg; and PO2, 242 mm Hg. The chest radiograph was negative. 1. What is the differential diagnosis for these patients’ symptoms? 2. How does this exposure typically occur? 3. What are the expected clinical effects following exposure to this toxin? 4. What treatment is indicated?

Case 29 A 37-year-old woman ingested 30 sleeping pills in an apparent suicide attempt. She was brought to the emergency department via EMS approximately 1 hour after ingestion. Her initial vital signs were: blood pressure, 130/80 mm Hg; pulse, 100 beats/min; respirations, 12 breaths/min; and she was afebrile. Her physical examination was significant for marked depression of her mental status, normal pupillary function, and normal neurologic findings. As part of the routine evaluation, dextrose (25 g), naloxone (2 mg), and 10 L of vasal oxygen, were given. The patient’s mental status continued to deteriorate, and she was intubated for airway protection. Orogastric lavage was performed with a 40-F tube, and activated charcoal was given. A pulse oximeter read 100% saturation, and a cardiac monitor revealed frequent multifocal premature ventricular beats and runs of nonsustained ventricular tachycardia (Fig. CS–5). 1. What sleep-inducing agents are available? 2. What are the clinical manifestations of poisoning by these agents? 3. Is there a role for empiric flumazenil administration?

Case 30 A 40-year-old woman was found unresponsive shortly after locking herself in the bathroom. Her husband found a suicide note and three syringes by her left arm, two of which were empty. EMS was summoned and found a lethargic woman, breathing spontaneously, with blood pressure 110 mm Hg by palpation and heart rate 80 to 90 beats/min. The patient was transported to the hospital along with the syringes. En route, a fingerstick revealed a glucose of 80 mg/dL, and the patient was given 50% dextrose (25 g) and 2 mg naloxone without improvement in her mental status. In the emergency department the patient was noted to be more arousable, with similar vital signs. Physical examination was significant for a slight contusion to her forehead and evidence of tongue biting. Pupils were 4 mm and reactive, and no toxidrome was identified. Her mental status gradually improved and was most consistent with a postictal period. The first electrocardiogram was interpreted as a sinus rhythm at 80 beats/min without evidence of axis devia-

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Figure CS–5 tachycardia.

A lead II rhythm strip from the patient demonstrating ventricular ectopy of varying morphology. The patient also had short runs of ventricular

tion or widened intervals. Laboratory analysis was significant for an arterial blood gas with a pH of 7.29, PCO2 of 40 mm Hg, and a PO2 of 70 mm Hg, consistent with a metabolic acidosis. Subsequent arterial blood gases revealed rapid resolution of the acidosis. Electrolytes were normal. Serum and urine drug screens were negative for opioids, barbiturates, phencyclidine, aspirin, cyclic antidepressants, and acetaminophen. A serum ethanol level was also negative. The patient’s sensorium cleared completely, and she had a normal mental status within a couple of hours; however, she would not elaborate on the substance she injected. The three syringes were sent to the laboratory for analysis. 1. What is the differential diagnosis for this exposure? 2. What are the manifestations of this poisoning? 3. What is the treatment?

Case 31 An 18-year-old man, recently immigrated from the Dominican Republic, presented to the hospital 1 hour after ingesting a granular rodenticide imported from his home country. He stated that the product was unavailable in this country. He complained of mild abdominal pain, appeared uncomfortable, and had vomited at least once. His vital signs were notable for a heart rate of 130 per minute, a normal blood pressure, and a respiratory rate of 30 per minute. On physical examination the patient had moist skin and mucous membranes, and his pupils were 1 mm in diameter. In addition, the patient was slightly lethargic with a normal mental status. The remainder of the neurologic examination was normal. Over the next hour, the patient developed pulmonary edema and required intubation.

nophen was undetectable in her serum, and her urine pregnancy test was qualitatively positive. 1. What toxins may have caused this patient’s hepatotoxicity? 2. Why is the history of herbal medicine important? 3. What herbal medications are used to treat female reproductive problems?

Case 33 A 52-year-old man presented to a Florida hospital emergency department complaining of nausea, vomiting, and leg weakness. The patient was well until 30 minutes after he ate a meal that included two fish he had caught that morning. The fish smelled and tasted normal. Initially he noted nausea, and this was followed shortly by several episodes of emesis and difficulty in standing and walking. His girlfriend, who had eaten a similar meal with the exception of the fish, remained asymptomatic. The patient was very ill-appearing, complaining of extreme fatigue and weakness. His vital signs included a blood pressure of 110/70 mm Hg, a heart rate of 120 beats/min, a respiratory rate of 12 breaths/min and labored, and a temperature of 97.7°F (36.5°C). His physical examination was remarkable for significant motor weakness throughout, including his respiratory muscles. During the first 30 minutes in the department, the patient’s blood pressure fell to 85/60 mm Hg, and his respiratory status worsened. He received fluids and was orotracheally intubated, and ventilation was assisted with a good response. Within 1 hour of intubation the patient was completely flaccid and unresponsive.

1. What is the differential diagnosis of “rat poison” ingestion? 2. How does this type of poison work? 3. What is the treatment for patients poisoned by these agents?

1. What is the differential diagnosis for this illness? 2. What common marine illnesses present with neurologic symptoms? 3. What is the treatment for this patient’s poisoning?

Case 32

Case 34

A 27-year-old woman who had used a herbal medication for 2 weeks to promote menstruation stopped the herb and sought medical care when she developed nausea, vomiting, and diarrhea. In the emergency department her vital signs were normal, and she was otherwise well. The patient was found to have jaundice, right upper quadrant tenderness, and an AST of 2000 IU, an ALT of 2000 IU, an LDH of 4000 IU, and a PT of 18 seconds. Acetami-

A 35-year-old man presented to the hospital stating he ingested 1 pint of antifreeze. He had no significant past medical history and was asymptomatic. Vital signs were remarkable for tachycardia at 105 beats/min. Otherwise, the physical examination was negative. The first laboratory tests received were a measured serum osmolality of 365 mOsm/kg and an ethanol level of 0 mg/dL. The BUN and blood glucose levels were normal.

CASE STUDIES FROM THE TOXICOLOGY CONSULTATION SERVICE

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1. What is the differential diagnosis for an increased osmolar gap? 2. What chemicals may be in antifreeze? 3. How do patients with this poisoning typically present? 4. How is the causative agent predicted? 5. What is the therapy?

ice. The dry ice had been stored in the refrigerator (4°C, 39.2°F) at approximately 9 AM that day to reduce sublimation. The researcher was last seen at approximately noon, indicating that at least 3 hours had elapsed between storage and exposure. There were no signs of struggle, and the victim had no history of psychiatric disorders, recent personal crises, or medical illnesses.

Case 35

1. 2. 3. 4.

A 22-year-old man was brought to the hospital by ambulance. His family said that they had found him at home confused, sweaty, and vomiting. A suicide note found at his side indicated that he had ingested as many as sixty 200-mg sustained-release theophylline pills approximately 3 hours earlier. On arrival at the emergency department he was noted to be confused and diaphoretic, with a blood pressure of 70/50 mm Hg, a pulse of 120 beats/min, a respiratory rate of 30 breaths/min, and a temperature of 98.6°F (37°C). The patient was lavaged with a large-bore orogastric tube and given activated charcoal (1 g/kg in a slurry of water with 70 mL of 70% sorbitol solution). A large-bore intravenous line was started, and bloods were sent for a complete blood count, electrolytes, and glucose, theophylline, and acetaminophen levels. The patient was given a bolus of lactated Ringer solution, and his blood pressure increased to 90/50 mm Hg. Suddenly the patient seized and was noted to be in a regular supraventricular tachycardia at a rate of 150 beats/min (Fig. CS–6). The patient was intubated and treated with diazepam, phenytoin, pancuronium, and lidocaine. His blood pressure rose to 150/100 mm Hg, and his pulse remained at 150 beats/min.

What is “dry ice”? What is its toxicity? What is asphyxiation? In what other settings may this type of poisoning occur? What is the treatment?

Case 37 A 60-year-old man with a history of untreated hypertension presented to the ED complaining of chest pain. The diagnosis of aortic dissection was confirmed, and the patient was started on nitroprusside and esmolol to control his blood pressure, which on presentation was 220/130 mm Hg. Because his aortic dissection was distal, medical rather than surgical management was provided, and his blood pressure was reduced to 170/80 mm Hg while he received 200 µg/min of a nitroprusside infusion. Two days later, in the ICU, the patient became confused, although his level of consciousness was normal. His arterial blood pH was 7.35, his PCO2 was 37 mm Hg, his lactate level was minimally elevated, and his renal function was modestly abnormal. 1. What toxicities are associated with nitroprusside? 2. How does thiocyanate poisoning differ from cyanide poisoning? 3. How are patients with cyanide and thiocyanate poisoning managed?

Case 38

Figure CS–6 Rhythm strip from the patient demonstrating a regular narrow-complex rhythm characteristic of supraventricular tachycardia (SVT).

A nephrology consultation was obtained to facilitate immediate extracorporeal drug removal. At that time the first theophylline level was reported as 148 mg/mL. The patient was begun on a regimen of multiple-dose activated charcoal (1 g/kg/h), and plans for hemodialysis were made. 1. What are the major manifestations of acute theophylline toxicity? 2. What is the treatment of patients with acute theophylline overdoses? 3. Which patients qualify for extracorporeal drug removal?

A 22-year-old man with no past medical history was brought to the ED after falling in the bathroom. His roommates reported that the patient had had a seizure, although it is unclear if the fall was the cause of his seizure or a sequela. The previous night the patient went to a dance club, where he had “had a few drinks” and may have used recreational drugs. His vital signs in the ED were normal, and he was awake but lethargic. An electrocardiogram, pulse oximeter, fingerstick glucose, and head CT were normal. The patient’s laboratory values revealed a serum sodium of 120 mEq/L, a serum osmolality of 245 mOsm/L, and a urine osmolality of 491 mOsm/L. The patient inadvertently received 2 L of intravenous 0.9% NaCl, and his sodium fell to 107. Infusion of 1 cc/kg of 3% hypertonic saline improved his serum sodium and mental status. 1. What are the possible etiologies of this patient’s seizure? 2. How should patients with drug-induced seizures be managed? 3. What is specific about the management of this patient’s seizure?

Case 39 Case 36 A 50-year-old medical researcher was discovered dead in a refrigerated room (8 ft wide × 14 ft deep × 8 ft high; 896 ft3) that contained 15 new blocks (10 inches × 10 inches × 10 inches) of dry

A 35-year-old man and his son mixed water into a plastic container of pool shock (a granular substance used to prepare a swimming pool for its first annual use) and reclosed the lid tightly. After several seconds, the container exploded, covering the man in

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a cloud of green smoke. He rapidly noted a burning in his eyes and throat and came to the ED for evaluation. On arrival, he had erythematous mucosal surfaces of his mouth and eyes and had a raspy voice. No stridor was present, and his lungs were clear. His vital signs were all normal; his oxygen saturation by pulse oximetry was 92% on room air.

1. What are irritant gases? How do they cause injury? 2. How can the type and extent of damage in patients exposed to irritant gases be predicted? 3. What is the evaluation and management strategy?

STUDY GUIDE:ANSWERS TO CASE STUDY QUESTIONS

Case 1 1. The patient had uncontrollable twitching of all extremities. Although a seizure disorder should be considered, it is extremely unlikely that a patient would have bilateral seizurelike activity and retain a normal mental status. Although a partial motor seizure (twitching of one extremity) is often associated with a normal mental status, when seizures cross the midline, consciousness is usually lost. Another cause of twitching could include electrolyte abnormalities. Either hypocalcemia or hypomagnesemia could produce these symptoms, but this patient’s serum calcium and magnesium were both normal. Muscle fasciculations are seen with neuromuscular blocking agents, some snake and arthropod envenomations, and organic phosphorus agent toxicity. This patient’s strength was normal, and he had none of the other signs or symptoms associated with these toxins. Myoclonus can result from muscle fatigue, anticholinergic agents, lithium, chlorinated hydrocarbons, or cocaine. Again, however, the patient had no other findings associated with these exposures. The most likely diagnosis is strychnine toxicity, the etiology of which would be the patient’s new supply of heroin. 2. Strychnine is extracted from the seeds of the Indian tree Strychnos nux vomica. It has been used for centuries as a stimulant, an aphrodisiac, and, more recently (but no longer), as a rodenticide. Although strychnine poisoning is relatively rare, as many as 100 cases are reported annually. The alkaloid is an odorless white powder with a bitter taste that resembles that of heroin or quinine. It is rapidly and almost completely absorbed from the gastrointestinal or nasal mucosa and by all parenteral routes. Absorption does not occur, however, through intact skin. The toxin is quite potent, with an estimated human lethal dose of 5 to 8 mg/kg. Case reports note symptoms in adult patients who have been exposed to as little as 0.5 to 1.0 mg/kg. Once absorbed, strychnine impairs resting inhibitory muscle tone by decreasing the ability of glycine to bind postsynaptically (refer to Fig. 10–12). Because glycine receptors are located for the most part in the spinal cord, the loss of inhibition produces motor, but not cognitive, disturbances. Although strychnine toxicity is usually said to produce seizures, these are more likely to be motor events that resemble seizures; patients often have a normal mental status and no postictal period. Because glycine receptors are present throughout the central nervous system (CNS) but decrease rostrally, higher brain functions may occasionally become impaired. 3. Within 15 to 20 minutes of exposure, patients begin to show signs of excitation. Early signs include nausea, fear, and apprehension. This is usually followed rapidly by myoclonus, hyper-

reflexia, and “seizures.” These muscle events are characteristically described as episodic, involving largely extensor muscles, and are exacerbated by stimuli. Opisthotonos and the classic risus sardonicus are described. These events are all predictable from an understanding of glycine inhibitory physiology. When extensor muscles are stimulated, the normal response is for glycine to inhibit function of the flexor groups. The reverse is also true. This pharmacologic action prevents simultaneous contraction of both the flexor and extensor groups. Thus, in the presence of strychnine toxicity, the motor activity is often tonic (as opposed to tonic-clonic), with the direction of contraction favoring the strongest muscles in each group. Because extensor muscles are used to maintain posture, the extensors of the neck, back, and legs are often stronger than their corresponding flexors, and they contract. Complications of strychnine toxicity include hyperthermia, rhabdomyolysis, and hypoventilation from the inability to move the muscles of respiration. This latter effect has been associated with fatalities.

4. Although laboratory confirmation of strychnine exposure (with either blood or urine specimens) is routinely available from reference laboratories, concentrations correlate poorly with either signs and symptoms or prognosis. Furthermore, analysis is rarely available on an immediate basis. Treatment is usually based on history, suspicion, and suggestive clinical findings. The principles of management include airway protection, temperature control, prevention of absorption, reduction of muscle spasms, and prevention of secondary complications by maintaining good urine output. Although phenobarbital was used successfully in the past, benzodiazepines have become the therapeutic agents of choice. These agents function by increasing γ-aminobutyric acid (GABA) activity. γ-Aminobutyric acid is the other major inhibitory neurotransmitter in the CNS. Patients who fail to respond to benzodiazepines or barbiturates should be treated with neuromuscular blockade. Activated charcoal is useful, as its ability to adsorb strychnine in vitro has been well described. Volume resuscitation and rapid cooling may be required for severe cases. Finally, some authors have suggested the use of forced diuresis, potassium permanganate, peritoneal dialysis (PD), and urinary acidification. These techniques do not substantially increase strychnine elimination (forced diuresis and PD), have intrinsic toxicities (potassium permanganate), and may increase the risk of renal failure secondary to rhabdomyolysis (acidification). Most patients will have resolution of symptoms within 24 hours. This patient was treated with diazepam and IV fluids and did well. He supplied a sample of his heroin, which was found to contain strychnine and no opioid whatsoever. This substitution, called a “death hit” on the street, is usually reserved for a client in poor standing.

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SUGGESTED READINGS Chapter 10, Neurotransmitter Principles. Chapter 90, Rodenticides. Anon. Case Records of the Massachusetts General Hospital. Case 12–2001. A 16-year old boy with an altered mental status and muscle rigidity. N Engl J Med 2001;344:1232–1239. Anderson AH: Experimental studies on the pharmacology of activated charcoal: III. Adsorption from gastrointestinal contents. Acta Pharmacol 1948;4:275–284. Boyd RE, Brennan PT, Deng JF, et al: Strychnine poisoning: Recovery from profound lactic acidosis, hyperthermia, and rhabdomyolysis. Am J Med 1983;74:507–512.

Case 2

1. Although the incidence of isoniazid (INH)-induced hepatotoxicity is dependent on the population investigated, a general rule of thumb is that about 10% of patients taking INH will have some chemical evidence of hepatic involvement (clinically asymptomatic with liver enzyme abnormalities); 10% of these patients (or 1%) will develop clinical evidence of hepatitis (anorexia, jaundice, right upper quadrant pain); and, if not discontinued, 10% of these patients (or 0.1% of all patients) will develop fulminant hepatic failure, potentially leading to death. In 1970, more than 2000 Capitol Hill employees converted their PPD status as a result of close exposure to a patient or several patients with active tuberculosis (Garibaldi). A total of 2321 employees were started on isoniazid prophylaxis. Although the incidence of chemical hepatitis is unknown, clinical evidence of hepatitis developed in 19 employees (0.08%), and two died of fulminant hepatic failure (0.09%). About half of the employees (9 of 19) became symptomatic within 60 days of the initiation of therapy, and all who developed symptoms did so within 6 months of initiation of therapy. The risk of hepatitis is almost doubled in alcoholics (33%) when compared to nonalcoholics (17%), and age greater than 35 years increases the risk almost 2.5-fold (27% vs 11%) (Dickinson). However, the risk appears to be lower when close monitoring and early intervention are performed (Nolan). Pediatric patients are relatively protected from hepatotoxicity. In children receiving INH prophylaxis, 7% (39 of 564) of patients had some elevation of liver enzymes, and only one had an AST greater than 100 IU/L (Nakajo).

2. One of the major pathways for the metabolism of INH is through acetylation to form acetylisoniazid. This acetylation is genetically determined, such that patients may be classified as either fast or slow acetylators (refer to Fig. 43–2). More than 90% of Asian Americans are rapid acetylators, whereas about 55% of African and white Americans are slow acetylators. Because one of the metabolites produced by acetylation was thought to be hepatotoxic, for many years it was generally accepted that fast acetylators were at increased risk of hepatotoxicity. However, detailed investigations demonstrate that acetylation status is not a risk factor for hepatotoxicity (Dickinson; Gurumurthy). This does not mean that metabolism is not important. Isoniazid is also metabolized by the cytochrome P450 system to form a hepatotoxic metabolite. Concomitant use of drugs that induce P450 activity (notably rifampin, ethanol, and oral contraceptives) increase the risk for hepatotoxicity.

3. Classic toxin-induced hepatic injury from acetaminophen or carbon tetrachloride produces massive centrilobular necrosis. Damage occurs primarily in this area because the cells surrounding the terminal hepatic vein are relatively oxygen-deprived and thus most sensitive to toxin-induced stresses. This is in contradistinction to classic viral hepatitis, which largely involves the periportal areas. Distinct histology is associated with chronic ethanol abuse. Liver enzyme abnormalities can be used to help differentiate acute alcoholic hepatitis from toxin-induced or viral hepatitis. Ethanol toxicity usually results in an AST that is twice the alanine aminotransferase (ALT), and the total elevation is rarely greater than 1000 IU/L. In acute toxic hepatitis, such as might result from an acetaminophen overdose, the AST and ALT are approximately equal, and the patient is not considered to be hepatotoxic until the values are greater than 1000 IU/L because lower values are rarely associated with symptoms. In fact, aminotransferase values in excess of 10,000 are commonly noted. In isoniazid hepatotoxicity the total aminotransferase elevations may reach the thousands, but the histology often has evidence of injury to both the terminal hepatic and periportal areas (Black). 4. Although this patient had no history or clinical evidence of acetaminophen poisoning, patients with hepatic failure of all etiologies may benefit from the administration of N-acetylcysteine (NAC) because of its ability to increase oxygen delivery, increase cardiac index, decrease systemic vascular resistance, and increase oxygen extraction (Harrison). The mechanisms for these effects are unclear. 5. Isoniazid prophylaxis should be started only when clinically indicated. Patients must be thoroughly educated to identify early symptoms of hepatotoxicity. In addition, they should be instructed to seek immediate attention if these signs and symptoms occur. Finally, high-risk patients should have biweekly monitoring of liver function tests at least during the first 6 months of therapy.

SUGGESTED READINGS Chapter 14, Hepatic Principles Chapter 43, Antituberculous Agents Antidotes in Depth: N-Acetylcysteine Black M, Mitchel JR, Zimmerman HJ, et al: Isoniazid-associated hepatitis in 114 patients. Gastroenterology 1975;69:289–301. Dickinson DS, Bailey WC, Hirschowitz B, et al: Risk factors for isoniazid (INH)-induced liver dysfunction. J Clin Gastroenterol 1981;3: 271–279. Garibaldi RA, Drusin RE, Ferebee SH, Gregg MD: Isoniazid-associated hepatitis: Report of an outbreak. Am Rev Respir Dis 1972;106: 357–365. Gurumurthy P, Krishnamurthy MS, Nazareth O, et al: Lack of relationship between hepatic toxicity and acetylator phenotype in three thousand South Indian patients during treatment with isoniazid for tuberculosis. Am Rev Respir Dis 1984;129:58–61. Harrison PM, Wendon JA, Gimson AES, et al: Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852–1857. Nakajo MM, Rao M, Steiner P: Incidence of hepatotoxicity in children receiving isoniazid chemoprophylaxis. Pediatr Infect Dis 1989;8: 649–650. Nolan CM, Goldberg SV, Buskin SE: Hepatotoxicity associated with isoniazid preventive therapy: A 7-year survey from a public health tuberculosis clinic. JAMA 1999;281:1014–1018.

ANSWERS TO CASE STUDY QUESTIONS

Case 3 1. The differential diagnosis of drug-induced seizures is quite long but should include common causes such as cocaine, cyclic antidepressants, theophylline, carbon monoxide, ethanol and sedative-hypnotic withdrawal, camphor, organophosphates, carbamazepine, lithium, hypoglycemic agents (sulfonylureas and insulin),
-adrenergic antagonists, type I antidysrhythmics, and isoniazid. Less common agents, such as gyramitrin-containing mushrooms, propoxyphene, MAO inhibitors, phenothiazines, lead, caffeine, cyanide, and agents that produce methemoglobinemia, should also be considered. True status epilepticus is uncommon and is more suggestive of toxicity from cocaine, theophylline, isoniazid, carbamazepine, or chlorinated hydrocarbons. Subsequent history determined that the patient had been recently diagnosed as having a positive PPD and was started on isoniazid. A large number of her INH tablets had been ingested during her suicide attempt. 2. Isoniazid-induced seizures result from a depletion of GABA, which is one of the major inhibitory neurotransmitters and thus may be considered a natural anticonvulsant. Glutamic acid serves as an immediate precursor of GABA, and the conversion of glutamic acid to GABA is facilitated by a pyridoxine-dependent enzyme L-glutamic acid decarboxylase (GAD). Isoniazid interferes with this conversion of glutamic acid to GABA by at least three different mechanisms (refer to Fig. 43–3): (1) Isoniazid directly combines with pyridoxine to result in enhanced urinary elimination. (2) To be active, pyridoxine must be converted to pyridoxal 5′-phosphate by the enzyme pyridoxine phosphokinase. This enzyme is inhibited by isoniazid. (3) Isoniazid itself inhibits GAD. When GABA is reduced below a critical threshold, seizures result (Wood). Isoniazid also inhibits other enzyme systems, including lactate dehydrogenase. This enzyme uses nicotinamide adenine dinucleotide (NAD) to interconvert lactate and pyruvate. By interfering with this conversion, any lactate formed (as occurs during seizures) might persist longer than expected. This may account for the clinical data that suggest that the acidosis formed during INH toxicity is “resistant” to therapy, but this has not been studied. 3. Emesis, coma, and seizures usually occur within 1 to 3 hours after a significant overdose. Although gastrointestinal decontamination is indicated, syrup of ipecac–induced emesis is contraindicated in patients with INH overdose. Orogastric lavage and activated charcoal seem to be the safest approach. Seizures should initially be treated with standard doses of a benzodiazepine (preferably diazepam or lorazepam). When ingestion of isoniazid is suspected, IV pyridoxine (vitamin B6) should be administered as soon as possible. For INH ingestions of known quantity, it is generally recommended that pyridoxine be administered on a gramfor-gram basis. For patients in whom the quantity ingested is unknown, a dose of 5 g of pyridoxine can be administered to adults. Whether the amount ingested is known or not, the first dose of pyridoxine should never exceed 5 g in an adult or 70 mg/kg in children (Wason). At higher initial or total doses, pyridoxine itself may cause neurologic toxicity. Acute effects include incoordination, ataxia, seizures, and death (in animals). Chronic exposure to high doses of pyridoxine causes a peripheral sensory neuropathy, which may

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not resolve completely after the medication is discontinued (Schaumberg). In animal studies the anticonvulsant effects of pyridoxine were synergistic with diazepam (Chin). Thus, during the pyridoxine infusion, repeat doses of benzodiazepines should be administered. Pyridoxine may also be efficacious in reversing persistent coma caused by INH overdose (Brent). Finally, in cases of severe intoxication, both hemodialysis and hemoperfusion have been reported to be successful at enhancing INH elimination but would rarely be indicated. 4. Given the frequency of tuberculosis in some populations, it may be resonable to give to any patient who presents with status epilepticus an empiric dose of pyridoxine (Shah). This decision depends in part on the clinician’s individual patient population. Although seizures are common following overdose, status epilepticus is less common. Administering pyridoxine at a dose of 70 mg/kg or less is generally thought to be safe and may be effective in INH or monomethylhydrazine overdose. When seizures are refractory to benzodiazepines, an empiric trial of pyridoxine (and another dose of benzodiazepine) may be beneficial. When a history of intentional drug overdose is available, more liberal criteria for the administration of pyridoxine may be warranted. The New York City Health Department recently estimated that more than 1 million New Yorkers are PPD-positive. As tuberculosis continues in epidemic proportions in New York City and elsewhere, INH overdoses are likely to occur. A 10-fold increase in INH overdoses has occurred in New York City over the last few years.

SUGGESTED READING Chapter 43, Antituberculous Agents. Antidotes in Depth: Pyridoxine. Brent J, Nguyen V, Kulig K, et al: Reversal of prolonged isoniazid-induced coma by pyridoxine. Arch Intern Med 1990;150:1751–1753. Chin L, Sievers ML, Laird HE, et al: Evaluation of diazepam and pyridoxine as antidotes to isoniazid intoxication in rats and dogs. Toxicol Appl Pharmacol 1978;45:713–722. Schaumberg H, Kaplan J, Widenbank A, et al: Sensory neuropathy from pyridoxine abuse: A megavitamin syndrome. N Engl J Med 1983;309: 445–448. Shah BR, Santucci K, Sinert R, Steiner P: Acute isoniazid neurotoxicity in an urban hospital. Pediatrics 1995;95:700–704. Wason S, Lacouture PG, Lovejoy FH: Single high-dose pyridoxine treatment for isoniazid overdose. JAMA 1981;246:1102–1104. Wood JD, Peesker SJ: A correlation between changes in GABA metabolism and isonicotinic acid hydrazide-induced seizures. Brain Res 1972;45:489–498.

Case 4 1. Although many hair products have similar names and uses, their ingredients may be quite varied. Initially, we must distinguish between hair or permanent relaxers and neutralizers. Relaxers usually contain an alkaline caustic (dilute sodium hydroxide or thioglycolate), whereas the neutralizers may contain bromates. 2. Nausea, vomiting, or oropharyngeal irritation may be the first symptoms to occur following an ingestion of either a caustic or bromate. If a caustic was ingested, drooling, stridor, and signs of gastrointestinal perforation or bleeding may develop. However,

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distinctly different delayed symptoms may result from bromate poisoning, specifically hearing loss and renal insufficiency. More commonly, skin reactions, including severe contact dermatitis, occur with topical exposure to bromates.

houses because of the vast commercial and research applications for these compounds. Recent reports of thallium toxicity concentrate on its use as a homicidal and suicidal agent, as unintentional exposures have almost been eliminated.

3. Initial therapy for patients with bromate ingestion consists of dilution and fluid and electrolyte resuscitation. Esophagoscopy is indicated if signs or symptoms of significant gastrointestinal burns are present. Sodium thiosulfate theoretically may act as an antidote by converting bromate to less toxic bromide. Most patients with small unintentional ingestions of this type of product do well with conservative therapy alone. In severe cases hemodialysis may be required, depending on the severity of renal insufficiency. This case was later confirmed as a bromate ingestion when the parents returned home to obtain the product container. The parents were given poison prevention education. No gross auditory deficits were noted, but testing in a child of this age is not very precise. Over the next several days her creatinine level returned to normal, and she was discharged.

2. Thallium salts most commonly enter the body by ingestion. Inhalation and insufflation of dust and dermal absorption are also reported. Experimentally, both the IV and SC routes produce toxicity as well. Although human data demonstrate some variability, many authors suggest that in adults fatality often results from ingestions of about 1 g of thallium salts (or 12 mg/kg in children). Because thallium distributes to most cells in the body, its volume of distribution is quite large, approximately 5 L/kg. Cellular absorption seems to be analogous to that of potassium, possibly accounting for the ECG changes noted in these patients and the theoretical role of potassium diuresis in the treatment strategy (see below). Once absorbed, thallium binds to sulfhydryl groups of diverse enzyme systems. In various experimental models inhibition of Na+-K+-ATPase, oxidative phosphorylation, the Krebs cycle, and monoamine oxidase have all been described. The elimination of thallium is slow, possibly as the result of enterohepatic circulation, with reported half-lives on the order of 1 to 5 days. The majority of elimination is fecal, and a small amount is renal.

SUGGESTED READINGS Chapter 87, Caustics and Batteries. De Vriese A, Vanholder R, Lameire N: Severe acute renal failure due to bromate intoxication: report of a case and discussion of management guidelines based on a review of the literature. Nephrol Dial Transplant 1997;12:204–209. Lue JN, Johnson CE, Edwards DL: Bromate poisoning from ingestion of professional hair-care neutralizer. Clin Pharmacol 1988;7:66–70. McElwee NE, Kearney TE: Sodium thiosulfate unproven as bromate antidote [letter]. Clin Pharmacol 1988;7:570.

Case 5 1. The most dramatic finding in these patients was the presence of a rapidly developing, isolated, severely painful sensory peripheral neuropathy. Many agents are associated with the production of a peripheral neuropathy, including solvents, organic phosphorus compounds, heavy metals, isoniazid, ethanol, and mitotic inhibitors. When eventual multisystem involvement is added (gastrointestinal, cardiovascular, and renal), the diagnosis of heavy metal poisoning becomes more likely. Among the heavy metals, thallium is the most likely diagnosis because of the unique nature of the neurologic symptoms. The presence of both severe painful neuropathy and alopecia is essentially diagnostic of thallotoxicosis. Further evidence comes from the lack of hematologic toxicity, which is fairly common with other heavy metal exposures. Thallium was first isolated in 1861 by Crookes. Its name is derived from the Greek, thallus, which means “budding twig,” because the color of sulfur ores containing thallium is suggestive of young vegetation. Most thallium salts are colorless and odorless powders. In the late 19th century thallium sulfate was used to treat syphilis, gonorrhea, tuberculosis, and tinea corporis. Thallium salts were subsequently widely available as rodenticides until 1965, when their use was prohibited because of the risk of toxicity in humans and domestic animals. Thallium is still used in the semiconductor and optical industries and in very small quantities in medical diagnostics (in its radioactive form). Although it is more difficult to obtain since its over-the-counter sale was prohibited, thallium salts are still available through most chemical supply

3. The clinical stages of thallium intoxication are well defined (Lovejoy). Within the first 3 to 4 hours of exposure gastrointestinal symptoms predominate. Although nausea and diarrhea are common, many reports have documented constipation, which is often refractory to cathartics. Within several hours to several days after exposure patients begin to manifest neurologic symptoms consisting of painful peripheral neuropathy, altered mental status, seizures, and respiratory dysfunction. A motor component may accompany the sensory neuropathy. Simultaneously (or within a few days following the onset of neurologic symptoms), patients may enter a phase of autonomic instability, consisting of hypertension, tachycardia, salivation, and fever. During this stage myocardial failure may occur. Alopecia is the most reliable finding and usually begins within 2 weeks of exposure. Late findings consist of residual neurologic dysfunction, Mee lines, and dry skin. 4. In addition to history and physical examination, the diagnosis of thallium intoxication is usually confirmed by laboratory determination of thallium in the urine. Normal (nonexposed) patients have urinary thallium concentrations less than 5 ng/mL (5 µg/L). Generally, urine concentrations greater than this value or wholeblood concentrations greater than 30 µg/dL are consistent with exposure. In addition, examination of the hair roots has been demonstrated to show hyperpigmentation in about 95% of cases studied later than 4 days after exposure. Finally, thallium salts are radiopaque, so abdominal radiographs, or in this case radiographs of the candy, may be helpful. The two more severely poisoned patients described had thallium spot urines obtained on day 2 of poisoning of 10,837 and 9569 µg/L, respectively. 5. Because of a paucity of both human and controlled animal data, there is little consensus on treatment. Gastrointestinal decontamination is indicated before the onset of vomiting and diarrhea, or at a later stage if radiopaque material is seen in the gastrointestinal tract. Thallium is adsorbed to activated charcoal in vitro, and there is a potential role for multiple-dose activated charcoal

ANSWERS TO CASE STUDY QUESTIONS because of the enterohepatic circulation. Although forced potassium diuresis increases urinary clearance and decreases the halflife substantially, it is also associated with a transient exacerbation of neurologic symptoms (seen in all four patients described) because potassium increases CNS thallium concentrations while mobilizing thallium from other compartments. This is analogous to using CaNa2 ethelenediaminetetraacetic acid (EDTA) alone for the treatment of severe lead intoxication. Prussian blue, which is not an FDA-approved antidote, may bind thallium in the gastrointestinal tract and supply potassium for enhanced urinary elimination as it exchanges potassium for thallium. Diverse chelators have been used with variable results. British anti-Lewisite (BAL) and CaNa2 EDTA are not effective. Dithiocarb and the use of penicillamine without Prussian blue may exacerbate symptoms, as they redistribute thallium into the CNS. Although standard hemodialysis has little efficacy because of thallium’s large volume of distribution, the combination of hemodialysis and hemoperfusion or hemoperfusion alone seems to be more beneficial than hemodialysis alone at enhancing elimination. Although only limited data are available, early coma, respiratory arrest, and cardiovascular instability appear associated with mortality. These patients were all treated with activated charcoal and forced potassium diuresis. Prussian blue and hemodialysis were used only in the two sicker patients. Their symptoms, except for the alopecia, resolved over 2 to 3 weeks. Hair regrowth usually takes substantially longer.

SUGGESTED READINGS Chapter 83, Thallium. Chamberlain PH, Stavinoha WB, Davis H, et al: Thallium poisoning. Pediatrics 1958;22:1170–1182. Hoffman RS, Stringer JA, Feinberg RS, et al: Comparative efficacy of thallium adsorption by activated charcoal, Prussian blue, and sodium polystyrene sulfonate. J Toxicol Clin Toxicol 1999;37:833–837. Moeschlin S: Thallium poisoning. Clin Toxicol 1980;17:133–146. Nordentoft T, Andersen EB, Mogensen PH: Initial sensorimotor and delayed autonomic neuropathy in acute thallium poisoning. Neurotoxicology 1998;19:421–426.

Case 6 1. The patient’s history permits the exclusion of most common allergens, and the history of a recent camping trip suggests several different exposures. Nontoxicologic etiologies should be considered, particularly herpes zoster, scabies, or Lyme borelliosis. Arthropods, such as caterpillars, or insects may result in vesicular lesions, but rarely do they manifest in a linear pattern. The patient went swimming in a lake and could have “swimmer’s itch,” a dermatitis involving exposed areas of the body caused by Schistosoma cercaride, a free-swimming parasitic flatworm found in fresh water. However, this rash is typically diffuse and not linear. Because he did not swim in the ocean, he should not have seabather’s eruption caused by larvae of “thimble jellyfish” (Linuche unguiculata). This rash is usually localized to areas covered by a bathing suit, where the larvae are trapped and cause localized irritation. The symptoms often worsen on bathing as a result of osmotically activated discharge of the larval nematocysts. Unfortunately, the causative organisms of seabather’s eruption are often inappropriately called “sea lice,” which are true crustacean fish

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parasites; this may potentially lead to the inappropriate application of a pediculocide. 2. The patient’s close contact with foliage is highly suggestive of exposure to plant toxins. There are many dermatologic manifestations of plant exposure, but the most common are allergic contact dermatitis and phototoxicity. Phototoxic reactions are caused by the presence of furocoumarins, notably psoralen, which cause exaggerated dermal injury following exposure to ultraviolet light. The Umbilliferae family consists of several psoralen-containing plants such as Queen Anne’s lace, wild parsnip, and celery. Phytophototoxicity also occurs in gardeners using a hand-held nylon fiber weed cutter, as plant fragments containing psoralen are thrown toward the patient, accounting for the appellation “weed wacker dermatitis.” Although psoralen is used therapeutically as a photosensitizer in the treatment of psoriasis (ie, PUVA therapy [pulsed ultraviolet actinotherapy]), uncontrolled exposure may result in bullous dermatitis analogous to a severe sunburn. Phototoxic reactions require not only exposure of moist skin to plant parts but also sun exposure, and when they result from direct dermal contact with the plant, the lesions that result are typically streaky and known as dermatitis bullosa striata pratensis. The presence of lesions in presumably covered areas such as the buttocks excludes phytophotodermatitis. 3. Allergic contact dermatitis caused by plants is a very common occupational disorder but is also seen frequently in campers, home gardeners, flower recipients, and perfume wearers. By far the most common type of allergic contact phytodermatitis is rhus dermatitis, caused by the various species of the family Anacardiaceae and the genus Toxicodendron. Rhus dermatitis, familiarly known as poison ivy or poison oak, appears as an edematous vesicular eruption in a telltale streaky pattern. The streaks result because the resin is applied while brushing against an implicated plant or spread manually by scratching while resin is lodged beneath the fingernails. The agent responsible for poison ivy is urushiol, which is actually a collection of several different catechol derivatives with long and variably saturated hydrocarbon side chains (poison ivy is predominantly pentadecylcatechol). This agent is metabolized to a quinone that attacks a skin protein, probably keratin. Acting as a hapten, the urushiol alters this protein, causing the immune system to initiate an immune response against the altered protein following the first exposure. Subsequent exposure induces an amnestic response, typically of the type IV delayed hypersensitivity. Hypersensitivity to urushiol occurs in over half the people in the United States, suggesting prior exposure, and as many as 85% of patients are capable of being sensitized. Allergic contact phytodermatitis is also produced by other plant toxins, notably the sesquiterpene lactones found in the Compositae family. This family includes chrysanthemum, feverfew, and dandelions. The dermatitis caused by these plants may appear similarly to poison ivy but is generally diffuse, not linear. 4. Clothing is the most effective prevention, but patients must be cautious when removing and washing clothes to avoid transfer of the resin to their skin. Similarly, because the resin is difficult to remove, particularly from beneath the fingernails, delayed exposure may occur. Soap and water may work best, but ethanol or isopropanol is often recommended. If the resin is washed off the skin within 10 minutes of exposure, it may be possible to avoid der-

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matitis. An effective barrier cream containing an organoclay, bentoquatam (IvyBlock®; quarternium-18 bentonite), was recently approved by the FDA. Treatment of mild dermatitis can include a soothing agent such as Domeboro solution (aluminum acetate) or a lubricating agent such as petrolatum. It is probably best to avoid drying antipruritic lotions such as calamine except for weeping lesions. Potent topical corticosteroids can be considered for moderate lesions or for severe pruritis, but only mild agents such as hydrocortisone 1% should be used on the face or genitals. Systemic steroids are rarely indicated and are used only for patients with severe dermatitis; they should be continued for at least 2 weeks to avoid rebound dermatitis. Systemic antipruritics such as diphenhydramine may be helpful, but topical versions are sensitizing and should be avoided. Patients with severe rhus dermatitis who cannot avoid exposure (eg, occupational contact) may be candidates for oral hyposensitization therapy. This is performed by administering orally incrementally larger doses of urushiol, which over time transiently suppresses the immunologic response if the patient is dermally exposed to rhus.

SUGGESTED READINGS Chapter 78, Plants. Fisher AA: Poison ivy/oak dermatitis. Part I: Prevention: soap and water, topical barriers, hyposensitization. Cutis 1996;57:384–386. Hjorth N, Roed-Petersen J, Thomsen K: Airborne contact dermatitis from Compositae oleoresins simulating photodermatitis. Br J Dermatol 1976;95:613–619. Marks JG, Trautlein JJ, Epstein WL, et al: Oral hyposensitization to poison ivy and poison oak. Arch Dermatol 1987;123:476–478. Marks JG Jr, Fowler JF Jr, Sheretz EF, et al: Prevention of poison ivy and poison oak allergic contact dermatitis by quaternium-18 bentonite. J Am Acad Dermatol 1995;33:212–216. McGovern TW, LaWarre SR, Brunette C: Is it, or isn’t it? Poison ivy lookalikes. Am J Contact Dermatol 2000;11:104–110. Reynolds NJ, Burton JL, Bradfield JWB, Matthews CAN: Weed wacker dermatitis. Arch Dermatol 1991;127:1419–1420.

Case 7 1. The terminology of acid–base disorders often leads to confusion and error. The following definitions provide an appropriate frame of reference. The terms acidosis and alkalosis refer to processes. By definition a patient is said to have: ■ A metabolic acidosis if the serum bicarbonate (HCO3) is less than 24 mEq/L ■ A metabolic alkalosis if the serum HCO3 is more than 24 mEq/L ■ A respiratory acidosis if the partial pressure of carbon dioxide (PCO2) is greater than 40 mm Hg ■ A respiratory alkalosis if the PCO2 is less than 40 mm Hg Any combination of acidoses and alkaloses can be present in any one patient at any given time. The terms acidemia and alkalemia refer only to the net pH of blood (acidemia being less than 7.40 and alkalemia being greater than 7.40). These terms do not describe the process or processes that led to the alteration in pH. The patient had a primary metabolic acidosis with compensatory respiratory alkalosis with a net acidemia. The metabolic

acidosis is of the high-anion-gap variety (anion gap = 35). The anion gap is calculated as follows: anion gap = [sodium]  {[chloride] + [bicarbonate]}. If increased, it represents the presence of an unmeasured anion, usually an organic acid (eg, lactic acid) but occasionally an inorganic acid (eg, SO42). 2. Many people use different memory aids to help recall the differential diagnosis of a high-anion-gap metabolic acidosis, the most popular of which is the acronym MUDPIES: methanol, uremia, diabetic ketoacidosis (and other ketoacidoses), paraldehyde and phenformin (and metformin), ischemia (meaning all causes of lactate), isoniazid, and iron, ethylene glycol, and salicylates and solvents (such as toluene). Others use MUDPILES, in which the L represents lactate. The best way to diagnose a metabolic disorder is via the history, physical examination, and simple laboratory tests. Is there a history of ingestion, alcoholism, or poorly controlled diabetes? In the absence of seizures, metabolic acidosis from INH should not occur. Iron poisoning should be accompanied by vomiting, and paraldehyde has a distinct odor. Visual symptoms often accompany methanol poisoning, and auditory symptoms (tinnitus) often accompany salicylate toxicity. The serum electrolytes and ABG (arterial blood gas) not only define the problem but also give some specific clues to the etiology. Uremia and hyperglycemia are immediately evident. Renal insufficiency and hypocalcemia may occur with ethylene glycol intoxication. In addition, some simple urine tests may be very useful. The absence of ketones will help exclude ketoacidosis (although not definitively), a ferric chloride test will confirm salicylate ingestion, and oxalate crystals and fluorescence may be noted in ethylene glycol intoxication. Finally, a serum lactate concentration is very helpful. With the toxic alcohols, uremia, ketoacidosis, salicylates and solvents, organic acids other than lactate cause the majority of the acidosis. Thus, a high lactate concentration, specifically one that can account for the majority of the anion gap, can help exclude these agents from the differential diagnosis. 3. In the absence of visual symptoms and a history, methanol intoxication seems unlikely but cannot be excluded. Although the BUN and creatinine are elevated, the acidosis seems out of proportion to this elevation making uremic acidosis an unlikely cause. Diabetic ketoacidosis usually has more than trace ketones with a higher serum glucose, but, again, this cannot be excluded. There was no odor of paraldehyde. Without vomiting or seizure activity, iron and INH toxicity become less likely. With the low blood pressure and low temperature, causes of lactic acidosis (such as sepsis) should be considered. The renal insufficiency and acidosis may be explained by ethylene glycol toxicity. Phenformin is an oral hypoglycemic of the biguanide class that was available in the United States until 1976. When phenformin was widely used, the incidence of life-threatening lactic acidosis was estimated at 1/4000 patients. Today, only metformin is available in the United States. Although severe metabolic acidosis is substantially less common with metformin, cases remain common given the drug’s wide use. Their exact mechanism of action is unknown, but biguanides are thought to moderate blood glucose by reducing hepatic glucose release and increasing insulin receptor sensitivity. It may impair oxidative metabolism, and this later effect, which increases anaerobic glycolysis, may be responsible for the consequent metabolic acidosis. In addition, the biguanides are

ANSWERS TO CASE STUDY QUESTIONS thought to be potent negative inotropes such that cardiac output is reduced (increasing lactate production) and glomerular filtration is decreased (inhibiting clearance of organic acids). Renal insufficiency seems to be a major risk factor for biguanide toxicity (Misbin). This probably relates to impaired drug elimination. In animal models, significant lactic acidemia does not occur unless the animal is nephrectomized. Similarly, hepatic dysfunction increases the risk of toxicity both through impaired drug clearance and from decreased lactate metabolism. Other contributing factors include increased dosing (as in this patient) and concurrent illnesses that may result in a lactic acidosis (sepsis, myocardial infarction). Further history revealed that this diabetic patient was taking phenformin, which he had obtained in Italy. When he developed polyuria and symptoms of a respiratory infection, he began to take increasing doses. 4. Gastrointestinal decontamination is indicated only in a recent acute oral overdose. Intravascular volume resuscitation is almost always required because of increased insensible losses. Correction of the pH with bicarbonate is often needed to prevent the pH from falling below 7.10 and is probably helpful as long as ventilation is adequate and volume overload does not occur. Many patients like this one are ketonuric. This ketoacidosis probably results from fatty acid degradation secondary to poor glucose utilization. Insulin (and glucose if necessary) can reverse this process, eliminating one cause of the patient’s acidosis. In addition, it has been suggested that insulin partially reverses the inhibition of pyruvate dehydrogenase, allowing more rapid lactate degradation as it is shunted back to pyruvate. Although hemodialysis will not effectively remove phenformin or metformin, it can correct fluid and electrolyte abnormalities while allowing large volumes of bicarbonate administration, if necessary. This patient received insulin and glucose and 15 ampules (>650 mEq) of sodium bicarbonate and was hemodialyzed twice. Over the course of 2 days his hemodynamic status stabilized, and his lactic acid concentration fell to 1.2 mEq/L. He was ultimately discharged from the hospital.

SUGGESTED READINGS Chapter 24, Fluid, Electrolyte, and Acid–Base Principles. Chapter 40, Antidiabetic and Hypoglycemic Agents. Fulop M, Hoberman HD: Phenformin-associated metabolic acidosis. Diabetes 1976;25:292–296. Gan SC, Barr J, Arieff AI, Pearl RG: Biguanide-associated lactic acidosis. Arch Intern Med 1992;152:2333–2336. Kwong SC, Brubacher J: Phenformin and lactic acidosis: A case report and review. J Emerg Med 1998;16:881–886. Lalau JD, Race JM: Metformin and lactic acidosis in diabetic humans. Diabetes Obes Metab 2000;2:131–137. Misbin RI: Phenformin-associated lactic acidosis: Pathogenesis and treatment. Ann Intern Med 1977;87:591–595. Stang M, Wysowski DK, Butler-Jones D: Incidence of lactic acidosis in metformin users. Diabetes Care 1999;22:925–927.

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causing bilateral motor movements must be associated with a change in consciousness. Thus, partial complex status epilepticus is not a concern here because of the bilateral motor movements and intact mental status. Fever, muscle rigidity, and an intact consciousness should always raise the possibility of strychnine toxicity or tetanus. Because these two disorders interfere with glycine-induced inhibitory tone in the spinal cord, mental status is normal until hypoventilation, acidemia, or hyperthermia becomes severe. Other considerations include fasciculations possibly induced by sympathomimetics (amphetamine and cocaine), cholinergic agents, black widow spider envenomation, or metal poisoning (arsenic, mercury, manganese), to name a few. Again, many of these disorders are associated with specific physical findings or impaired consciousness. Finally, myoclonus, which commonly results from exposure to tricyclic antidepressants, anticholinergics, bismuth, and DDT, should be considered. A clue to potentially limit this differential diagnosis is the history of a cold. Common nonprescription cold remedies include sympathomimetics, antihistamines, anticholinergics, and dextromethorphan. The hyperthermia, muscle activity, and absence of other findings are suggestive of the serotonin syndrome, which can be the result of an interaction between dextromethorphan and a serotonin agonist. The serotonin syndrome commonly results from the concomitant exposure to two agents that increase serotonin (5-HT) (see Fig. 10–8). These compounds can prevent neuronal degradation (MAO [monoamine oxidase] inhibitors), prevent reuptake (selective serotonin reuptake inhibitors, (tricyclic antidepressants) TCAs, meperidine, dextromethorphan), or increase serotonin synthesis (tryptophan). The resulting syndrome can be characterized by at least three of the following clinical criteria: altered mental status, agitation, myoclonus, hyperreflexia, fever, shivering, diaphoresis, ataxia, and diarrhea (Sporer). These symptoms should be present in association with exposure to serotonin agonists and in the absence of other causes of fever and altered mental status such as rapid increases in neuroleptic dosing. Serotonin syndrome can begin very rapidly, within minutes of exposure, and if minimal may last only several hours. Severe cases can result in fatality, usually resulting from substantial elevations in body temperature, seizures, respiratory failure, and disseminated intravascular coagulation. Further history revealed that the patient was taking Nardil (an MAO inhibitor).

Case 8

2. The serotonin syndrome can be reproduced in animal models with a variety of combinations of agents that increase synaptic serotonin. Early animal studies using tryptophan and an MAO inhibitor were able to produce characteristic findings such as tremor, rigidity, and forepaw treading (Green). Nonspecific serotonin (5HT1 and 5-HT2) antagonists such as cyproheptadine and methysergide attenuated these effects. Further delineation of the exact neurochemical mechanism for serotonin syndrome came from investigations with selective serotonin antagonists. More recent evidence suggests that stimulation of the 5-HT1A receptor may be the more important mechanism for generation of the serotonin syndrome, and 5-HT2 receptor agonism plays a lesser role.

1. Although this patient was originally described as having status epilepticus, it is important to remember that although seizures can occur with a normal mental status, global cerebral dysfunction

3. Initial therapy always begins with stabilization of the airway, breathing, and circulation. Next, attention should be paid to lifethreatening elevations in body temperature. Patients with severe hyperthermia should be cooled rapidly with mist and fan or by

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CASE STUDIES

submersion in iced water. The addition of a benzodiazepine is essential to prevent muscle activity, which contributers to hyperthermia (Brown). If muscular activity persists despite sedation, nondepolarizing neuromuscular blockade may be beneficial. There is no known specific advantage to dantrolene in this situation and its use for this indication should be rare. Additionally, many experimental therapies have been tried with limited anecdotal success. Two patients were successfully treated with propranolol (Sporer). Although
-adrenergic antagonist therapy is usually contraindicated in patients with agitated delirium and hyperthermia (cocaine, alcohol withdrawal), propranolol has antagonistic properties at the 5-HT1A receptor. Similarly, cyproheptadine and methysergide have been used with limited success (Brown; Sporer). Although all these therapies are promising, they remain experimental and should therefore be used only with extreme caution. Once control of muscle activity and body temperature have been achieved, the patient should receive intensive supportive care. Oral activated charcoal can be given if the ingestion was recent. Fluids should be administered in order to maintain a urine output of 3 mL/kg/h if there is a risk of myoglobinuric renal failure. Finally, electrolyte abnormalities should be evaluated and corrected. When the diagnosis is unclear, blood cultures, a CT scan of the head, and lumbar puncture may be indicated in addition to antibiotics. Most patients who are diagnosed and treated promptly respond to therapy with rapid restoration of body temperature, muscle tone, and mental status.

SUGGESTED READINGS Chapter 58, Serotonin Reuptake Inhibitors and Atypical Antidepressants Chapter 60, Monoamine Oxidase Inhibitors Brown TM, Skop BP: Pathophysiology and management of the serotonin syndrome. Ann Pharmacother 1996;30:527–533. Green AR, Grahame-Smith DG: The role of brain dopamine in the hyperactivity syndrome produced by increased 5-HT synthesis in rats. Neuropharmacol 1974;13:949–959. Radomski JW, Dursun SM, Reveley MA, et al: An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses 2000;55:218–224. Sporer KA: The serotonin syndrome. Implicated drugs, pathophysiology and management. Drug Safety 1995;13:94–104. Sternbach H: The serotonin syndrome. Am J Psychiatry 1991;148: 705–713. Yamada J, Sugimoto Y, Horisaka K: The evidence for the involvement of the 5HT1A receptor in 5-HT syndrome induced in mice by tryptamine. Jpn J Pharmacol 1989;51:421–425.

have resulted in a number of severe injuries (Fig. CS–7). Ultimately, the laboratory reported her serum glucose concentration as 22 mg/dL. Hypoglycemia is a common cause of presentation to the ED. In a 12-month period during 1980 and 1981, 125 cases were recorded at Harlem Hospital (Malouf). Of these, only three patients (2.4%) presented with hemiparesis. Although other series report on a number of hypoglycemic patients presenting with focal neurologic deficits, neither the total patient pool nor the time taken to collect these patients is given (Seibert; Wallis). Thus, for lack of better demographic data, it seems safe to say that although hemiparesis and other focal findings resulting from hypoglycemia have been well described, they seem to occur in a minority (probably 100 mg/dL) essentially eliminates consequential methanol poisoning unless the patient ingested ethanol following the development of methanol-induced blindness. Agents such as cocaine and ergot alkaloids, which provoke diffuse vasospasm, can produce retinal ischemia and blindness. Visible retinal changes such as pallor or arterial vasoconstriction are expected in this situation. Alternatively, phencyclidine use is associated with “sun-gazers retinopathy” as a result of prolonged staring at the sun with subsequent ultraviolet damage to the retina. The “blind as a bat” associated with the anticholinergic toxidrome refers not to visual loss but to the loss of accommodation or near focus. On extensive questioning, the patient reluctantly admitted to ingesting 30 tablets of quinine, 300 mg each, in a suicide attempt 3 to 4 hours before arriving in the ED. 2. Toxins may cause either irreversible or reversible hearing loss. The primarily reversible toxins include nonsteroidal antiinflammatory drugs (ibuprofen, naproxen, indomethacin, piroxicam), diuretics (furosemide, ethacrynic acid, acetazolamide, mannitol), antimicrobials (erythromycin, quinine), salicylates, and carbon monoxide. Those agents causing irreversible hearing loss include antimicrobials (aminoglycosides, vancomycin), antineoplastics (cisplatin, vincristine, vinblastine, bleomycin, nitrogen mustard), bromates, hydrocarbons (toluene, xylene, styrene), and heavy metals (arsenic, mercury). This patient had no history of renal insufficiency or congestive heart failure, reducing the likelihood of diuretic exposure. The

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CASE STUDIES

nonsteroidal antiinflammatory drugs (NSAIDs) and antimicrobials, however, are readily available. 3. Quinine is derived from the bark of the cinchona tree, the same tree from which aspirin is derived. It has a long history of use in herbal and homeopathic remedies and is still found in tonic water (about 2 mg/oz). It gained notoriety as a heroin adulterant because its bitter taste resembles that of heroin. It has only recently been removed from the market as a nonprescription remedy for leg cramps. It was also commonly used as an abortifacient, an agent that induces fetal miscarriage, often with disastrous results (Dannenberg). Quinine finds it widest use worldwide as an antimalarial agent, especially in regions where chloroquine resistance is endemic. This patient, a recently discharged Marine, had accumulated pills during his foreign service. Quinine shares many properties with the two other agents derived from the cinchona tree. Like salicylates, quinine induces cinchonism, consisting of nausea, vomiting, tinnitus, dizziness, and headache. Like its optical isomer quinidine, quinine has cardiac effects analogous to the type IA antidysrhythmic agents, including impaired inotropy and myocardial electrical abnormalities (ie, QRS and QT prolongation). Unique to quinine, however, is its ability to produce blindness. Visual changes were initially thought to be secondary to retinal vasospasm and ischemia, and they were even reported to respond favorably to stellate ganglion blockade to relieve the vasospasm. This conception may, in fact, represent reporting bias because subsequent studies have not confirmed this benefit. Alternatively, quinine, or possibly a metabolite, is likely a direct retinal toxin (Bacon). A large retrospective study of patients with acute quinine poisonings found that 42% had visual symptoms, 38% had tinnitus, 14% had altered mental status, and deep coma was present in 4%. Of those with visual symptoms, just over half had total blindness, which was permanent in about half of them. The risk of blindness was roughly correlated with quinine levels; patients with plasma quinine levels greater than 10 µg/mL at 10 hours postexposure are likely to suffer visual loss. However, there is currently little clinical utility for plasma quinine levels, as the test’s availability and therapeutic interventions are limited. 4. The use of oral activated charcoal reduces the half-life of quinine in human volunteers with nontoxic ingestions. To enhance elimination of the drug once absorbed, forced diuresis proved better than hemodialysis, plasma exchange, or peritoneal dialysis for increasing clearance of drug. However, no investigation has ever shown that increasing clearance speeds recovery. Indeed, forced diuresis is a potentially dangerous procedure and almost never indicated. Although not adequately studied, the clinical value of charcoal hemoperfusion may surpass the above methods of enhancing elimination (Morgan). Although case reports suggest that stellate ganglion blockade is curative of the vasospasm and blindness, in a study of 34 treated cases it may have helped in only one. Fortunately, the visual changes generally resolve with supportive care. The patient received several doses of oral activated charcoal. He was given intravenous saline at three times maintenance, and his urine pH remained below 7.5. He did not receive stellate ganglion blocks, nor was another method of enhanced elimination instituted. His electrocardiogram normalized over 12 hours, and his

vision improved over the subsequent 2 days without specific therapy. He was discharged to the psychiatry service.

SUGGESTED READINGS Chapter 27, Ophthalmic Principles. Chapter 28, Otolaryngologic Principles. Boland ME, Roper SMB, Henry JA: Complications of quinine poisoning. Lancet 1985;1:384–385. Dannenberg A, Dorman SF, Johnson J: Use of quinine for self-induced abortion. South Med J 1983;76:846–849. Lockey D, Bateman DN: Effects of oral activated charcoal on quinine elimination. Br J Clin Pharmacol 1989;27:92–94. Morgan MDL, Pusey CD, Rainford DJ, Robins-Cherry AM: The treatment of quinine poisoning with charcoal haemoperfusion. Postgrad Med J 1983;59:365–367. Nordt SP, Clark RF: Acute blindness after severe quinine poisoning. Am J Emerg Med 1998;16:214–215. Sabto J, Pierce RM, West RH, Gurr FW: Hemodialysis, peritoneal dialysis, plasmapheresis, and forced diuresis for the treatment of quinine overdose. Clin Nephrol 1981;16:264–268. Smilkstein MJ, Kulig KW, Rumack BH: Acute toxic blindness: Unrecognized quinine poisoning. Ann Emerg Med. 1987;16:98–101. Tridgell DE: Quinine-induced blindness during attempted heroin withdrawal. Med J Aust 1999;171:444,446.

Case 25 1. Both patients present with symptoms that are common but entirely inconsistent with their histories of exposure. Patient 25a appears to have ingested a caustic substance such as a strong acid or base. These findings would never be expected from Claritin ingestions. Patient 25b is suffering from a dystonic reaction. Dystonic reactions are common following neuroleptic or antiemetic therapy but, again, are not seen with corticosteroid administration. A careful review of patient 25b’s hospital record failed to identify any potential cause for her dystonic reaction. 2. Patient 25a’s medication prescription was reviewed. The bottle was properly labeled as Claritin, but the agent it contained had a very characteristic speckled appearance of Clinitest. Clinitest tablets contain copper sulfate, citric acid, sodium hydroxide, and sodium carbonate and are known for their ability to cause significant esophageal and gastric burns following ingestion of even a single tablet. Patient 25b had a very similar problem. Her prescription bottle was properly labeled for a prednisone taper but contained Prolixin (fluphenazine). Fluphenazine has a well-established association with dystonic reactions. 3. Prescribing errors can occur at any point in the prescription process. The pharmacist must be able to read the prescription. Because many medications sound or are spelled similarly, illegible prescriptions are the most common cause of this error. Table CS–1 lists some of the more common prescribing errors that have resulted from poorly written prescriptions. Other errors occur because medications are stored on shelves in alphabetical order. The best way to prevent this problem is by physicians taking responsibility for their prescription writing. Prescriptions should be clearly written or typed and should use the most recognizable

ANSWERS TO CASE STUDY QUESTIONS TABLE CS–1.

Common Prescription Errors

Intended Drug

Error

Intended Drug Error

Acetohexamide Amiodarone Atrovent Betagan Brevital Calcitrol Cefotan Cefprozil Ceftazidime Cefzil Celebrex Claritin Clinoril Clonidine Coumadin Cyclobenzaprine Cyclophosphamide Cyclosporine Cytoxan Cytoxan Diazepam Diamox Digoxin Dolobid Doxepin Dynacirc Eldepryl Etidronate Feldene Glipizide Glucotrol Hydromorphone Hydroxyzine Imdur Imferon Inderal Inderal Klonopin Lamictal Lanoxin Lanoxin Levoxine Leucovorin Levsin Librium Lithostat Lodine

Acetazolamide Amrinone Alupent Betagen Brevibloc Calciferol Ceftin Cefazolin Ceftizoxime Ceftin Celexa Clinitest Clozaril Klonopin Compazine Cyproheptadine Cyclosporine Cycloserine Cytotec Cytosar Ditropan Dymelor Digitoxin Slobid Doxycycline Dynapen Enalapril Etretinate Seldane Glyburide Glyburide Morphine Hydralazine K-Dur Interferon Imdur Isordil Clonidine Lomotil Lasix Lanoxin Levoxine Leukeran Levoxin Librax Lithobid Iodine

Lopid Lopid Lortab Lotensin Lotrimin Lovastatin Metoprolol Nifedipine Nifedipine Norflex Norvasc Oruvail Oruvail Paxil Paxil Penicillamine Pindolol Pitocin Plendil Prednisone Prednisone Premarin Prilosec Propranolol Prozac Quinidine Retrovir Ridaura Rimantadine Rimantadine Reserpine Saquinavir Slobid Soma Sulfasalazine Terbutaline Symmetrel Tagamet Thiamine Tobrex Toradol Torsemide Vancenase Vincristine Xanax Xanax Zosyn

Lorabid Slobid Lorabid Loniten Lotrisone Lotensin Misoprostol Nicardipine Nimodipine Nofloxin Navan Elavil Clinoril Taxol Paclitaxel Penicillin Parlodel Pitressin Prinivil Prednisolone Prolixin Primaxin Prozac Propulsid Proscar Quinine Ritonavir Cardura Amantadine Ranitidine Respirdal Sinequan Lopid Soma compound Sulfisoxazole Tetracycline Synthroid Tegretol Tenormin Tobradex Torecan Furosemide Vanceril Vinblastine Zantac Tenex Zofran

Medication errors can result from similar sounding or spelling of medications. This risk is compounded when prescriptions are not clearly written.

name (generic vs proprietary) when appropriate. A clear explanation in the “Sig” section will also help this problem. If the prednisone taper said “Sig: one pill PO QD for asthma,” rather than “Sig: one pill PO QD,” the pharmacist would have recognized the inconsistency with Prolixin and questioned the prescription. The same logic would apply to the Claritin prescription. Pharmacists should not fill prescriptions that are incomplete or at all questionable. Finally, physicians should counsel their patients with regard to any medication prescription. The patient should be told the name of the medication and its indications, thus allowing for pa-

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tient recognition to help limit adverse effects if the wrong medication is dispensed.

SUGGESTED READINGS Chapter 117, Adverse Drug Events. Ansari MZ, Collopy BT, Brosi JA: Errors in drug prescribing. J Qual Clin Pract 1995;15:183–190. Johnson KB, Butta JK, Donohue PK, Glenn DJ: Discharging patients with prescriptions instead of medications: Sequelae in a teaching hospital. Pediatrics 1996;97:481–485. Kaushal R, Bates DW, Landrigan C, et al: Medication errors and adverse drug events in pediatric inpatients. JAMA 2001;285:2114–2120. Lesar TS, Briceland L, Stein DS: Factors related to errors in medication prescribing. JAMA 1997;277:312–317. Ross LM, Wallace J, Paton JY: Medication errors in a paediatric teaching hospital in the UK: five years operational experience. Arch Dis Child 2000;83:492–497.

Case 26 1. The differential diagnosis of the severe gastrointestinal distress in these two patients should include bacterial and viral gastroenteritis, food poisoning, toxic mushrooms, plant toxins, heavy metals, organic phosphorus compounds, and exposures to cathartics. In the absence of a better history, exposure to cathartics and heavy metals seems unlikely. Likewise, although exposures to plants (eg, pokeweed) would be expected to produce very similar clinical findings to those manifested in these patients, once again a history of exposure is lacking. Similarly, whereas organic phosphorus insecticides often cause severe gastrointestinal symptoms, in the absence of associated muscarinic (ie, salivation, lacrimation, bronchorrhea, etc) or nicotinic (ie, muscle fasciculations and weakness) findings, the diagnosis of organic phosphorus poisoning seems equally unlikely. If the patients’ symptoms were attributable to food poisoning, the agent would have to be a preformed toxin (Staphylococcus spp). However, because neither of the children is ill, and they ate the same meal except for the mushrooms, a mushroom-related illness is immediately implicated. Mushroom-related gastrointestinal distress is quite common and can result from both relatively benign and life-threatening mushroom toxins. The major discriminating factor is the time of onset of the gastrointestinal symptoms. Mushrooms with nonspecific gastrointestinal toxins (eg, Russula emetica) produce nausea, vomiting, and diarrhea within a few hours of ingestion. Muscarine-containing mushrooms (eg, Inocybe napipes) will produce gastrointestinal symptoms as soon as 30 minutes after ingestion (but like organic phosphorus exposure should have associated muscarinic findings). Nausea and vomiting are both common in patients exposed to hallucinogenic mushrooms (eg, Psilocybe cubensis) and in patients who coingest alcohol with coprinecontaining mushrooms (Coprinus atramentarius through an Antabuselike reaction), but diarrhea is uncommon. Once again, these symptoms present early after ingestion. Delayed gastroenteritis (after 6 hours) is common after ingestion of monomethylhydrazine-containing mushrooms (eg, Gyromitra esculenta) and is often followed by seizures and hepatic toxicity. Patients who ingest mushrooms containing orelline and orellanine (eg, Cortinarius orellanus) similarly remain asymptomatic for at least 6 to 8 hours and then develop gastrointestinal

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symptoms followed, in a number of days, by renal failure. Finally, hepatic failure and death from cyclopeptide-containing mushrooms (eg, Amanita phalloides) usually occurs several days after ingestion. The first sign of toxicity is gastrointestinal symptoms that occur no sooner than 6 hours postingestion. If there has been an ingestion of a single kind of mushroom, the onset of symptoms can be used to discriminate between relatively benign and life-threatening exposures. Assessment of toxidromes (Antabuse reaction, muscarinic syndrome, hallucinations) will allow for a further subdivision of the type of ingestion based on clinical parameters. A problem that may arise, however, is that patients may simultaneously ingest different types of toxic mushrooms, creating a continuum of gastrointestinal symptoms.

Jander S, Bischoff J, Woodcock BG: Plasmapheresis in the treatment of Amanita phalloides poisoning: II. A review and recommendations. Ther Apher 2000;4:308–312. Nordt SP, Manoguerra A, Clark RF: 5-Year analysis of mushroom exposures in California. West J Med 2000;173:314–317. Pinson CW, Daya MR, Benner KG, et al: Liver transplantation for severe Amanita phalloides mushroom poisoning. Am J Surg 1990;159: 493–499. Schneider SM, Borochovitz D, Krenzelok EP: Cimetidine protection against alpha amanitin hepatotoxicity in mice: A potential model for the treatment of Amanita phalloides poisoning. Ann Emerg Med 1987;16:1136–1140. Wauters JP, Rossel C, Farquet JJ: Amanita phalloides poisoning treated by early charcoal hemoperfusion. Br Med J 1970;2:1465.

2. As illustrated above, clinical criteria are often sufficient to allow for the diagnosis of a specific type of ingestion. When additional evidence is required, analysis of the uneaten portion of the mushroom, or spores recovered from leftover food, emesis, or stool may be helpful. This analysis usually requires a trained mycologist because many mushroom species look similar, and specimens of the same species may look dissimilar at different stages of development (see Fig. 76–6). In this case, the spores found in the patients’ emesis were confirmed as having come from an Amanita (cyclopeptide-containing) mushroom.

Case 27

3. Cyclopeptides are large-molecular-weight compounds that interfere with protein synthesis by inhibiting RNA polymerase. As a result, the cells in organs with the highest replication rates are those most sensitive to cyclopeptide toxicity. These target organs include the gastrointestinal tract (especially the liver) and the kidneys. Within the liver classic centrilobular necrosis results, as those cells most sensitive to chemical stress die first. Clinically, patients develop signs of fulminant hepatic failure over the course of several days. 4. Treatment of cyclopeptide toxicity is somewhat controversial. In some case series, fatality rates as high as 40 to 50% are reported. Initial therapy should begin with volume resuscitation and the administration of oral activated charcoal. In vitro evidence supports the use of activated charcoal, and repetitive dosing may be helpful because the toxin undergoes enterohepatic circulation. Multiple agents including thioctic acid, high-dose penicillin, silibinin, silymarin, cytochrome c, cimetidine, and N-acetylcysteine have all been used in experimental models. Human data regarding efficacy of these agents are generally inadequate, and many of these antidotes are not available. Anecdotal evidence is often presented in support of a role for charcoal hemoperfusion and plasmapheresis, but again, controlled data are lacking. Liver transplant has been used successfully in patients with fulminant liver failure.

SUGGESTED READINGS Chapter 76, Mushrooms. Becker CE, Tong TG, Boerner U: Diagnosis and treatment of Amanita phalloides-type mushroom poisoning: Use of thioctic acid. West J Med 1976;125:100–109. Floersheim GL: Treatment of human amatoxin mushroom poisoning: Myths and advances in therapy. Med Toxicol 1987;2:1–9.

1. The history of running out of Xanax (alprazolam) should raise the possibility of sedative-hypnotic withdrawal. The findings of tachycardia and altered mental status are compatible with this diagnosis; however, withdrawal would also be expected to cause pupillary dilation, tremor, diaphoresis, fever, and hypertension, which the patient did not manifest. Furthermore, the time course is not right for withdrawal. Alprazolam has an intermediate half-life (12–15 hours), and the onset of withdrawal symptoms would not be expected to be delayed beyond several days to perhaps 1 week. Symptoms of ethanol withdrawal should also be present within the first few days of abstinence. The patient’s confusion and hallucinations could be caused by a broad variety of medical conditions. A careful medical evaluation to exclude CNS infection, head trauma, and metabolic derangements is mandatory. Acute intoxication with a hallucinogen could cause this clinical scenario. Sedative-hypnotic or ethanol intoxication may cause confusion, small pupils, and relatively normal vital signs, although hallucinations would be uncommon. Cocaine or amphetamines would be expected to cause more prominent sympathomimetic findings including diaphoresis, dilated pupils, marked agitation, and fever. Phencyclidine toxicity may present with relatively small pupils, but prominent nystagmus would be expected. Psychiatric illness could, of course, explain the patient’s initial presentation but should be a diagnosis of exclusion. Although it is rare today, bromism was a common diagnosis earlier this century. In the 1930s, between 3 and 7% of patients admitted to psychiatric hospitals were suffering from bromism, and some authors recommended routine bromide levels be sent on all psychiatric patients (Hanes). Characteristic findings of bromism in case series from this era included mental confusion, stupor, delusions, headache, hallucinations, nervousness, and weakness. A series of 400 cases of mild bromism found that the most common symptoms were headache, irritability, emotional instability, weakness, lethargy, slurred speech, irrelevant speech, delusions, disorientation, hallucinations, memory loss, and confusion. The “characteristic” acneiform eruption of bromism (also known as bromoderma) occurred in only 5 of 49 patients in one series and in 100 of 400 patients in another series (Sensenbach). The course of patients with bromism is often characterized by fluctuations in mental status. In a review of cases admitted to Boston City Hospital, Perkins wrote: “The course in these cases was characterized by pronounced, sudden and unpredictable ups and downs. These sudden

ANSWERS TO CASE STUDY QUESTIONS changes were characteristic enough to suggest the diagnosis of bromidism [sic] in hitherto unsuspected cases” (Perkins). Bromism, although rare, should be suspected in patients with altered mental status and the characteristic laboratory findings of a markedly elevated chloride and a low or negative anion gap. A 1990 survey of reference laboratories estimated that the incidence of bromism (arbitrarily defined as bromide concentration greater than 20 mmol/L) in the United States is now less than 100 cases per year (Bowers). Bromide-containing medications currently available include the rare use of bromide salts such as sodium bromide, potassium bromide, and ammonium bromide for treating refractory epilepsy or as sedatives. A few common medications also contain bromide as a “nonactive” ingredient. These include bromocriptine (Parlodel), dextromethorphan hydrobromide (Robitussin DM, Nyquil, Cheracol), pyridostigmine hydrobromide (Mestinon), and brompheniramine maleate (Drixoral, Dimetane, Bromarest). Bromism from these medications is not reported. 2. Remember that the anion gap, defined as anion gap = [sodium]  {[chloride] + [bicarbonate]}, is the difference between the measured cations and the measured anions. Equivalently, the anion gap could also be considered as the difference between the unmeasured anions and the unmeasured cations. With modern laboratory techniques, the normal range for the anion gap is 3 to 11 (Winter). An abnormally low anion gap will be caused by any condition resulting in increased unmeasured cations or decreased unmeasured anions. Causes of increased unmeasured cations include hypercalcemia, hypermagnesemia, hyperkalemia, high lithium levels, and multiple myeloma. Note that in all but the last of these cases, the cation can be easily measured, giving the correct diagnosis. Decreased unmeasured anions occurs with hypoalbuminemia. The anion gap will also be low if the chloride is falsely elevated. This occurs with bromide toxicity and might also be expected with iodide toxicity. Dilution of serum with water or normal saline (each of which has no unmeasured ions) will cause a decreased anion gap because the same number of unmeasured anions will be distributed in a greater volume of serum (Emmet). 3. Bromide may interfere with some standard laboratory tests for chloride, although this effect is much less pronounced now than it was in the past. The SMAC analyzer measures chloride by detecting the amount of thiocyanate released from mercuric thiocyanate. Bromide has a greater affinity for mercuric ion than chloride and therefore will displace more thiocyanate (Blume). The SMAC will measure an increase in chloride concentration of 1.6 mmol/L for each 1 mmol/L of bromide. Bromide will cause even greater interference with chloride in analyzers that use ion-specific channels. In these instruments each bromide molecule will be measured as 2.25 chloride molecules. Finally, chloride can be determined by a colorimetric technique. In this technique, each molecule of bromide will be counted as one molecule of chloride (Elin). In some automated electrolyte analyzers, bromide will also interfere with bicarbonate determinations. This has been reported on several occasions with the Kodak Ektachem instrument. This machine uses an ion-selective channel for determining bicarbonate concentrations. Apparently bromide is able to cross this channel and cause a false elevation in measured bicarbonate. In one test, each 1 mEq/L of bromide falsely elevated the bicarbonate by about 2.5 mEq/L (Bowers). Kodak stopped marketing this machine in 1994.

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4. Most patients suffering from bromide toxicity will recover with supportive care. Hydration with saline solutions will decrease the half-life of bromide from almost 2 weeks to about 3 days and is a useful addition to treatment. Forced diuresis with saline and loop diuretics has also been suggested. Although hemodialysis will reduce bromide’s half-life to about 1 hour, especially in patients with renal dysfunction, it is rarely indicated in the absence of renal insufficiency except in the most severe cases. Further history revealed that the patient had been taking sodium bromide for the preceding month. According to his diary he had taken up to 51 g on some days. Although this history had been available on admission, and a bromide level had been sent, the diagnosis of bromism was discounted or not considered. The patient was admitted to the intensive care unit, vigorously hydrated with 0.9% NaCl solution, and treated supportively. His mental status improved slowly over a period of 2 weeks, and he was extubated and regained consciousness. Serial bromide levels showed an initial level of 5481 mg/L (68.5 mmol/L), which dropped to 1355 mg/L (16.9 mmol/L) over a 2-week period. By the time the bromide level had dropped to 1355 mg/L, the patient was awake and oriented but not yet completely normal.

SUGGESTED READINGS Chapter 24, Fluid, Electrolyte, and Acid–Base Principles. Chapter 63, Sedative-Hypnotic Agents. Blume RS, MacLowry JD, Wolff SM: Limitations of chloride determination in the diagnosis of bromism. N Engl J Med 1968;279:593–595. Bowers GN, Onoroski M: Hyperchloremia and the incidence of bromism in 1990. Clin Chem 1990;36:1399–1403. Elin RJ, Robertson EA, Johnson E: Bromide interferes with determination of chloride by each of four methods. Clin Chem 1981;27:778–779. Emmet M, Narins RG: Clinical use of the anion gap. Medicine 1977;56: 38–54. Hanes FM, Yates A: An analysis of four hundred instances of bromide intoxication. South Med J 1938;31:667–671. Matsufuji H, Hayashi T, Nishikawa M, et al: Bromide-induced pseudohyperchloridemia. Pediatr Neurol 2000;22:333. Perkins HA: Bromide intoxication: Analysis of cases from a general hospital. Arch Intern Med 1950;85:783–794. Sensenbach W: Bromide intoxication. JAMA 1944;125:769–772. Winter SD, Pearson RJ, Gabow PA, et al: The fall in the serum anion gap. Arch Intern Med 1990;150:311–313.

Case 28 1. When presented with a scenario such as this, several toxins should come to mind immediately. Were the workers exposed to a simple asphyxiant such as carbon dioxide, methane, or nitrogen, which displace oxygen, thus inducing hypoxia? It is not likely that these agents were involved because the history is more consistent with a rapidly evolving toxicity, whereas hypoxia may take several minutes to develop. Asphyxiation often occurs in small chambers and enclosed spaces with limited ventilation, which was not the case here. The ubiquitous poison carbon monoxide must also be considered as well as the chemical asphyxiants cyanide, hydrogen sulfide, and carbon disulfide. These later agents bind to cytochrome oxidase, blocking cellular respiration (refer to Fig. 13–2). Oxygen utilization is interrupted and cellular energy is rapidly depleted, causing cardiovascular collapse. Following resuscitation, cyanide

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causes a persistent metabolic acidosis, which mandates treatment with the Cyanide Antidote Kit (nitrites to induce a methemoglobinemia and thiosulfate to enhance cyanide detoxification). Removal from exposure and supportive care comprise the first-line therapy for hydrogen sulfide and carbon disulfide exposures, as their toxicities are usually rapidly reversible. A final consideration in this case is the irritant gases such as ammonia, nitrogen dioxide, or chlorine, which may rapidly induce pulmonary edema or bronchospasm. The patients’ physical examination, chest radiographs, and arterial blood gases do not support these irritants as the cause of their collapse. While general supportive measures were undertaken, the plant supervisor was contacted and revealed that the patients may have been exposed to hydrogen sulfide.

tion to sulfates is enhanced in the presence of increased oxygen. Last, hyperbaric oxygen is an effective therapy used to minimize postanoxic tissue injury and increase oxygen delivery to marginally perfused regions. This is one of the proposed mechanisms of hyperbaric oxygen therapy following carbon monoxide exposure. The two patients remained deeply obtunded and were transferred to the regional hyperbaric oxygen unit and received 100% oxygen at 2.8 ATA for 48 minutes. One patient awoke on emerging from the chamber and was extubated shortly afterwards. He had a full neurologic recovery and was discharged the following day. Unfortunately, the other patient (the one who collapsed first and thus had the longer exposure) remained in a state of postanoxic encephalopathy.

2. Hydrogen sulfide is a highly toxic colorless gas produced commonly during petroleum refining, during rayon manufacturing, and in the fishing and tanning industries. Natural sources of hydrogen sulfide include bacterial decomposition of sulfur in soil and decay of organic sulfur-containing products (sewers, manure, septic tanks). It is heavier than air, and many poisonings have occurred in tanks and wells where the gas concentrates at the bottom. Hydrogen sulfide does have the odor of rotten eggs, but olfactory fatigue occurs at higher concentrations of gas (>100 ppm), so most of the deadliest exposures occur without warning.

SUGGESTED READINGS

3. At lower levels of exposure, hydrogen sulfide is irritating to mucous membranes and conjunctivae. Increasing respiratory tract irritation occurs at higher levels, with pulmonary edema ultimately developing. At high levels, hydrogen sulfide inhibits cellular respiration by binding to cytochrome a3 oxidase in the electron transport chain. This binding prevents oxidative phosphorylation from occurring, and thus, ATP cannot be generated, and cellular energy is depleted. The poisoned patient may suffer immediate collapse and imminent death if not removed from exposure. As was probably the case here, very brief exposure to more than 1000 ppm causes paralysis of respiration and collapse. 4. Hydrogen sulfide toxicity is often compared to cyanide poisoning because they both inhibit oxidative phosphorylation through the same mechanism. This has led to the suggestion that utilization of nitrites to induce a methemoglobinemia as in the Cyanide Antidote Kit would decrease the binding of hydrogen sulfide from cytochrome aa3 as it does with cyanide. However, an important difference exists between cyanide and hydrogen sulfide toxicity. Cyanide binds tightly to the heme portion of cytochrome aa3, and the induction of methemoglobinemia allows cyanomethemoglobin to be formed, thus freeing the cytochrome from the cyanide inhibition. Hydrogen sulfide binds more reversibly to the cytochrome complex, and thus, removal from exposure alone will decrease the binding of hydrogen sulfide so that further induction of methemoglobin is unnecessary and may be harmful. Methemoglobinemia, following a hypoxic insult, may further impair oxygen-carrying capacity and oxygen delivery to tissues and should be reserved for the moribund patient who has suffered a prolonged exposure. Thus, treatment in this patient following resuscitation is primarily oxygenation and ventilation. Hyperbaric oxygen is another modality described for use in the hydrogen sulfide–poisoned patient. Increased tissue oxygen concentrations promote the binding of oxygen to cytochromes in place of sulfide–cytochrome binding. In addition, sulfide oxida-

Chapter 98, Cyanide and Hydrogen Sulfide. Milby TH, Baselt RC: Hydrogen sulfide poisoning: clarification of some controversial issues. Am J Indust Med 1999;35:192–195. Ravizza AG, Carugo D, Cerchiari EL, et al: The treatment of hydrogen sulfide intoxication: Oxygen versus nitrites. Vet Hum Toxicol 1982; 24:241–242. Smilkstein MJ, Bronstein AC, Pickett HM, Rumack BH: Hyperbaric oxygen therapy for severe hydrogen sulfide poisoning. J Emerg Med 1985;3:27–30. Smith RP, Kruszyna R, Kruszyna H: Management of acute sulfide poisoning. Arch Environ Health 1976;31:166–169. Whitcraft DD, Bailey TD, Hart GB: Hydrogen sulfide poisoning treated with hyperbaric oxygen. J Emerg Med 1985;3:23–25.

Case 29 1. Most of the currently available nonprescription sleeping pills, or hypnotics, contain an antihistamine (H1 receptor antagonist). The available agents, diphenhydramine, doxylamine, and pyrilamine, all have antimuscarinic effects. These effects would certainly be pronounced at doses that produce the degree of sedation seen in this patient. The other common nonprescription sleep aid is ethanol. At high doses, ethanol produces profound central nervous system (CNS) and respiratory depression. Patients may have an odor of alcohol, but this finding is neither sensitive nor specific for intoxication. Until 1989, the amino acid L-tryptophan was available without a prescription as a “natural” sleep aid. However, a contaminant in the production of this serotonin precursor was linked to the eosinophilia-myalgia syndrome and led to the removal of L-tryptophan from the market. It was recently replaced by L-hydroxytryptophan, a related molecule. Although the same contaminant that led to the withdrawal of L-tryptophan is present in L-hydroxytryptophan, there are no reports of eosinophilia-myalgia syndrome with L-hydroxytryptophan. Barbiturates were widely used as prescribed hypnotics in the past, but because of their narrow therapeutic index (difference between therapeutic and toxic doses), they have fallen out of favor. Severe respiratory depression occurs in patients who overdose on barbiturates. This finding was not noted in this case. The barbiturates have been largely replaced by benzodiazepines, which produce no respiratory depression when ingested alone, even in overdose. Benzodiazepines work via a specific receptor, where they potentiate the effect of the inhibitory neurotransmitter GABA. Patients who overdose with benzodiazepines generally present with normal vital signs despite being deeply comatose. A

ANSWERS TO CASE STUDY QUESTIONS new sleep agent, zolpidem (Ambien), is a nonbenzodiazepine agent that also works via the benzodiazepine receptor and produces similar clinical effects. When dispensing of benzodiazepines in New York State changed to require a triplicate prescription form, there was a rise in the use and abuse of older sedative-hypnotic agents. This was presumably related either to the prescriber’s perception of excessive governmental oversight or the laborious process required to complete a triplicate prescription. Meprobamate (Miltown, Equanil), widely used in the 1950s, produces CNS and respiratory depression similar to the barbiturates and may be associated with mild euphoria. It has a tendency to form concretions in the gastrointestinal tract, delaying complete absorption and producing a prolonged or cyclic coma. Glutethimide (Doriden) produces a toxidrome similar to the barbiturates but also manifests some mild anticholinergic effects. Ethchlorvynol (Placidyl) also produces a similar toxidrome, but it carries a distinctive odor similar to plastic. Chloral hydrate (Noctec) is a chlorinated hydrocarbon that is still favored by some pediatricians for procedural sedation. The chlorinated hydrocarbons are well known for their ability to sensitize the myocardium to catecholamines and produce dysrhythmias. The combination of deep coma and dysrhythmias, in the absence of hypoxia, should raise the suspicion of a chloral hydrate ingestion. New York State no longer requires triplicate prescribing but still monitors the prescribing of scheduled substances. The effect that this change will have on the prescribing habits of physicians remains to be seen. 2. Chloral hydrate has been available for more than 100 years. Although it is directly sedating, it is so rapidly metabolized by alcohol dehydrogenase that only its metabolite, trichloroethanol, can be found in the blood. The trichloroethanol, which is responsible for the CNS and respiratory depression, is further metabolized to trichloroacetic acid or is glucuronidated and excreted. An interaction with ethanol forms the pharmacologic basis for the “Mickey Finn” or “knockout drops.” By increasing the supply of the necessary reducing agent, NADH, ethanol metabolism enhances trichloroethanol production. In addition, ethanol inhibits the glucuronidation, and thus slows elimination, of trichloroethanol. Thus, higher trichloroethanol levels are maintained, with the expected result of enhanced toxicity. Cases of chloral hydrate-induced ventricular dysrhythmias have been recognized for 50 years. Early therapeutic endeavors in these cases consisted of observation, or occasionally the use of lidocaine, which did not appear to be more successful therapeutically than observation alone. Procainamide is demonstrated it to be of little value in management. This may be related to the mechanism of enhanced dysrhythmia formation, which is believed to be a heightened sensitivity to catecholamines. This etiology is similar to dysrhythmogenesis produced by other halogenated hydrocarbons. For example, the general anesthetic agents, such as halothane, which capitalize on the CNS depressive abilities of the halogenated hydrocarbons, are known to produce ventricular dysrhythmias. During the act of abusing halogenated hydrocarbon solvents, patients have developed ventricular dysrhythmias and death, a phenomenon known as “sudden sniffing death.” This effect is presumably caused by the outpouring of catecholamines, which further stimulates a myocardium made irritable by the solvent. In the 1960s it was demonstrated that effective therapy of such dysrhythmias could be based on the underlying pathophysiology.

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That is, if the myocardium is sensitive to catecholamines, an agent that reduces catecholamine binding could reduce the tendency for dysrhythmias. The agent first used was the
-adrenergic antagonist alprenolol, and several other
-adrenergic antagonists are also efficacious, including practolol and propranolol. On the basis of this hypothesis of toxicity, it is more easily understood why the class I antidysrhythmic agents were ineffective. 3. Flumazenil is a competitive antagonist of benzodiazepines. In the setting of an isolated acute benzodiazepine overdose, significant morbidity is not expected. When benzodiazepines are combined with other sedatives such as ethanol, however, death may occur if timely supportive care is not instituted. Despite this, with appropriate supportive care, all such patients are expected to survive without morbidity. Therefore, the need to use flumazenil to reverse sedation in such a patient is questionable, especially given the potential pitfalls. If the patient is a chronic benzodiazepine user and has developed tolerance, abrupt reversal of the benzodiazepine may result in an acute withdrawal syndrome, which, like ethanol withdrawal, can result in altered consciousness, seizures, and death. Flumazenil would not be expected to have an effect in a patient with a pure chloral hydrate overdose. In addition, in the setting of a mixed benzodiazepine and chloral hydrate overdose, flumazenil has been reported to exacerbate ventricular dysrhythmias. This is probably a result of the catecholamine release secondary to acute benzodiazepine withdrawal. This patient received lidocaine, 100 mg, with no response. Metoprolol was given with prompt resolution of all dysrhythmias. Gastric decontamination was performed, and the patient received activated charcoal. A pregnancy test and acetaminophen level were both negative. She remained stable for 24 hours and was discharged to the psychiatry service on day 2.

SUGGESTED READINGS Chapter 63, Sedative-Hypnotic Agents. Bowyer K, Glasser SP: Chloral hydrate overdose and cardiac arrhythmias. Chest 1980;77:232–235. Cote CJ, Karl HW, Notterman DA, et al: Adverse sedation events in pediatrics: Analysis of medications used for sedation. Pediatrics 2000;106: 633–644. Graham SR, Day RO, Lee R, et al: Overdose with chloral hydrate: A pharmacologic and therapeutic review. Med J Aust 1988;149:686–688. Gustafson A, Svensson SE, Ugander L: Cardiac arrhythmias in choral hydrate poisoning. Acta Med Can 1977;201:227–230. Pershad J, Palmisano P, Nichols M: Chloral hydrate: the good and the bad. Pediatr Emerg Care. 1999;15:432–435. Short TG, Maling T, Galletly DC: Ventricular arrhythmia precipitated by flumazenil. Br Med J 1988;296;1070–1071.

Case 30 1. In generating the differential diagnosis of possible agents that could induce this scenario, it must be remembered that the patient has chosen a very serious route of administration and has probably also chosen an injectable agent that she felt to be lethal. In addition, she appears to have had a seizure but is now rapidly improving. If the potentially long list is limited to agents readily available, it shortens considerably: insulin, opioids, sedative-hypnotics, barbiturates, neuromuscular blocking agents, potassium chloride, lidocaine, and air embolus. Through varying postulated mecha-

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CASE STUDIES

nisms of poor cerebral perfusion, it is possible that any of these agents could induce seizures. The first three agents mentioned can probably be excluded by her normal glucose and negative drug screen and failure to respond to naloxone; however, the use of a short-acting neuromuscular blocking agent such as succinylcholine to induce transient respiratory paralysis may be possible. Potassium chloride is an obvious consideration, as it has been implicated in multiple physician- or nurse-assisted suicides and is widely known as lethal. A transient dysrhythmia inducing a seizure that abated spontaneously as the potassium was redistributed intracellularly could be postulated. A third consideration would be lidocaine, which could also induce a seizure in high dose that would subsequently abate. Fortunately, all of these remaining possibilities simply required supportive care for the patient to do well. The fluid of the third syringe was analyzed. It was colorless and odorless and noted to have a pH of 7.0, consistent with an injectable drug. Gas chromatography–mass spectrometry was completely negative for any organic substance; however, 1 to 2 mL injected intraperitoneally in a mouse caused collapse and death in 5 minutes. The remaining fluid in the syringe was taken to the hospital chemistry laboratory and analyzed. It had a potassium concentration of 2001.9 mEq/L and a chloride concentration of 2459 mEq/L, consistent with the available form of injectable KCl, which had 20 mEq/10 mL. As suspected, the gravity of her intentions was confirmed. 2. Potassium chloride, in intravenous administration, is of constant concern in hospital settings. Errors in infusion rate or concentration are well known to induce dysrhythmias, which may be fatal. It has often been implicated as the lethal modality utilized by the “Angel of Death” in hospital homicides of the terminally ill. Because 98% of body potassium is intracellular, transient extracellular hyperkalemia induces rapid toxicity before redistributing to intracellular stores. This transient hyperkalemia may be difficult to detect clinically in the living because redistribution is rapid and on postmortem because serum potassium routinely rises after death. It appeared that our patient may have been able to inject only some fraction of a lethal dose, resulting in a dysrhythmia, hypoperfusion, seizure, and then redistribution and recovery. In addition, the 25 g of dextrose given by the paramedics likely prompted insulin release and a further mechanism for uptake of the potassium load to intracellular stores. In contrast, oral potassium overdoses have only rarely resulted in toxicity in patients with normal renal function. The sustainedrelease potassium preparations and the potassium “salt substitutes” have more often been implicated. In addition to routine management of the cardiovascular effects with calcium salts, insulin, dextrose, and sodium bicarbonate, further efforts must be directed at gastrointestinal decontamination to prevent further absorption. Typical electrocardiographic findings progress with increasing potassium levels. Initially, “peaked” or tall T waves are seen in the chest leads. This can be followed by a shortened QT interval. At higher levels, the PR interval prolongs, and then the P waves disappear. Widening of the QRS complex and heart block occur shortly before the QRS joins the T wave in the characteristic “sine wave” pattern, which often degenerates into ventricular fibrillation and asystole. 3. Therapy for the cardiovascular toxicity of hyperkalemia should be initiated immediately with calcium salts. This tran-

siently antagonizes the effects of potassium on the myocardium but does not alter the serum potassium concentration. It should be followed by a glucose bolus with infusion and 5 to 10 units of regular insulin to increase potassium uptake into cells. Sodium bicarbonate therapy further shifts potassium intracellularly and may increase renal excretion of potassium. Potassium exchange resins such as sodium polystyrene sulfonate can be used both orally and rectally and are the only significant modality, excepting dialysis, to remove excess potassium from the body. These resins exchange potassium for sodium, and thus, serum electrolytes should be closely followed during therapy. This patient recovered completely within the first 24 hours and was transferred for psychiatric evaluation.

SUGGESTED READINGS Chapter 9, Electrocardiographic Principles. Chapter 24, Fluid, Electrolyte, and Acid–Base Principles. Cohen MR: Potassium chloride injection mix-up. Am J Hosp Pharm 1990; 47:2457–2458. Saxena K: Clinical features and management of poisoning due to potassium chloride. Med Toxicol Adverse Drug Exp 1989;4:429–443. Wetli CV, Davis JH: Fatal hyperkalemia from accidental overdose of potassium chloride. JAMA 1978;240:1339.

Case 31 1. In the United States, the commonly used rodenticides fall into two groups: anticoagulants and cholecalciferol. Anticoagulants, including coumadin, prevent activation of vitamin K–dependent clotting factors II, VII, IX, X. Following a latent period of at least 24 hours before the onset of significant coagulopathy, hemorrhagic complications such as intracranial hemorrhage may occur. Cholecalciferol causes the typical findings of hypercalcemia: confusion, weakness, hyporeflexia, and electrocardiographic changes. In other countries, however, different agents are more commonly used as rodenticides. For example, in India, aluminum and zinc phosphides, which are both very highly toxic, are responsible for large numbers of suicides because of their easy availability and low cost. Phosphides, after liberation of phosphine gas, result in diffuse cellular poisoning, and patients manifest multisystem organ failure including pulmonary edema, seizures, and cardiac dysrhythmias. In many developing countries, cholinesterase inhibitors, such as organic phosphorus compounds and carbamates, are widely available as rodenticides because of their ease of production and low cost. Although not used as rodenticides in the United States, these same classes of chemicals are widely available here as various types of insecticides. The patient stated that he had ingested Tres Pasitos, a rodenticide imported into this country from the Dominican Republic. 2. Acetylcholine (ACh), an excitatory neurotransmitter found in several organ systems of the body, is normally hydrolyzed by cholinesterases within the synapse (refer to Fig. 88–4). Inhibition of cholinesterases results in persistence of ACh and repetitive stimulation of the postsynaptic effector organ. Stimulation of muscarinic cholinergic receptors (M), found in various organs, results in salivation, lacrimation, urination, and diarrhea; the classic SLUD (salivation, lacrimation, urination, and defecation) findings. Also innervated by muscarinic receptors are the pupil (mio-

ANSWERS TO CASE STUDY QUESTIONS sis), the heart (bradycardia), and the bronchi (bronchorrhea, bronchospasm). In reality, it is the effects of the last two systems that are the most life-threatening muscarinic effects. At the neuromuscular junction, nicotinic cholinergic receptor (NM) stimulation results in muscle fasciculations and subsequent depolarizing blockade, an effect analogous to that occurring with succinylcholine. Finally, agonism of nicotinic cholinergic receptors (NN) in the autonomic ganglia enhances sympathetic outflow with resultant hypertension, tachycardia, and mydriasis. Finally, in the central nervous system, ACh excess leads to diffuse cerebral dysfunction, producing anxiety, seizures, respiratory depression, and coma. Because of the diverse functions of the cholinergic system, the clinical findings of cholinesterase inhibitor toxicity can be highly confusing. For example, direct parasympathetic stimulation to the heart produces bradycardia, whereas autonomic stimulation or bronchorrhea-induced hypoxia indirectly leads to tachycardia. Pupil size is also highly variable and results from interplay of the sympathetic and parasympathetic systems. The effects that predominate are difficult to predict but are related to the agent in question (lipid solubility, concentration, preference for various cholinesterase subtypes), route of administration, and individual patient variability. 3. Care of patients poisoned by organic phosphorus or carbamate agents is easily focused when one appreciates that death generally results from bronchorrhea-induced hypoxia or from respiratory failure secondary to neuromuscular blockade. Early intubation and management of pulmonary secretions are essential, as is assessment of oxygenation status. Both cutaneous and gastrointestinal decontamination are essential, with special precaution given to protect the caregiver, as dermal exposure or inhalation of the poison may lead to secondary toxicity. Patients with more than minimal symptoms, and certainly those with bronchorrhea or bradycardia, require antidotal therapy. This consists of both atropine and pralidoxime. Atropine, a competitive muscarinic antagonist, is utilized to eliminate continued respiratory secretions or to elevate heart rate. Rapidly escalating doses may be needed, starting with 1 mg in an adult. The clinical endpoint of atropinization is drying of respiratory secretions and improvement in oxygenation status. If any questions about the diagnosis existed before atropine therapy, failure of the patient to become anticholinergic after a standard dose of atropine (eg, dry, flushed skin, absent bowel sounds, mydriasis) should allay these concerns. Because respiratory paralysis is a result of nicotinic receptor overstimulation and atropine is effective only at muscarinic receptor sites, pralidoxime must be added in patients in whom concern for such complications exist. Pralidoxime, also known as 2-PAM, binds to the cholinesterase enzyme at a site distinct from the implicated cholinesterase inhibitor. Following a chemical interaction between the pralidoxime and the cholinesterase inhibitor, the product is released, allowing the cholinesterase enzyme to resume acetylcholine metabolism. Pralidoxime works directly on the enzyme, and it ameliorates toxicity at both muscarinic and nicotinic sites regardless of cholinergic receptor subtype. Any patient requiring more than a trial dose of atropine should receive pralidoxime. The initial dose of pralidoxime is 1 g intravenously over 15 to 30 minutes. In the past, some have questioned the safety of pralidoxime in patients poisoned by carbamates. Because carbamates, unlike organic phosphorus compounds, undergo spontaneous hydrolysis

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from cholinesterase, these authors feel that deliberate enzyme reactivation is unnecessary. In addition, one rodent model of carbamate (carbaryl) poisoning in which treatment included a different cholinesterase reactivator (obidoxime) suggests that the use of a cholinesterase reactivator alone, without atropine, may be dangerous. Another rodent model using pralidoxime in a lower equivalent dose than the former study could not reproduce these initial findings. This concern has no clinical relevance, as atropine should be used in all patients receiving pralidoxime. Importantly, because product identification is often inexact, and toxicity from the two agents cannot be differentiated clinically, the use of 2-PAM is generally indicated. This patient received an initial 1-mg dose of atropine intravenously, which was doubled every 5 minutes. Resolution of the bronchorrhea occurred after the administration of 8 mg. He also received an initial 1-g bolus of pralidoxime intravenously, followed by an infusion of 500 mg per hour. Frequent readministration of atropine was required, and an infusion was initiated. Although atropine was initially effective at 6 mg per hour, the rate of infusion was increased to 9 mg per hour to prevent recurrent bronchorrhea. The patient remained on this regimen for approximately 5 days with frequent trials of atropine tapering. It was not until day 5 that the patient tolerated reduction in the dose, which was terminated over the next 36 hours. The total atropine dose received was approximately 1 g. Pralidoxime infusion continued for an additional 18 hours after the atropine was stopped and was then discontinued. Approximately 50 g of pralidoxime was infused over the patient’s hospital course. The patient awoke on day 4 and was alert and oriented by day 5.

SUGGESTED READINGS Chapter 90, Rodenticides. Chapter 88, Insecticides: Organic Phosphorus Compounds, and Carbamates. Antidotes in Depth: Pralidoxime. Mercurio-Zappala M, Hack J, Salvador A, Hoffman RS: Carbaryl poisoning: 2-PAM or not 2-PAM. J Toxicol Clin Toxicol 1998;36:428. Natoff IL, Reiff B: Effect of oximes on the acute toxicity of anticholinesterase carbamates. Toxicol Appl Pharmacol 1973;25: 569–575. Nelson LS, Hoffman RS, Rao R, et al: Poisonings associated with illegal use of aldicarb as a rodenticide—New York City, 1994–1997. MMWR 1997;46:961–963.

Case 32 1. The list of pharmaceuticals and chemicals that produce liver damage is exceedingly long. However, because of the acuity and severity of the patient’s clinical presentation, most hepatotoxins can be eliminated. For example, alcohol-induced liver damage is uncommon in such a young person, and the magnitude of the liver enzyme elevation is inconsistent with this diagnosis. Similarly, patients with alcohol-induced hepatitis typically demonstrate AST elevations that are twice that of the ALT. The absence of acetaminophen in the serum, although it does not fully exclude acetaminophen-induced hepatotoxicity, certainly makes it less likely for that drug to be the cause. Iron salts, such as ferrous sulfate, are readily accessible for many women of childbearing age and may produce hepatotoxicity in overdose. However, hepatotoxicity is usually part of a syndrome of multiorgan system failure, which this patient does not manifest.

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CASE STUDIES

A large number of herbal medicines contain plant derivatives that are potentially hepatotoxic. Comfrey (Symphytum officinale), Senecio, and Jamaican Bush tea contain pyrrolizidine alkaloids, which are metabolized by the liver to compounds capable of alkylating cellular macromolecules. Reaction with endothelial cells in the hepatic vein results in chronic inflammation and subsequent fibrosis with sustained use that ultimately produces hepatic venooclusive disease. This syndrome is similar to the Budd-Chiari syndrome and may lead to hepatic failure. A constituent of germander (Teucrium chamaedrys) is metabolized to a reactive hepatotoxic metabolite. Recently, epidemic poisoning by germander occurred in France when capsules containing the concentrated extract were sold to facilitate weight loss. High-dose vitamin A capsules may produce swelling of the hepatic sinusoidal lining endothelial cells, causing hepatic failure. Many other herbals, such as chaparral and jin bu huan, have been associated with hepatic toxicity. 2. Despite the widespread use of herbal medicines in the United States, little scientific proof of their efficacy exists. When used in small amounts and on a short-term basis, most herbals are probably harmless. However, excessive dosing, drug interactions, and contamination or adulteration are common problems, primarily because the herbal industry is poorly regulated. Furthermore, many herbalists and alternative care providers treat empirically based on a patient’s symptoms rather than on a specific diagnosis, as is standard in conventional medical practice. Although this form of therapy may at times appear effective, given the lack of formal scientific validation of many therapies, it remains unclear if their efficacy represents spontaneous resolution or actual cure. 3. Although this patient suggested that she used the herbal medication to “promote menstruation,” this is often a euphemism for “inducing abortion.” Pregnancy is a common cause of amenorrhea in women of childbearing age, and individual patients may at times not recognize the correlation. Several agents are available for legal use in the United States to induce abortion. Misoprostol (Cytotec, a prostaglandin analogue), methotrexate (an antimetabolite and embryocidal agent), and mifepristone (RU-486, a progesterone antagonist) are used alone or in combinations to terminate undesired intrauterine or ectopic pregnancies. Oral contraceptives are effective for emergency contraception if used shortly after unprotected intercourse. Quinine has a reputation as an abortifacient despite unproved efficacy and significant maternal toxicity. Herbals have long been used as emmenagogues, or menstrual flow stimulators, and abortifacients. Because herbal medicines are easily obtained without a physician contact or prescription, herbal abortifacient and emmenagogue use remains common. Herbal abortifacients, like conventional drugs used for similar purposes, induce abortions through one of several different means. For example, they may initiate or enhance uterine contractions, arrest embryonic development, or interfere with the implantation environment. Patients who develop muscle weakness, fasciculations, and vomiting after consumption of an herbal abortifacient tea may be exposed to blue cohosh (Caulophyllum thalictoides). This herb contains methylcytisine, a nicotinic agonist similar to nicotine. Although most herbs are probably safe at small doses, their efficacy is based on anecdotal or historical evidence, and many have little scientific foundation. Pennyroyal oil is the herbal abortifacient most highly associated with hepatotoxicity and the one taken by this patient. This oil,

which is a derivative of either Mentha pulegium (European or Old World pennyroyal) or Hedeoma pulegioides (American pennyroyal), contains approximately 75% pulegone. Pulegone, a chemical with a pungent odor, is found in low concentrations in other mints such as spearmint and peppermint and is commercially available as a flavoring agent and insect repellent. Pulegone is metabolized by the liver and placenta to menthofuran, a reactive electrophilic compound. In a manner analogous to acetaminophen’s metabolite NAPQI, menthofuran interacts with and destroys nearby cells, such as hepatocytes and placental cells. Because of the mechanistic similarity to acetaminophen, oral N-acetylcysteine use is suggested, although experimental or clinical proof of its benefit remains elusive. It is unclear whether pennyroyal oil is an effective abortifacient without simultaneously inducing maternal toxicity. The patient was hospitalized following initiation of oral N-acetylcysteine. Over the next 3 days the patient’s symptoms and liver enzyme abnormalities resolved. Her pregnancy spontaneously aborted.

SUGGESTED READINGS Chapter 14, Hepatic Principles. Chapter 30, Genitourinary Principles. Chapter 77, Herbal Preparations. Anderson IB, Mullen WH, Meeker JE, et al: Pennyroyal toxicity: measurement of toxic metabolites in two cases and review of the literature. Ann Intern Med 1996;124:726—734. Brown PS: Female pills and the reputation of iron as an abortifacient. Med Histol 1977;21:291—304. Rumack B, Sullivan J, Edell TA, Ferguson S: Fatality and illness associated with consumption of pennyroyal oil—Colorado. MMWR 1978; 27:511—513.

Case 33 1. The differential diagnosis of gastrointestinal distress followed shortly by neurologic impairment should include tetanus, botulism, organic phosphorus compound poisoning, ciguatera poisoning, shellfish poisoning, and tetrodotoxin poisoning. Because of the rapid progression (2 days) may exhaust the endogenous supply of sulfur donor (eg, thiosulfate). Interestingly, patients with renal failure may be less likely to develop cyanide poisoning because of the larger burdens of retained sulfur-containing substrates for rhodanese. However, as noted, in this same population, thiocyanate accumulates because its elimination is completely dependent on renal function. The diagnosis of both cyanide and thiocyanate toxicity is usually established on clinical grounds alone because timely laboratory analysis is often impractical. If cyanide poisoning is suspected, the only routine laboratory test with diagnostic implications is the serum lactate level because it is typically above 10 mmol/L following acute poisoning. However, thiocyanate poisoning occurs in the absence of a lactate-associated metabolic acidosis but is often associated with renal insufficiency. Thiocyanate levels may be predictive of toxicity but not generally available in a clinically useful fashion. 3. Once the diagnosis of cyanide poisoning is seriously entertained, the patient should receive a standard dose (12.5 g in an adult) of intravenous sodium thiosulfate. This is the final part of the cyanide antidote kit and is notably benign. It may be utilized without administering the first two parts of the kit, amyl nitrite and sodium nitrite, respectively, which generate methemoglobin, a cyanide scavenger. Although potentially beneficial, their administration is not critical to antidotal function and often produces undesired effects such as hypotension and reduced oxygen delivery.

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CASE STUDIES

Because cyanide toxicity is predictable based on a rapid rate and long duration of infusion, patients in this situation should receive empiric therapy by the inclusion of sodium thiosulfate (5–10 g intravenously daily) in the infusion. Other non-FDAapproved antidotes, such as hydroxocobalamin, are used successfully in a similar prophylactic role. This latter antidote may be particularly beneficial in the patient with potential thiocyanate toxicity because it does not entail the conversion of cyanide to thiocyanate. Thiocyanate toxicity, although of clinical concern, is not typically life threatening. Treatment is directed at reducing the formation of additional toxin by reducing the infusion rate or switching vasodilators. Hemodialysis is effective in patients with renal failure who develop thiocyanate toxicity. The patient received 12.5 g of sodium thiosulfate, and his antihypertensive regimen was changed to labetolol with a modest improvement in his mental status. His serum cyanide level was undetectable, and his thiocyanate level was elevated.

SUGGESTED READINGS Chapter 98, Cyanide and Hydrogen Sulfide. Antidotes in Depth: Cyanide Antidotes. Baud FJ, Barriot P, Toffis V, et al: Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991;325:1761–1766. Food and Drug Administration: New labeling for sodium nitroprusside emphasizes risk of cyanide toxicity. JAMA 1991;265:847. Friedrich JA, Butterworth JF: Sodium nitroprusside: Twenty years and counting. Anesth Analg 1995;81:152–162. Zerbe NF, Wagner BK: Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity. Crit Care Med 1993;21: 465–467.

Case 38 1. The differential diagnosis of a drug-induced seizure is lengthy, but this patient’s history suggests that the prior night’s events may be related. Nevertheless, common and treatable causes of seizure, such as hypoglycemia, must still be evaluated. In particular, ethanol-induced hypoglycemia, which occurs as a result of the alteration of the body’s redox state during the metabolism of large amounts of ethanol, should be considered and assessed (see Chap. 64). Although profound ethanol intoxication is associated with seizures, such cases are uncommon. Ethanol withdrawal seizures, sometimes termed “rum fits,” are common in an ED population but unlikely in a patient of this young age. Ethanol withdrawal seizures typically begin 12 to 24 hours following the patient’s last drink and, although self-limited, are often treated with benzodiazepines to prevent the development of delirium tremens. Many other drugs are commonly available at dance clubs, and several are prominently associated with seizures. The increasing use of heroin by a younger, club-going crowd is commensurate with the increasing purity of the available heroin and its capability for intranasal administration. Heroin or other opioids occasionally produce hypoxia-related seizures, which result from the profound respiratory depressant effects of these drugs. However, this patient’s normal pulse oximetry and respiratory rate preclude heroininduced hypoxia. γ-Hydroxybutyrate (GHB) and its precursors, γ-butyrolactone and butanediol, are used by dance club patrons as euphoriants and sedatives. Excessive dosing of GHB rapidly pro-

duces coma. Seizures occur occasionally, although their mechanism is not yet fully defined. However, GHB is very rapidly metabolized, and the clinical effects would not be expected to persist the following morning. Withdrawal from GHB and its congeners may also cause seizures. Ketamine, a dissociative anesthetic agent, is popular with a small segment of the club-going community. Its clinical effects, which are often described as dysphoric rather than euphoric, probably account for its relatively small, although growing, audience. It is likely that ketamine-induced seizures are rare because the drug has prominent anticonvulsant activity mediated by antagonism of the excitatory neurotransmitter glutamate at its NMDA receptor subtype. Cocaine causes seizures, both through a direct pharmacologic means (sodium channel blockade) or by causing cerebrovascular ischemia or hemorrhage. Although cocaine is still widely available as a recreational agent, the patient’s normal vital signs essentially eliminate acute cocaine toxicity as a diagnostic possibility. The intracranial complications require further evaluation. Methamphetamine similarly produces dramatic alterations in users’ vital signs and is less frequently associated with seizures because it lacks the sodium channel effects of cocaine. Ecstasy, or methylenedioxymethamphetamine (MDMA), is an amphetamine derivative with a duration of effect of approximately 6 hours. It is widely used in dance clubs, during which time patrons dance continually until the euphoric effects of the drug subside. MDMA’s effects are differentiated from those of methamphetamine by its specific potentiation of serotonergic neurotransmission, an effect that may also be the cause of MDMA-related seizures. 2. Seizures should be rapidly controlled to prevent the development of life-threatening complications such as hyperthermia, hypoxia, or rhabdomyolysis. Glucose and oxygen should be administered as needed. The optimal method for terminating an unrelenting seizure is the intravenous administration of a benzodiazepine, such as diazepam or lorazepam. Patients with suspected poisoning whose seizures remain refractory to the aforementioned interventions should receive intravenous pyridoxine, 5 g, for the possibility of isoniazid poisoning. Continuing seizure activity may require administration of a barbiturate (preferably a rapidly acting agent such as pentobarbital). Most drug-induced seizures will be controlled with these interventions, but rarely neuromuscular blockade will be required to prevent the development of lifethreatening acidosis, rhabdomyolysis, or hyperthermia. During or immediately following the termination of a seizure, patients should be assessed for hyperthermia and ventilatory status, and an attempt should be made to determine the etiology of the seizure. Most patients with new-onset seizures, without an identified reversible etiology, should have an assessment of their glucose and electrolytes in addition to a cranial CT. The specific need for these and other tests (such as a lead level) and the timing of these tests depend on the patient’s clinical condition and related historical factors. 3. As a derivative of amphetamine, MDMA shares many of the parent’s pharmacologic and clinical properties. Amphetamines enhance the release of biogenic amines (eg, norepinephrine, dopamine, serotonin) predominantly through the alteration of their presynaptic vesicular packaging. MDMA, however, is less active than methamphetamine at potentiating norepinephrine release and is associated with dramatically less autonomic stimulation. Importantly MDMA, perhaps because of its double-ring structure, has

ANSWERS TO CASE STUDY QUESTIONS more pronounced effects on serotonin release than methamphetamine. Clinically, this translates into more profound psychedelic effects including distortions and illusions, but despite its categorization as a “hallucinogenic” amphetamine, MDMA does not produce overt hallucinations. Rather, it produces an elevation in the user’s mood and sense of well-being. Psychotherapists have attempted to enhance their therapeutic relationship with patients through the use of MDMA as an “entactogen” or an “empathogen,” meaning an agent that enhances introspection. However, these attractive psychoactive serotonergic effects of MDMA are not without a price. In animal models and human subjects the habitual use of MDMA produces demonstrable neuronal toxicity that likely relates to the excitatory effects of serotonin. Although this effect is only beginning to be defined, chronic MDMA use risks this loss of serotonergic neurons with resultant alterations in cognition, mood, sleep, and memory. Each of these brain processes utilizes serotonin. The acute adverse effects include lifethreatening hyperthermia and its sequelae, and this presentation may actually represent a form of the serotonin syndrome. Furthermore, and particularly relevant to this case, serotonin is the neurotransmitter intimately related to the regulation of antidiuretic hormone (ADH) release. In the setting of serotonin overabundance, excessive release of ADH may produce the syndrome of inappropriate ADH (SIADH), the most important consequence of which is hyponatremia. SIADH may be aggravated or masked by exercise (dancing)-induced loss of intravascular volume, which also causes ADH release and hampers the ability to differentiate SIADH from appropriate ADH release. Further, hyponatremia may be intensified by repletion of salt and water losses with water or other nonelectrolyte solutions. The management of SIADH must emphasize volume restriction because saline administration generally worsens the hyponatremia. In the presence of life-threatening complications of hyponatremia, such as status epilepticus, sufficient hypertonic saline to raise the serum sodium above 120 mEq/L is beneficial. In patients with volume depletion, repletion of intravascular volume with normal saline may be appropriate. Based on his adverse response to normal saline, this patient likely had true SIADH with hyponatremia-related seizures.

SUGGESTED READINGS Chapter 68, Amphetamines. Greer G, Tolbert R: Subjective reports of the effects of MDMA in a clinical setting. J Psychoactive Drugs 1986;18:319–327. Henry JA, Jeffreys KJ, Dawling S: Toxicity and deaths from 3,4-methylenedioxymethamphetamine (“ecstasy”). Lancet 1992;340:384–387. Henry JA, Fallon JK, Kicman AT, et al: Low-dose MDMA (“ecstasy”) induces vasopressin secretion. Lancet 1998;351:1784. McCann UD, Szabo Z, Scheffel U: Positron emission tomographic evidence of toxic effect of MDMA (“ecstasy”) on brain serotonin neurons in human beings. Lancet 1998;352:1433–1437.

Case 39 1. Gases may be irritant in nature through two distinct mechanisms. Certain chemicals, such as those used as tear gas, enhance the neuronal release of substance P, the neurotransmitter involved in the pain response. In conventional doses, the pain from these agents is accompanied by minimal visible changes in the surfaces they contact. Alternatively, irritant gases produce toxicity follow-

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ing their dissolution in mucosal water to form an acid or an alkali or by liberation a free radical. Once dissolved, these toxicologic mediators both activate pain or irritant receptors and directly injure the cell membranes of nearby tissue, producing clinical symptoms. In the eyes and oropharynx this manifests as pain, erythema, injection, or induration, and in the distal bronchopulmonary tree it causes capillary leak. The clinicopathologic syndrome associated with capillary leak is acute lung injury, which was formerly termed noncardiogenic pulmonary edema. Insight into the physicochemical nature of the irritant gas allows the prediction of the expected clinical findings. 2. In general, irritant gases fall into one of three categories, which differ based on the solubility of the chemical in water. Examples of agents that are highly irritating in low concentration include ammonia, hydrogen sulfide, hydrogen chloride, and chloramine gas. Chloramine is of interest not because of its extreme toxicity but because it is most commonly encountered as the result of an inadvertent household chemistry experiment. In a misguided attempt to “superclean” a surface, such as a toilet, ammonia and a hypochlorite containing product (eg, bleach) may be used in combination. The result of this mixture is the production of chloramine gas, which, in a closed space such as a typical bathroom, may produce an immediate irritant response prompting escape. Such highly irritant gases are said to have good warning properties because they produce burning in the eyes and throat immediately on exposure. More intense exposure as a result of either highly concentrated gas or inability to escape may result in dyspnea, stridor, bronchospasm, or upper airway obstruction. Agents with poor water solubility are often nonirritating in moderate to high concentrations, and some agents in fact may be pleasant. Phosgene, the prototype, has an odor akin to “freshly mown hay” and was used effectively as a war gas because it lacked aversive qualities even at toxic doses. Because of their low solubility, patients exposed to such gases remain in the toxic environment, and the prolonged exposure allows the gas to reach the alveoli. On dissolution, irritation of both the upper and lower respiratory epithelium occurs, which may lead to acute lung injury. Other examples of poorly soluble gases include ozone and oxides of nitrogen such as nitrogen dioxide. Although initially asymptomatic, patients exposed to significant concentrations of these substances may develop pulmonary edema 12 to 16 hours following their exposure. The agents with intermediate water solubility, of which chlorine is most representative, are irritating in high concentrations but may be quite tolerable at low levels. Very low-level exposure occurs poolside, and obviously no significant toxicity occurs. This patient, who was exposed to a high concentration of chlorine gas released from the pool shock container, which typically contains either concentrated calcium hypochlorite [Ca(OCl)2] or trichloroS-triazinetrione (TST), suffered rapid mucosal irritation. Because of the concentration of the gas, even with the brief exposure, the patient inhaled a sufficient quantity of gas to allow it to enter the bronchopulmonary tree. Chlorine releases both hydrochloric acid and reactive oxygen species, and both likely participate in the development of acute lung injury. In fact, the patient’s chest radiograph revealed mild, diffuse, bilateral pulmonary infiltrates consistent with pulmonary edema. 3. Because upper airway swelling may be profound and lead to stridor and glottic occlusion, aggressive airway management is the

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CASE STUDIES

rule. Direct visualization of the vocal cords and supraglottic area is indicated in symptomatic patients. Although orotracheal or nasotracheal intubation is preferred if needed, cricothyrotomy may become necessary. Although they are not well studied, corticosteroids should probably be used in patients with significant airway edema. Pulmonary evaluation including serial physical examination, pulse oximetry or blood gas analysis, and radiography may be needed to adequately assess the extent of pulmonary damage. Supplemental oxygen should be used to prevent hypoxemia. Bronchospasm should be treated with
-adrenergic agonist nebulizers at standard doses. There is no current role for the routine use of corticosteroids as prophylaxis or treatment for acute lung injury, but their use in intractable bronchospasm is probably warranted. Nebulized sodium bicarbonate has been shown to provide symptomatic relief in patients exposed to chlorine and is probably useful in all irritant gases that liberate acid. Through a neutralization reaction, the damaging effect of the acid is limited. Any heat or gas generated by this process should be readily dissipated by the bronchopulmonary system. Nebulized sodium bicarbonate should be used in concentrations less than 2%, which generally means about 4:1 dilution of standard 8% sodium bicarbonate. Note that although symptoms may improve, it remains undocumented that complications are reduced or that the natural history of the syndrome is altered. This is certainly of most concern following exposure to irritant gases, such as chlorine or ozone, that liberate

reactive oxygen species. Thus, patients who receive nebulized sodium bicarbonate should be observed for a prolonged period. Irritated eyes should receive copious irrigation with normal saline. Fluorescein staining may reveal corneal abrasions. Ophthalmologic consultation or followup is recommended if symptom resolution is not rapid. Observation is required for all patients exposed to irritant gases. Those exposed to highly soluble agents may be safely discharged if they do not become symptomatic within 2 to 4 hours of exposure or after symptom resolution if prolonged or intense exposure did not occur. In such cases, delayed symptoms would not be expected. Admission is required for all symptomatic patients who were exposed to intermediate or poorly soluble gases because the extent of toxicity is unpredictable. History of exposure will determine the need for admission of patients exposed to intermediate or poorly soluble gases who are not initially symptomatic. If exposure is extensive, or the patient’s ability to return if symptoms develop is not guaranteed, 24 hours of hospital observation with continuous pulse oximetry is warranted. Despite significant findings of hypoxemia (ABG 7.47/30/65 on room air) and clinical and radiographic evidence of acute lung injury, the patient turned around rapidly and improved over the following 16 hours. The patient’s dyspnea resolved by the morning, and although stridor did not develop, his throat irritation took 2 days to fully resolve. He was discharged the following day.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION CHAPTER

1

D. Heroin E. Strychnine

HISTORICAL PRINCIPLES AND PERSPECTIVES

1.6. The “poison squad” investigated A. B. C. D. E.

1.1. Toxicology appears to be derived from the word toxikon. What does the word toxikon mean? A. B. C. D. E.

An evil curse Death Judicial punishment Poisons of animal, vegetable, or mineral origin The poison into which arrowheads are dipped

1.7. Which of the following substances is detected by the Marsh test? A. B. C. D. E.

1.2. Which of the following was the poison of choice used by the ancient Greeks to execute criminals and dissidents? A. B. C. D. E.

Arsenic Digitalis leaf Hemlock Heroin Strychnine

A. B. C. D. E.

Ambroise Paré Galen Maimonides Paracelsus Theodore Wormley

1.4. The author of Traité des Poisons ou Toxicologie Générale is often referred to as the father of modern toxicology. Who is this scientist? A. B. C. D. E.

Arsenic Chloroform Cocaine Mercury Thallium

1.8. Poisonings from which of the following agents precipitated important federal regulatory legislation in the 1920s?

1.3. Who is often credited with developing the concept of dose-response in toxicology? A. B. C. D. E.

“Bad” street drugs Chemicals in the workplace Contaminated food Environmental poisonings Pharmaceutical disasters

Bonaventure Orfila Claude Bernard Richard Mead Robert Christison Theodore Wormley

1.5. In the late 19th century, which of the following was the drug of choice recommended for the treatment of opioid addiction? A. Caffeine B. Chloral hydrate C. Cocaine

1847

Caustics Opioids Pesticides Petroleum distillates Strychnine

1.9. Which of the following characteristics of early European poison centers was not a significant factor in the initial development of American poison centers? A. Cataloging poison identification and treatment information B. Data collection C. Emphasis on prevention D. Organization of toxicology treatment centers E. Service to healthcare professionals 1.10. Which of the following was the focus of the much publicized Institute of Medicine report in 1999? A. B. C. D. E.

Cocaine epidemic Emergency department staffing Medical errors Overproliferation of poison centers Suicide

1848

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

CHAPTER

2

deaths. Which diluent was responsible for these deaths?

TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY 2.1. In which city was a dense smog in 1952 thought responsible for 4000 excess deaths? A. B. C. D. E.

London Mexico City New York City Paris Warsaw

2.2. A combination therapy used in obstetric anesthesia and known as “twilight sleep” refers to which of the following? A. B. C. D. E.

Bromide and caffeine Bromide and chloral hydrate Chloral hydrate and ethanol Morphine and cocaine Morphine and scopolamine

2.3. What toxin was responsible for the 2500 deaths that occurred in Bhopal, India in 1984 after an explosion at a pesticide factory? A. B. C. D. E.

Carbaryl DDT Hydrogen sulfide Methyl isocyanate Parathion

2.4. The use of Agent Orange during the Vietnam War created intense public health concern. Which chemical contaminant in this preparation has been the focus of attention? A. B. C. D. E.

Anthrax Botulinum toxin Dioxin Mercury Sarin

2.5. The use of which of the following agents for the treatment of tinea infections caused needless morbidity and mortality during the 1930s? A. B. C. D. E.

Cadmium Chromium Lead Mercury Thallium

2.6. The therapeutic use of Elixir of SulfanilamideMassengill was responsible for more than 100

A. B. C. D. E.

Benzyl alcohol Diethylene glycol Ethylene glycol Glycerol Propylene glycol

2.7. The eosinophilia-myalgia syndrome was associated with which of the following agents? A. B. C. D. E.

Folate Melatonin Niacin Pyridoxine Tryptophan

2.8. Phossy jaw (mandibular necrosis) was associated with which of the following occupations? A. B. C. D. E.

Felt hat makers Leather manufacturers Match makers Shipyard workers Synthetic dye makers

2.9. Which of the following chemicals is associated with an increased incidence of male infertility? A. B. C. D. E.

Dibromochloropropane (DBCP) Diethylstilbestrol (DES) Diethyltin Dioxane Dioxin

2.10. A serious radiation incident occurred in 1987 in Brazil when 244 people were exposed to a radiation source found in a junkyard. The radiation was an isotope of which of the following elements? A. B. C. D. E.

CHAPTER

Cesium Iodine Plutonium Thallium Uranium

5

TECHNIQUES USED TO PREVENT GASTROINTESTINAL ABSORPTION OF TOXIC COMPOUNDS 5.1. Which of the following is a proven effect of wholebowel irrigation?

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. Decreased drug absorption after actual human poisoning B. Clinical benefit after actual human poisoning C. Decreased drug absorption in volunteer studies D. Electrolyte disturbances following massive dosing E. Interference with drug adsorption to activated charcoal in vivo 5.2. Which of the following is a proven effect of cathartics? A. Decreased drug absorption after actual human overdose B. Clinical benefit after actual human overdose C. Decreased drug absorption in volunteer studies D. Electrolyte disturbances after massive dosing E. Interference with drug adsorption to activated charcoal 5.3. Which of the following cathartics is/are associated with life-threatening fluid and electrolyte disturbances? A. B. C. D. E.

Sodium sulfate Sodium phosphate Magnesium sulfate Sorbitol All of the above

5.4. Which of the following is the best guideline for an initial dose of activated charcoal? A. B. C. D.

200 g 100 g 50 g A 10:1 ratio, ie, 10 times the amount ingested, by history E. 0.5–1.5 g/kg

5.5. Which of the following would be most completely adsorbed by 100 g of activated charcoal? A. 100 tablets (325 mg) of aspirin B. 100 sustained-release tablets (300 mg) of theophylline C. 100 tablets (500 mg) of L-dopa D. 100 mL of 30% ethanol E. 1 g of potassium cyanide 5.6. Which of the following is true of activated charcoal and N-acetylcysteine interactions? A. Activated charcoal adsorbs N-acetylcysteine in vitro but does not actually decrease bioavailability.

1849

B. Activated charcoal adsorbs N-acetylcysteine and decreases its bioavailability, but probably not to a clinically significant degree. C. A clinically significant decrease in N-acetylcysteine bioavailability by activated charcoal has been demonstrated, but this can be overcome by increasing N-acetylcysteine dosage. D. The need to use activated charcoal and Nacetylcysteine concomitantly is an absolute indication for the use of IV NAC. E. Well-controlled clinical studies have proven that the interaction between N-acetylcysteine and activated charcoal is of no significance. 5.7. Which of the following has/have been demonstrated in at least one study? A. Emesis is more effective than orogastric lavage in preventing drug absorption. B. Orogastric lavage is more effective than emesis in preventing drug absorption. C. Orogastric lavage and emesis are equivalent in preventing drug absorption. D. Activated charcoal is more effective than either emesis or orogastric lavage in preventing drug absorption. E. All of the above 5.8. Which of the following has been adequately proven about emesis or orogastric lavage? A. Both are clinically effective in most patients if done within 1 hour after an overdose. B. Neither is clinically effective if performed more than 4 hours after an overdose. C. Both are clinically effective at most times. D. Neither is clinically effective at any time. E. None of the above 5.9. Which of the following characteristics would make multiple-dose activated charcoal (MDAC) a more rational intervention? A. B. C. D. E.

The ingested agent is rapidly absorbed. There is a highly effective antidote available. The amount of drug ingested is 25 g. It has been 4 hours since ingestion. The ingested agent has a low intrinsic clearance and small Vd.

5.10. Multiple-dose activated charcoal does not increase the clearance of which of the following? A. Phenobarbital B. Phenytoin C. Carbamazepine

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. Doxepin E. Nortriptyline

CHAPTER

6.6. Continuous arteriovenous hemofiltration has the following advantage over conventional hemodialysis:

6

PRINCIPLES AND TECHNIQUES APPLIED TO ENHANCE ELIMINATION OF TOXIC COMPOUNDS 6.1. Alkalinization of the urine by administration of NaHCO3 is likely to enhance the elimination of which of the following ? A. B. C. D. E.

Strong acids Strong bases Weak acids Weak bases Both weak acids and weak bases

6.2. Elimination by hemodialysis would not be expected to be useful for a compound with which of the following characteristics? A. B. C. D. E.

Low volume of distribution High degree of protein binding Low lipid solubility Low molecular weight Highly ionized at physiologic pH

6.3. Charcoal hemoperfusion may be preferable to hemodialysis in the case of toxins that exhibit A. B. C. D. E.

Large volumes of distribution High degrees of protein binding High lipid solubility Low molecular weight Neutral charge at physiologic pH

6.4. “Gastrointestinal dialysis” with multiple-dose activated charcoal may be effective for a toxin with which of the following characteristics? A. B. C. D. E.

D. Efficacy of N-acetylcysteine (NAC) E. Poor intestinal absorption

Not absorbed by the intestine High lipid solubility Ingested with food Diminished bowel motility Low molecular weight

6.5. Which of the following characteristics of acetaminophen overdose makes hemoperfusion an undesirable treatment for overdoses? A. High renal clearance B. Lack of major morbidity C. High volume of distribution

A. It may be better tolerated in hypotensive patients. B. It achieves higher clearance rates. C. It requires less monitoring and less staff. D. It is indicated for a more varied range of toxins. E. It can clear lipid-soluble toxins more rapidly. 6.7. Which of the following characteristics of paraquat diminish the efficacy of hemoperfusion for the clearance of the drug? A. B. C. D. E.

High molecular weight High degree of protein binding Tight binding to tissue sites High volume of distribution Nonpolar molecule

6.8. To which toxin does the following statement apply? Rebound of serum levels after hemodialysis as a result of equilibration from intracellular stores often requires repeat dialysis. A. B. C. D. E.

Ethylene glycol Lithium Salicylate Theophylline Ethanol

6.9. Removal of digoxin–antibody complexes from a patient with renal failure might best be accomplished by A. Hemodialysis B. Sorbent hemoperfusion C. Continuous venovenous hemodiafiltration (CVVHD) D. Plasmapheresis E. Oral multiple-dose activated charcoal 6.10. Which statement most accurately describes the efficacy of peritoneal dialysis for the treatment of theophylline poisoning? A. Complexity of the procedure precludes its practical use. B. It can be done simultaneously, as a useful adjunct, with hemoperfusion. C. Lack of hemodynamic effect makes it valuable for hypotensive patients.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. It adds too little to clearance to ever be useful for seriously ill patients. E. The peritoneum is impermeable to theophylline.

CHAPTER

7

LABORATORY PRINCIPLES AND TECHNIQUES FOR EVALUATION OF THE POISONED OR OVERDOSED PATIENT 7.1. Which laboratory technique is most commonly used to measure methanol and isopropanol? A. B. C. D. E.

Atomic absorption spectroscopy Automated enzyme assay Gas chromatography Gas chromatography + mass spectrometry Immunoassay

7.2. Which of the following laboratory measurements are not available as a point-of-care testing format? A. B. C. D. E.

Drugs of abuse in urine Carbon monoxide Blood lead Digoxin Tricyclic antidepressants

7.3. CLIA-88 requirements for moderately complex testing include which of the following? A. Following manufacturer’s instructions B. Package insert must be available to all testing personnel C. Biennial competency certification for all testing personnel D. Controls must be run once a week E. Entry of all results into laboratory computer 7.4. The gold standard for confirmation of drugs of abuse in urine is an analysis performed by which of the following? A. B. C. D. E.

Automated enzyme assay Gas chromatography Gas chromatography + mass spectrometry Immunoassay Thin-layer chromatography

7.5. Which statements about the analysis of drugs in body fluids are correct?

1851

A. False-positive results are more common than false-negative results B. Gas chromatography/mass spectroscopy should always be used, if available C. A confirmed positive finding on a toxicology screen confirms the diagnosis of poisoning D. The sensitivity of thin-layer chromatography is extremely high. E. Immunoassays provide both high sensitivity and high specificity 7.6. Which laboratory methods does not use chemical modification to improve the detection or quantitation of drugs in body fluids? A. B. C. D. E.

Immunoassay Gas chromatography Mass spectroscopy Thin-layer chromatography Spectrophotometry

7.7. Concentrations of which of the following do not require knowledge of the time of ingestion or chronicity of exposure for proper interpretation? A. B. C. D. E.

Acetaminophen Cocaine metabolites (benzoylecgonine) Digoxin Lithium Theophylline

7.8. Which tests are likely to be readily available in the most hospital clinical laboratories? A. Comprehensive toxicology screening B. Drugs of abuse in urine (cocaine, opiates, amphetamines, cannabinoids, phencyclidine, benzodiazepines, barbiturates) C. Heavy metals D. Tricyclic antidepressants (quantitative) E. “Volatile alcohols” (ethanol, methanol, isopropanol, acetone) 7.9. Comparable ethanol concentrations will be present in which pairs of specimens? A. B. C. D. E.

Serum and whole blood Serum and urine Serum and plasma Serum and breath Serum and saliva

7.10. Which types of tests are not regulated by CLIA-88? A. Breath tests for ethanol and carbon monoxide B. Salicylate and acetaminophen spot tests

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Urine dipsticks D. Visual examination of urine for fluorescein and oxalate crystals E. Arterial blood gas

CHAPTER

8

DIAGNOSTIC IMAGING IN TOXICOLOGY 8.1. Which of the following hydrocarbons is the most radiopaque? A. B. C. D. E.

Methylene chloride Methylbromide Dichloromethane Trichloroethylene Carbon tetrachloride

8.2. Chronic exposure to which of the following may cause a decrease in bone density on radiographs? A. B. C. D. E.

Corticosteroids Fluoride Lithium carbonate Calcium carbonate Lead

8.3. Cerebellar atrophy can be noted on CT in patients who are exposed to which of the following? A. B. C. D. E.

Lithium carbonate Cadmium Manganese Methylmercury Magnesium

8.4. Bilateral basal ganglia lucencies have been associated with which of the following toxins? A. B. C. D. E.

Ethanol Methanol Manganese Carbon dioxide Vitamin A

8.5. Which of the following tablets or capsules would be expected to be most radiopaque in an overdosed patient? A. B. C. D. E.

Chloral hydrate Trifluoperazine Ferrous sulfate Sustained-release verapamil Enteric-coated aspirin

8.6. A welder developed respiratory symptoms several hours after working in a poorly ventilated workplace. Which of the following inhaled toxins could

be responsible for coughing, wheezing, and diffuse airspace filling on chest film (acute lung injury)? A. B. C. D. E.

Carbon monoxide Ozone Nitrogen dioxide Carbon dioxide Zinc fumes

8.7. Which of the following agents could be responsible for diffuse intestinal distension (adynamic ileus) seen on an abdominal radiograph? A. B. C. D. E.

Amitriptyline Oxycodone and acetaminophen Cocaine Ergotamine All of the above

8.8. Abdominal radiographs are unlikely to be helpful in which of the following situations? A. Abdominal pain after smoking crack cocaine B. Bloody diarrhea in an 18-month-old child C. Jaundice and coagulopathy occurring 3 days after an acetaminophen overdose D. Suicidal ingestion of hydrochloric acid E. A 27-year-old woman of Asian descent complaining of 3 weeks of abdominal cramping, anorexia, and constipation 8.9. The finding of a diffuse reticular or reticulonodular infiltrate on a chest radiograph is not associated with exposure to which of the following? A. B. C. D. E.

Nitrofurantion Bleomycin Nitrogen dioxide Asbestos Malathion

8.10. Chest radiographic abnormalities associated with procainamide administration include which of the following? A. B. C. D. E.

CHAPTER

Hilar adenopathy Diffuse patchy infiltrates Fine reticular interstitial pattern Pleural effusion All of the above

9

ELECTROCARDIOGRAPHIC PRINCIPLES 9.1. Bidirectional ventricular tachycardia is particularly characteristic of poisoning by what agent?

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

Diphenhydramine Digoxin Quinidine Theophylline Magnesium

9.2. Which of the following opioids can cause repolarization abnormalities in overdose patients? A. B. C. D. E.

Heroin Morphine Meperidine Propoxyphene Diphenoxylate

9.3. Prolongation of the QRS complex to greater than 100 milliseconds would not be expected with which of the following overdoses? A. B. C. D. E.

Thioridazine Cyclic antidepressants Amantadine Omeprazole Procainamide

9.4. The continuous cardiac monitor recording from a modified left chest lead is similar in appearance to which of the following leads from a 12-lead ECG recording? A. B. C. D. E.

aVF V1 Lead II Leads I and III combined V6

9.5. Ventricular depolarization begins with depolarization and ends with the completion of repolarization. This period is defined by what portion of the ECG? A. B. C. D. E.

PR interval QT interval QRS complex ST segment P wave

9.6. All of the following ECG changes may be found in a patient with hypokalemia, except A. B. C. D. E.

ST elevation Increased PR interval Diminished or inverted T waves Increased U-wave amplitude QT prolongation

9.7. Exposure to hydrofluoric acid can cause life-threatening hypocalcemia. ECG changes consistent with this diagnosis include all of the following except

A. B. C. D. E.

1853

Prolonged ST segment Unchanged T wave Widened QRS complex Increased QTc interval Flattened P wave

9.8. A resident shows you an ECG revealing atrial fibrillation with a slow ventricular response. The patient’s heart rate is 30 beats/min, and there are frequent premature ventricular contractions. Further questioning reveals that the patient has chronic atrial fibrillation and has the following medications in her purse: furosemide, digoxin, and nifedipine. She was brought to the ED by her granddaughter for the “flu,” with nausea, vomiting, and dry chapped lips. Your initial working diagnosis should be A. B. C. D. E.

Pyloric stenosis Digoxin toxicity Calcium channel blocker toxicity Staphylococcus aureus food poisoning Depression

9.9. Which of the following conditions could increase the chances of torsades de pointes developing in a patient with hereditary long QT syndrome? A. B. C. D. E.

Hyperkalemia Tachycardia Hypermagnesemia Bradycardia Hypercalcemia

9.10. Ergot alkaloids are effective therapy for some migraine headaches. However, in ergot overdose, toxicity includes all of the following except A. B. C. D. E.

CHAPTER

Coronary vasospasm Valvular fibrosis and stenosis Gangrene Interstitial nephritis Q waves on the ECG

10

NEUROTRANSMITTER PRINCIPLES 10.1. Which one of the following receptors is an ion channel? A. B. C. D. E.

Nicotinic acetylcholine GABAB
-Adrenergic D2 dopamine A1 adenosine

1854

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

10.2. Which of the agents listed is thought to be responsible for self-termination of seizures? A. B. C. D. E.

Serotonin Dopamine Adenosine Norepinephrine GABA

10.3. Following the ingestion of clonidine, which of the following receptors is thought to mediate CNS depression? A. B. C. D. E.

2-Adrenergic Imidazoline GABAA
2-Adrenergic Acetylcholine muscarinic

10.4. Which one of the following agents causes the release of acetylcholine from nerve endings? A. B. C. D. E.

Black widow spider venom Botulinum toxin Cocaine Clonidine Diphenhydramine

10.5. Which of the following neurotransmitters is antagonized by strychnine? A. B. C. D. E.

Serotonin Glutamate Adenosine Dopamine Glycine

10.6. Which of the following agents antagonizes glutamate NMDA receptors? A. B. C. D. E.

Phencyclidine Domoic acid Valproic acid Clozapine Cocaine

10.7. Which of the following agents inhibits dopamine-hydroxylase? A. B. C. D. E.

Propranolol Disulfiram Clonidine Mescaline Chlorpromazine

10.8. Which of the following agents activates serotonin receptors to enhance gut motility? A. Cisapride B. Cyproheptadine C. Ondansetron

D. Propranolol E. Sumatriptan 10.9. Which of the following agents antagonizes adenosine receptors? A. B. C. D. E.

Theophylline Phenytoin Ethanol Diazepam MPTP

10.10. Which of the following agents produces seizures through antagonism at the GABAA receptor complex? A. B. C. D. E.

CHAPTER

Domoic acid Baclofen Penicillin Muscimol Carbamazepine

11

PHARMACOKINETIC AND TOXICOKINETIC PRINCIPLES 11.1. Which of the following factors may influence xenobiotic clearance? A. B. C. D. E.

Age Enzyme induction or inhibition Gender Genetic phenotypes All of the above

11.2. If a 50-kg patient ingests 500 mg of ethanol and is found to have a peak ethanol level of 2 mg/dL (20 µg/mL), assuming 100% absorption and no metabolism, what is the volume of distribution for ethanol? A. B. C. D. E.

5 L/kg 25 L/kg 50 L/kg 0.5 L/kg 0.005 L/kg

11.3. The phase I oxidative process alcohol dehydrogenation occurs primarily in the A. B. C. D. E.

Mitochondria Cytosol Colonic microflora Golgi apparatus Phospholipid membrane of the GI tract

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

11.4. Lithium is best described by a A. B. C. D. E.

Zero-compartment model One-compartment model Two-compartment model Michaelis-Menten model Andover-Martin model

1855

11.10. Pharmacodynamics is a technique used to characterize A. B. C. D. E.

Absorption across semipermeable membranes Distribution kinetics Concentration and clinical effects Metabolic rates and processes Elimination rates and processes

11.5. Xenobiotic distribution is affected by A. B. C. D. E.

Active transport Ionization Lipid solubility Blood flow to the absorption site All of the above

CHAPTER

12

CHEMICAL PRINCIPLES 12.1. Which of the following is true about the elements?

11.6. A 3-year-old, 10-kg child ingests 10 mL of a 100% methanol solution. If the volume of distribution (Vd) for methanol is 0.6 L/kg, what is the predicted peak methanol level (assuming instantaneous distribution)? A. B. C. D. E.

16.7 mg/dL 167 mg/dL 167 mg/mL 1.67 mg/L 1.67 mg/dL

11.7. Phenytoin elimination is best characterized by which of the following processes? A. B. C. D. E.

Michaelis-Menten kinetics Zero-order kinetics First-order kinetics Linear-order kinetics None of the above

11.8. A patient with an acetaminophen level of 150 mg/mL at 4 hours and a level of 37.5 mg/mL at 16 hours has an acetaminophen half-life of A. B. C. D. E.

2 hours 3 hours 4 hours 6 hours 12 hours

A. The periodic table is divided into metals and metalloids. B. All elements in a given period on the periodic table have similar chemical reactivity. C. Most of the elements represented on the periodic table are metals. D. The noble gases are so named because they are capable of reacting with all of the other elements. E. The alkali metals include chlorine and fluorine. 12.2. The transition metals are extremely important in the study of toxicology. Which one of the following statements is true? A. The elemental form of most transition metals is highly reactive and can be found only under special circumstances. B. The reactivity of transition metals is exploited by various physiologic enzyme systems. C. What makes the transition metals so important to toxicologists is that they form brightly colored salts. D. Chronic poisoning by transition metals cannot occur. E. Transition metals are incapable of accepting electrons, only donating them. 12.3. Which of the following is not a heavy metal?

11.9. A 25-year-old, 60-kg man is taking 0.25 mg of digoxin each day to control his atrial fibrillation. Approximately 80% of the oral dose is absorbed. A steady-state digoxin level is 0.8 ng/mL. What is the patient’s clearance of digoxin each day? A. B. C. D. E.

1100 ng/kg/d 2100 ng/kg/d 3100 ng/kg/d 4100 ng/kg/d 5100 ng/kg/d

A. B. C. D. E.

Mercury Thallium Lead Arsenic Bismuth

12.4. Which of the following regarding molecular bonding is correct? A. Bonds in which electrons are nearly equally shared are considered electrovalent.

1856

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

B. The degree to which electrons are shared between elements is determined by the differences in the electronegativity of the elements. C. When one mole of the ionic compound NaCl is dissolved in water one equivalent of NaCl is generated. D. Most chemicals adsorb to activated charcoal via covalent bonds. E. Truly symmetric bonds, such as between the chlorine atoms in Cl2, are always polar. 12.5. Which of the following represents a toxicologically important reactive oxygen species? A. B. C. D. E.

CO O2 H2O OH• O6

12.6. Which of the following substances effects is mediated via redox chemistry? A. B. C. D. E.

Paraquat Phenytoin NaOH Ba2+ Hg0

12.7. Methanol and isopropanol both contain the alcohol functional group. Which of the following statements is most accurate? A. They have identical boiling points. B. They have identical patterns of chemical reactivity. C. They have similar physical and chemical properties. D. They are metabolized at the same rate. E. They have identical toxic effects. 12.8. The two stereoisomers ()physostigmine and (+)physostigmine differ only in their three-dimensional orientation at one chiral center. Which of the following statements is true? A. They have identical boiling points. B. They have identical patterns of chemical reactivity, such as with acetylcholinesterase. C. They have different structural formulas. D. They are metabolized at the same rate. E. They have identical toxic effects. 12.9. Which of the following is most accurate regarding nucleophiles and electrophiles? A. Nucleophiles react most readily with other nucleophiles.

B. Electrophiles have a center or centers that are relatively electron deficient. C. Nucleophiles are always radioactive. D. Electrophiles are always negatively charged. E. The term electrophile is synonymous with the term free radical. 12.10 Which of the following represents a nucleophile of importance to toxicologists? A. B. C. D. E.

CHAPTER

Pb2+ As3+ NAPQI Pralidoxime 2,5-Hexanedione

13

BIOCHEMICAL PRINCIPLES 13.1. Which of the following is a phase I biotransformation reaction? A. B. C. D. E.

Sulfation Glucuronidation Carboxylation Conjugation with glutathione Transesterification

13.2. Which of the following undergoes hepatic metabolism to a toxic compound? A. B. C. D. E.

Paraquat Cycasin Salicylate Bromobenzene Cocaine

13.3. Which of the following toxins is associated with an uncoupling of oxidative phosphorylation? A. B. C. D. E.

Hydrogen sulfide Sodium fluoroacetate Dinitrophenol Ricin Carbon tetrachloride

13.4. Which of the following statements about biotransformation reactions is true? A. The majority of the metabolites produced by phase I biotransformation of lipophilic toxins are water soluble and readily excretable. B. Phase I biotransformation of a xenobiotic is always a mechanism for detoxification.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. The metabolism of ethanol to acetaldehyde is a phase II reaction. D. CYP2E1 has a higher Km for ethanol than alcohol dehydrogenase, making it less likely to be involved in the metabolism of ethanol in most individuals. E. Most phase I biotransformation enzymes are highly specific with regard to which substrates they act on. 13.5. Which of the following statements about phase II reactions is true? A. Decreased availability of glutathione limits the rate of detoxification of both acetaminophen and bromobenzene. B. Phase II reactions decrease the polarity of foreign compounds. C. Phase II reactions are primarily oxidationreduction reactions. D. In many cases, the products of phase II biotransformation reactions are highly toxic. E. Phase II enzymes result in addition of sulfhydryl, hydroxyl, or carboxyl groups to xenobiotics. 13.6. Which substance does not reduce the metabolic activity of CYP3A4? A. B. C. D. E.

Naringenin Erythromycin Ketoconazole Phenytoin Cimetidine

13.7. Which of the following drugs or toxins does not exert its toxic effects through inhibition of a specific enzyme? A. B. C. D. E.

Methotrexate Ricin MPTP Sodium fluoroacetate Coumadin

13.8. Which of the following agents is not known to exert its effects through a specific protein receptor? A. B. C. D. E.

Morphine Atropine Pancuronium Mercury Flumazenil

13.9. All of the following result in decreased cellular production of ATP except which drug or toxin? A. Cyanide B. Sodium fluoroacetate

1857

C. Arsenic D. Salicylates E. Isoniazid 13.10. Which of the following agents causes injury at the site of its metabolic transformation? A. B. C. D. E.

CHAPTER

Cyanide Succinylcholine Salicylate Carbon tetrachloride MPTP

14

HEPATIC PRINCIPLES 14.1. Which of the following statements about hepatotoxins is true? A. The liver injury caused by most hepatotoxins is dose dependent. B. Following ingestion of similar quantities of the mushroom Amanita virosa, some individuals may suffer severe effects while others remain asymptomatic. C. Most hepatotoxins are idiosyncratic in that their effects cannot be predicted for any individual person. D. Following exposure to halothane, acute hepatitis is extremely rare, occurring in fewer than 1/10,000 cases. E. Because of the predominance of the portal circulation in the liver, only ingested toxins cause hepatotoxicity. 14.2. The toxic metabolite of acetaminophen is which of the following? A. B. C. D. E.

Benzquinolone Benzidine N-Mercaptophenetidin N-Acetyl-p-benzoquinoneimine Phenacetin

14.3. Which of the following statements is true? A. Intrahepatic bile flow is a passive process, driven by secretion of large volumes of bile into the canaliculi. B. Cholestasis rarely occurs in the absence of extensive hepatocellular injury. C. Injury localized to the canalicular tight junctions results in hyperbilirubinemia because of bile leakage.

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. Small sulfated macromolecules are avidly taken up into an enterohepatic circulation. E. Cholestasis is the most prominent early pathologic manifestation of vitamin A hepatotoxicity. 14.4. The localization of toxic hepatic injuries to specific zones of the liver may be related to which of the following? A. Decreasing oxygen tension between the portal and central vein areas B. Selective delivery of a toxin to the portal areas C. Localization of specific biotransformation enzymes within the periportal or centrilobular areas D. Regional decreased availability of substrates for phase II biotransformation reactions E. All of the above 14.5. Which of the following statements regarding ethanol-induced liver disease is not correct? A. An AST of 2000 IU/L is inconsistent with the diagnosis of acute ethanol-induced hepatitis. B. The pathologic effects of amiodarone-induced hepatotoxicity are very similar to those of ethanol. C. The AST is usually two to three times greater than the ALT. D. Steatosis most likely occurs because of the altered oxidative capacity of the hepatocyte. E. Alcoholic liver disease, in reality, is caused by thiamine deficiency. 14.6. Acute intraperitoneal hemorrhage is associated with hepatotoxicity caused by which of the following drugs? A. B. C. D. E.

Chlorpromazine Anabolic steroids Tetracycline Isoniazid Erythromycin

14.7. An AST of 5000 IU is consistent with hepatic injury caused by which of the following? A. Acute extrahepatic obstruction of the common bile duct B. Acute alcoholic hepatitis C. Hepatotoxicity as a result of chronic treatment with methotrexate D. Acute hepatic injury caused by acetaminophen toxicity E. All of the above

14.8. The Bacillus cereus toxin induces a type of hepatic injury that is similar to all of the following except which? A. B. C. D. E.

Fialuridine Reye syndrome Acute fatty liver of pregnancy Chlorpromazine Zidovudine

14.9. Which biochemical marker is most predictive of the severity of liver injury in patients with acute hepatocellular necrosis? A. B. C. D. E.

Prothrombin time (INR) AST Serum bilirubin Serum creatinine Alkaline phosphatase

14.10. All of the following are true about hepatotoxicity caused by carbon tetrachloride except which statement? A. It has been shown to be increased by the administration of oxygen. B. It has been shown to be decreased by the administration of glutathione. C. CCl4 is metabolized by the ethanol-inducible CYP2E1. D. Hepatocellular injury is initially localized to the zone 3, or centrilobular areas of the liver. E. The most likely mechanism of hepatocellular injury is the initiation of lipid peroxidation by free radicals.

CHAPTER

15

IMMUNOLOGIC PRINCIPLES 15.1. Which of the following toxins is the poorest candidate for the development of antibody therapy? A. B. C. D. E.

Digoxin Colchicine Theophylline Botulinum toxin Tetanus toxin

15.2. The reactive airways dysfunction syndrome (RADS) is a chronic asthmalike condition associated with a single high-dose exposure to a respiratory irritant. Which of the following has been reported to induce RADS? A. Toluene diisocyanate B. Chlorine gas

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Sulfur dioxide D. Ethylene oxide E. All of the above 15.3. Environmental adjuvants are substances that potentiate production of IgE in response to other substances. Which of the following is known to be such an adjuvant in experimental models? A. B. C. D. E.

Diesel exhaust particles Ozone Sulfur dioxide Nitrogen dioxide All of the above

15.4. An advantage of Fab fragments over whole antibody molecules in the immunotoxicotherapy of poisoning is A. There is less risk of serum sickness. B. There is less risk of anaphylaxis. C. A smaller volume of antibody fragment is infused. D. The volume of distribution of Fab fragments is greater than the volume of distribution of whole antibody. E. All of the above 15.5. Selective IgA deficiency has been associated with which of the following pharmaceuticals? A. B. C. D. E.

Ticlopide Aspirin Hydrochlorothiazide Phenytoin Trimethoprim

15.6. Inhalation exposure to burning oil in Kuwait during the Persian Gulf War has been associated with A. B. C. D. E.

Systemic lupus erythematosus Rheumatoid arthritis Aplastic anemia Testicular cancer Parkinsonian syndrome

15.7. Systemic lupus erythematosus has not been associated with which of the following? A. B. C. D. E.

Procainamide Hydralazine Tartrazine Hydrazine Lidocaine

15.8. Penicillin induces autoimmune hemolytic anemia by A. Altering the immune regulatory system that protects against self antigens

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B. Molecular mimicry, in that the chemical structure of penicillin is so similar to antigens on the red blood cell surface that antibodies against penicillin will bind to red blood cells C. Binding to red blood cells and producing an antibody against this bound penicillin D. Directly damaging red cell membranes by the same mechanism by which it damages bacterial membranes E. Binding to the first component of complement, thereby activating the complement cascade 15.9. A feature of the Spanish toxic oil syndrome was A. Few people who were injured in this epidemic recovered. B. Toxic induction of collagen vascular disease was most common in individuals with DR3 and DR4 HLA haplotypes associated with genetic susceptibility to the disease. C. There were no hematologic abnormalities associated with this syndrome. D. The etiologic agent in this syndrome was olive oil contaminated with heavy metals. E. A hypersensitivity response to imported L-tryptophan. 15.10. Adverse effects reported in association with exposure to the dioxin TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) include A. An increase in cancer mortality and a decrease in cellular immune responses B. An increase in cancer mortality but no effects on cellular immune responses C. A decrease in cancer mortality but no effects on cellular immune responses D. No effect on cancer mortality or cellular immune responses E. An increase in cancer mortality and an increase in cellular immune responses

CHAPTER

16

MUTAGENS, CARCINOGENS,AND TERATOGENS 16.1. Which of the following is not a recognized criterion for teratogenicity? A. There should be biologic plausibility for the mechanism of action of the putative teratogenic agent. B. There should be animal models of the exposure that mimic the effects in humans.

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. There should be quantitative proof of exposure with biologic markers. D. There should be findings from epidemiologic studies showing that exposure produces an increase in the occurrence of specific phenotypic effects and a recognizable pattern of both major and minor malformations. E. There should be a dose–response relationship that has been demonstrated in either animal models or human exposures. 16.2. Which of the following statements about smoking is true? A. Mothers generally recall accurately the number of cigarettes they smoked during their pregnancy. B. Maternal smoking has not been shown to have any neurobehavioral teratogenicity. C. Blood nicotine levels acccurately reflect the extent of chronic smoking. D. Maternal smoking is associated with an increased rate of congenital malformations. E. Infants of passive smokers are at risk of measurable exposure to cigarette smoke. 16.3. Which of the following outcomes has not been associated with maternal cigarette smoking? A. B. C. D. E.

Decreased birth weight Congenital heart defects Prematurity Spontaneous abortions Sudden infant death syndrome

16.4. Which of the following statements is not correct? A. Mutagens produce alterations in DNA. B. Mutations may occur in somatic and germ cells. C. All mutagens are carcinogens. D. The Ames test is a screen for mutagenicity. E. Mutagenic activity cannot be predicted on the basis of chemical structure alone. 16.5. Which of the following agents is not a recognized human carcinogen? A. B. C. D. E.

Melphalan Mercury Cadmium Diethylstilbestrol Aflatoxin

16.6. Which statement regarding meconium is correct? A. Drugs are present in meconium only after 26 weeks of gestation.

B. Meconium testing cannot be used for mass screening. C. Meconium testing is less accurate than urine testing. D. Meconium can only be used to detect cocaine and opioids. E. Drugs are detectable in the first three meconium stools. 16.7. Which statement regarding prenatal exposure to methylmercury is false? A. It is characterized by severe neurotoxicity. B. First-trimester exposure is most critical. C. Methylmercury achieves higher fetal than maternal concentrations. D. Hair may be used to measure exposure in both mothers and infants. E. Cord blood and maternal hair levels correlate well. 16.8. Which statement regarding prenatal lead exposure is false? A. Prenatal lead exposure may result in neurodevelopmental toxicity. B. Cord blood lead levels greater than 0.48 mmol/L are associated with low developmental scores at 6–24 months of age. C. Prenatal lead exposure may result in obstetric complications such as spontaneous abortion, premature rupture of membranes, and preterm delivery. D. There is poor correlation between maternal and cord blood lead levels. E. Lead crosses the placenta by both active and passive transfer. 16.9. Which statement regarding hair is false? A. Using hair analysis, it is not possible to differentiate systemic exposure and exposure by passive smoking of crack cocaine. B. Hair can be used to estimate both maternal and fetal xenobiotic exposures. C. Adult hair grows at a rate of approximately 1.5 cm per month D. Maternal and fetal accumulation of cocaine and its metabolites follows a linear pattern. E. Cocaine and its metabolites, including cocaethylene and benzoylecgonine, can be measured in hair. 16.10. Which of the following statements is false? A. Nicotine and its metabolites accumulate in the amniotic fluid.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

B. Amniocentesis is not commonly used as a routine investigation following xenobiotic exposure. C. Specific fetal anomalies related to teratogenic exposures may be detected on ultrasound in the second trimester. D. Following first-trimester retinoic acid use, neural tube defects have been demonstrated on midtrimester ultrasound. E. Counseling regarding xenobiotic exposure may prevent unnecessary termination of pregnancy.

CHAPTER

17

VITAL SIGNS AND TOXIC SYNDROMES 17.1. Which of the following medications is likely to cause hypotension and tachycardia in overdose? A. B. C. D. E.

Clonidine Digoxin Morphine Nifedipine Nadolol

17.2. Which of the following can cause respiratory stimulation? A. B. C. D. E.

Opioids Salicylates Flunitrazepam Propofol Secobarbital

17.3. Which of the following agents is associated with hypertension? A. B. C. D. E.

Disulfiram/ethanol Iron Isopropanol Lead Organic phosphorus compounds

17.4. A bradycardia has been associated with which of the following ingestions? A. B. C. D. E.

Phenylpropanolamine Iron Isoniazid Diphenhydramine Phencyclidine

17.5. Chronic exposure to which of the following toxic inhalants may cause an increase in the incidence of hypertension?

A. B. C. D. E.

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Nitrates Carbon disulfide Carbon monoxide Sulfur dioxide Methane

17.6. Which of the following vital signs or physical findings permits the differentiation of opioid withdrawal from ethanol withdrawal? A. B. C. D. E.

Blood pressure Pulse Respiratory rate Temperature Pupil size

17.7. Which of the following vital signs or physical findings is most useful in the differentiation of adrenergic agent exposure from anticholinergic agent exposure? A. B. C. D. E.

Pulse Temperature Mental status Pupil size Peristaltism

17.8. In which of the following clinical situations would the patients’ mental status be expected to be normal? A. B. C. D. E.

Adrenergic agent overdose Anticholinergic agent overdose Opioid agent overdose Opioid agent withdrawal Ethanol withdrawal

17.9. Which of the following agents is associated with life-threatening hyperthermia? A. B. C. D. E.

Arsenic Botulism Carbamazepine Mercury Phencyclidine

17.10. While treating a patient with cholinergic poisoning with atropine, which of the following is most important to monitor? A. B. C. D. E.

Blood pressure Pulse Respiratory rate Temperature Mental status

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CHAPTER

18

THERMOREGULATORY PRINCIPLES 18.1. In the central nervous system, thermosensitive neurons are located predominantly in which area? A. B. C. D. E.

Posterior hypothalamus Substantia nigra Locus ceruleus Anterior hypothalamus Thalamus

18.2. Which of the following is the primary neurotransmitter causing stimulation of sweat glands? A. B. C. D. E.

Norepinephrine Serotonin Acetylcholine Antidiuretic hormone Aldosterone

18.3. Which of the following is the main thermoregulatory response to cold in adult humans? A. B. C. D. E.

Vasoconstriction Shivering Gluconeogenesis Mobilization of brown fat Piloerection

18.4. Which of the following best describes the classic electrocardiographic change associated with hypothermia? A. B. C. D. E.

PR segment prolongation QTc shortening Peaked T waves U waves J-point deflection

18.5. All of the following are part of the definition of heatstroke except A. B. C. D. E.

Absence of sweating Temperature >106°F (41.1°C) Altered mental status Clear mental status Presence of sweating

18.6. All of the following drugs predispose to hyperthermia except A. B. C. D. E.

Cocaine Antihistamines Lithium Cyclic antidepressants Organophosphates

18.7. Dantrolene sodium is the accepted treatment of choice in which condition? A. B. C. D. E.

Exertional heatstroke Neuroleptic malignant syndrome Malignant hyperthermia Classical heatstroke Strychnine poisoning

18.8. All of the following may predispose to hypothermia except A. B. C. D. E.

Thiamine deficiency Phenobarbital Hypoglycemia Carbon monoxide Salicylates

18.9. Which of the following is of greatest prognostic significance in hypothermia? A. B. C. D. E.

Temperature 70–80°F (21–27°C) K+ >10 meq/L Frostbite Unconsciousness Ethanol intoxication

18.10. Which of the following is not true regarding drug metabolism in hypothermia? A. B. C. D. E.

CHAPTER

Hepatic metabolism decreases. Renal clearance decreases. Glomerular filtration rate decreases. Volume of distribution increases. Neuromuscular blockade is prolonged.

19

NEUROLOGIC PRINCIPLES 19.1. Asymmetric (focal) neurologic findings can be found with which of the following overdoses? A. B. C. D. E.

Amphetamine Diazepam Glyburide Haloperidol Phenytoin

19.2. Which of the following combinations of findings is most characteristic of coma caused by an overdose? A. Equal, reactive pupils with absent oculovestibular response B. Equal, reactive pupils with marked nystagmus in response to cold calorics

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Unequal, reactive pupils with flaccid right arm and leg D. Equal, nonreactive pupils with intact oculocephalic response E. Equal, reactive pupils with gaze palsy at rest, easily broken with oculocephalic maneuver 19.3. A young woman presents with normal pupils and bilateral papilledema. She is awake and alert, complaining of headache. She frequents health food stores and takes large quantities of multiple vitamins. Which of the following is the most likely etiology? A. B. C. D. E.

Vitamin C Niacin Vitamin D Vitamin E Vitamin A

19.4. Through what mechanism does Clostridium tetani exert its effect on the CNS following initial infection? A. B. C. D. E.

Blood-borne via C. tetani bacteremia Lymphatics Myelin sheath Axon Attachment of exotoxin to red blood cells

19.5. A pyridoxine overdose most commonly causes which of the following findings? A. Proximal weakness secondary to myopathy B. Marked atrophy caused by demyelination of peripheral nerve fibers C. Diffuse loss of reflexes secondary to an acute axonopathy D. Ataxia caused by sensory neuronopathy E. Autonomic instability caused by interference with transmission at the neuromuscular junction 19.6. Which of the following agents is most likely to produce permanent Parkinson disease? A. B. C. D. E.

Droperidol (depot injection) Thioridazine Thiothixene Clozapine MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

19.7. Which of the following is an essential feature of delirium? A. Disorientation to place and time B. Stable level of consciousness

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C. Perceptual distortion D. Selectively impaired short-term memory loss E. Inattention 19.8. Asterixis is most reliably indicative of which of the following? A. B. C. D. E.

Hepatic failure Overdose Postictal state Delirium Toxic metabolic encephalopathy

19.9. Which of the following is most likely to produce a kinetic tremor? A. B. C. D. E.

Lithium Levodopa Phenothiazines Cocaine Hypomagnesemia

19.10. A patient being treated with increasing doses of antipsychotic agents for worsening “agitation” may actually be suffering from which of the following side effects of these medications? A. B. C. D. E.

CHAPTER

Tardive dyskinesia Tardive dystonia Parkinsonian tremor Chorea Akathisia

20

RESPIRATORY PRINCIPLES 20.1. Impaired ventilation as a result of chest wall rigidity is associated with which of the following toxins? A. B. C. D. E.

Morphine Fentanyl Heroin Codeine Ethchlorvynol

20.2. Nebulized 2% sodium bicarbonate may be useful in patients exposed to which of the following pulmonary irritants? A. B. C. D. E.

Nitrogen dioxide Chloracetophenone Chlorine Ammonia Ozone

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

20.3. Which of the following statements about monitoring parameters in patients with carbon monoxide poisoning is true? A. The oxygen saturation from the arterial blood gas will be low, the PO2 will be low, the pulse oximeter O2 saturation will be low, and the oxygen saturation determined by the COoximeter will be low. B. The oxygen saturation from the arterial blood gas analysis will be normal, the PO2 will be normal, the pulse oximeter oxygen saturation will be low, and the oxygen saturation determined by the CO-oximeter will be low. C. The oxygen saturation from the arterial blood gas will be normal, the PO2 will be normal, the pulse oximeter O2 saturation will be normal, and the oxygen saturation determined by the CO-oximeter will be low. D. The oxygen saturation from the arterial blood gas will be low, the PO2 will be normal, the pulse oximeter saturation will be low, and the oxygen saturation determined by the COoximeter will be low. E. The oxygen saturation from the arterial blood gas will be low, the PO2 will be normal, the pulse oximeter O2 saturation will be low, and the oxygen saturation determined by the COoximeter will be low. 20.4. Which of the following gases is not a simple asphyxiant? A. B. C. D. E.

Carbon dioxide Argon Propane Nitrogen Nitrogen dioxide

20.5. Which of the following gases is not a chemical asphyxiant? A. B. C. D. E.

Cyanide Hydrozoic acid Hydrogen sulfide Amyl nitrite Chloracetophenone

20.6. Which of the following statements about monitoring parameters in patients with methemoglobinemia is true? A. The oxygen saturation from the arterial blood gas will be low, the PO2 will be low, the pulse oximeter O2 saturation will be low, and the oxygen saturation determined by the COoximeter will be low.

B. The oxygen saturation from the arterial blood gas will be normal, the PO2 will be normal, the pulse oximeter O2 saturation will be low, and the oxygen saturation determined by the COoximeter will be low. C. The oxygen saturation from the arterial blood gas will be normal, the PO2 will be normal, the pulse oximeter O2 saturation will be normal, and the oxygen saturation determined by the CO-oximeter will be low. D. The oxygen saturation from the arterial blood gas will be low, the PO2 will be normal, the pulse oximeter O2 saturation will be low, and the oxygen saturation determined by the COoximeter will be low. E. The oxygen saturation from the arterial blood gas will be low, the PO2 will be normal, the pulse oximeter O2 saturation will be low, and the oxygen saturation determined by the cooximeter will be low. 20.7. Which of the following is not directly associated with the development of acute lung injury? A. B. C. D. E.

Phenobarbital overdose Chlorine gas Phosgene gas Salicylate overdose Heroin overdose

20.8. Which of the following mechanisms best explains the generation of opioid-induced acute lung injury? A. Naloxone administration B. Aspiration during a period of unconsciousness C. Elevation of catecholamines produced by hypercapnia D. Direct opioid-induced alterations in pulmonary capillary integrity E. Acute myocardial dysfunction from high levels of opioid 20.9. The disasters at Lake Nyos and Lake Monoun in Cameroon resulted in over 1700 deaths by which toxin? A. B. C. D. E.

Carbon dioxide Carbon monoxide Cyanide Hydrogen sulfide Hydrogen chloride

20.10. Barotrauma (pneumothorax, pneumomediastinum, pneumopericardium) is associated with the use of all of the following drugs of abuse except

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

CHAPTER

Intranasal cocaine Smoking “crack” cocaine Marijuana Methlyenedioxymethamphetamine Nitrous oxide

21

CARDIOVASCULAR PRINCIPLES 21.1. Overdose of which of the following medications has caused torsades de pointes? A. B. C. D. E.

Diphenhydramine Lidocaine Terfenadine Propoxyphene Magnesium

21.2. Which of the following opioids can cause intraventricular conduction delays in overdose? A. B. C. D. E.

Heroin Morphine Meperidine Propoxyphene Diphenoxylate

21.3. Cardiac dysrhythmias from chloral hydrate and other halogenated hydrocarbons are believed to be caused by A. Increased adrenergic release B. Sensitization of the myocardium to catecholamines C. AV conduction defects D. Intraventricular conduction delays E. Hypoxia 21.4. Prolongation of the QRS complex to greater than 100 msec would not be expected with which of the following overdoses? A. B. C. D. E.

Thioridazine Amitriptyline Amantadine Omeprazole Procainamide

21.5. Which of the following overdoses exposure does not cause bradycardia and hypotension? A. B. C. D. E.

Verapamil Sotalol Propoxyphene Yohimbine Magnesium

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21.6. Overdoses of which of the following medications can cause hypotension that is refractory to therapy with intravenous dopamine? A. B. C. D. E.

Lithium Amitriptyline Ethchlorvynol Phenobarbital Propafenone

21.7. An increase in both blood pressure and pulse rate would be expected immediately following an overdose with which of the following? A. B. C. D. E.

Nifedipine Phenylpropanolamine Bretylium Theophylline Practolol

21.8. Which of the following toxic exposures would be least likely to cause intravascular volume depletion? A. B. C. D. E.

Theophylline Iron Cocaine Datura stramonium (Jimson weed) Organophosphates

21.9. Intraventricular conduction delay does not occur with which of the following antidysrhythmic drugs? A. B. C. D. E.

Lidocaine Quinidine Bretylium Procainamide Encainide

21.10. A decrease in blood pressure and a decrease in pulse rate would most commonly be expected to occur with which of the following overdoses? A. B. C. D. E.

CHAPTER

Chlorpromazine Amitriptyline Glutethimide Sotalol Nifedipine

22

GASTROINTESTINAL PRINCIPLES 22.1. Which of the following statements regarding the effects of caustics on the GI tract is true?

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. Acids cause a liquefactive necrosis of the mucosa. B. Alkalis produce more damage to the gastric mucosa than to other parts of the GI tract. C. Because the intragastric environment is already strongly acidic, strong acids are not likely to cause significant damage. D. The acidemia following acid ingestion is typically non-anion-gap (normal anion gap) acidosis. E. Caustic ingestions are associated with neoplasms years after the ingestion. 22.2. In the initial phase of acute radiation syndrome, vomiting that begins 2 hours after exposure indicates A. B. C. D. E.

A lethal exposure Exposure to 100 rads (1Gy) Exposure to over 600 rads (6Gy) Exposure to over 2000 rads (20Gy) An expected reaction to any degree of radiation exposure

22.3. Which of the following statements regarding the effects of alcohol on the GI tract is false? A. Alcohol-induced lesions occur after acute ingestions at concentrations of 8% or higher. B. Alcohol-induced erosive gastritis is a major cause of GI hemorrhage. C. Alcohol decreases the secretion of gastric juices. D. Alcohol increases gastric mucosal permeability. E. Alcohol-induced diarrhea is partly due to decreased disaccharidase activity. 22.4. The major toxicity associated with eating oxalatecontaining plants such as dumbcane (Dieffenbachia) is A. B. C. D. E.

Hypocalcemia Renal failure Pain and swelling of the mouth and tongue Constipation Peptic ulcers

22.5. Ingestion of which of the following caustic substances results in oral pain, ulcerations, pulmonary complications, and the formation of a pharyngeal pseudomembrane? A. B. C. D. E.

NaOH Concentrated hydrochloric acid Concentrated hydrofluoric acid Paraquat Ethanol in greater than 40% concentrations

22.6. Which of the following substances is associated with dry mouth? A. B. C. D. E.

Caustics Carbamates Tetrodotoxin Anticholinergics Obstruction caused by hastily swallowed drug packets

22.7. Which of the following substances does not cause diarrhea? A. B. C. D. E.

Colchicine Mercuric chloride Pokeweed Phenothiazines Toxic mushrooms

22.8. All of the following substances are associated with black stools except A. B. C. D. E.

Blood Phenolphthalein Senna Bismuth subsalicylate Iron

22.9. Which of the following statements about pancreatitis is false? A. Acute pancreatitis may be differentiated from chronic pancreatitis by a lack of continuing inflammation, irreversible structural changes, and permanent impairment. B. The toxin most commonly associated with chronic pancreatitis is ethanol. C. Chronic obstructive pancreatitis is caused by pancreatic duct stenosis resulting from disruption of the duct during acute pancreatitis. D. Alcoholic pancreatitis is accompanied by hypertriglyceridemia, small amounts of activated trypsin, and high concentrations of protein, zymogen, and trypsin inhibitors within the ducts. E. Alcoholic pancreatitis histologically and clinically is considered a form of acute pancreatitis. 22.10. Which of the following drugs or toxins associated with pancreatitis significantly affects both the endocrine and exocrine pancreas? A. B. C. D. E.

Ethanol Pentamidine Estrogens Androgens Vacor

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

CHAPTER

23

RENAL PRINCIPLES 23.1. Which of the following drugs is associated with myoglobinuric acute renal failure? A. B. C. D. E.

Mercuric chloride Amphotericin Amphetamine Cisplatin Acyclovir

23.2. A patient is brought to the emergency department having been found on the floor following a heroin overdose. Which of the following is not correct? A. Intravenous normal saline may help prevent acute renal failure. B. Intravenous injection of mannitol may help prevent acute renal failure. C. Intravenous injection of furosemide may help prevent acute renal failure. D. Alkalinization of the blood may cause tetany. E. Alkalinization of the urine may prevent dissociation of hematin from the myoglobin molecule. 23.3. Which statement about acute interstitial nephritis is true? A. Acute interstitial nephritis is clinically different from acute renal failure. B. Acute interstitial nephritis caused by NSAIDs is often accompanied by the nephrotic syndrome. C. Most patients with acute interstitial nephritis caused by -lactam antibiotics have no signs of hypersensitivity. D. The trimethoprim in co-trimoxazole prevents the interstitial nephritis associated with the sulfonamides. E. Thiazides do not cause acute interstitial nephritis. 23.4. Which of the following causes nephrotic syndrome? A. B. C. D. E.

Bismuth Cyclosporine Cisplatin Radiocontrast agents Mercury

23.5. Which metal may cause chronic interstitial nephritis? A. Uranium B. Copper

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C. Bismuth D. Beryllium E. Chromium 23.6. Which of the following may cause urinary tract obstruction? A. B. C. D. E.

Amitriptyline Iodinated radiocontrast agents Mitomycin C Lithium Cisplatin

23.7. Which of the following may cause prerenal failure? A. B. C. D. E.

Aspirin/phenacetin combinations Carbon tetrachloride Furosemide Ampicillin Tobramycin

23.8. Which of the following substances produces a metabolite that is nephrotoxic? A. B. C. D. E.

Gentamicin Fenoprofen Iodinated radiocontrast agents Ethylene glycol Mercuric chloride

23.9. Which of the following is not characteristic of analgesic nephropathy? A. B. C. D. E.

Eosinophiluria Papillary necrosis Chronic interstitial nephritis History of gastric irritation Methemoglobinemia

23.10. Which statement is true with regard to gentamicin nephropathy? A. Oliguria is a common finding. B. The lesion is in the distal convoluted tubule. C. Smaller, more frequent doses decrease the injury. D. Papillary necrosis is often seen. E. Renal hypoperfusion worsens the toxicity.

CHAPTER

24

FLUID, ELECTROLYTE,AND ACID-BASE PRINCIPLES 24.1. Which of the following does not cause a low anion gap?

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

Hypermagnesemia Lithium toxicity Bromism Hypoalbuminemia Metformin toxicity

24.2. Which of the following substances is associated with a high-anion-gap metabolic acidosis? A. B. C. D. E.

Inorganic sulfur Digoxin Nitrates Organic mercury Acetazolamide

24.3. All of the following agents have been associated with the syndrome of inappropriate antidiuretic hormone (SIADH) except A. B. C. D. E.

Selective serotonin reuptake inhibitors MDMA Sulfonylureas Colchicine Cisplatinum

24.4. All of the following agents have been associated with diabetes insipidus (DI) except A. B. C. D. E.

Propoxyphene Methoxyflurane Imipramine Demeclocycline Lithium

24.5. A 52-year-old man presents to the hospital with an anion-gap (24 mEq/L) metabolic acidosis and is found to have an osmolar gap of 15. Which of the following is the most likely diagnosis? A. B. C. D. E.

Methanol intoxication Alcoholic ketoacidosis Lactic acidosis Renal failure Any of the above

24.6. The boiling point elevation technique of measuring osmolality might be appropriate for determining the presence of which of the following compounds? A. B. C. D. E.

Ethanol Methanol Isopropanol Ethylene glycol Theophylline

24.7. Which of the following substances is associated with hyponatremia?

A. B. C. D. E.

Glycyrrhizic acid Sorbitol Glycerol Amphotericin Foscarnet

24.8. All of the following agents cause hypokalemia except A. B. C. D. E.

Furosemide Heparin Theophylline Toluene Insulin

24.9. All of the following agents cause hyperkalemia except A. B. C. D. E.

Digoxin Barium Propranolol Fluoride Penicillin

24.10. All of the following agents are associated with hypomagnesemia except A. B. C. D. E.

CHAPTER

Theophylline Ethanol Furosemide Amphotericin Lithium

25

HEMATOLOGIC PRINCIPLES 25.1. Neonates are at particular risk for hypoxic insult because A. They are generally anemic. B. The volume of distribution of many toxins is altered in neonates. C. The persistence of fetal hemoglobin impairs oxygen unloading. D. The tidal volume of neonates is much smaller. E. The immature liver is less able to detoxify various toxins. 25.2. Which of the following is true of benzene? A. The primary route of exposure is transcutaneous. B. None of the metabolites are excreted in the urine. C. Exposure may result in thrombocytosis.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. Toxic metabolites are formed in the bone marrow. E. Exposure may result in acute lymphocytic leukemia. 25.3. Chloramphenicol (CAP) toxicity is characterized by which of these statements? A. The development of aplastic anemia is inevitable in all patients who develop anemia following exposure. B. Aplastic anemia usually occurs within 5 months of exposure to CAP. C. Toxicity to bone marrow is based on an immune mechanism. D. Affected bone marrow cells are morphologically normal when viewed with an electron microscope. E. Recovery following the onset of aplastic anemia occurs in about 25% of patients. 25.4. Which is true of an exposure to ionizing radiation? A. Rapidly proliferating cells are at the greatest risk of injury. B. A significant exposure will result in anemia almost immediately. C. Inflammation is the most significant harmful effect. D. One of the most sensitive indicators of an acute recent exposure is the platelet count. E. It is not known to result in hematologic malignancies. 25.5. In the clinical course of aplastic anemia A. B. C. D. E.

Onset is fulminant. Platelets are unaffected. Most patients respond well to therapy. Reticulocytosis is an important finding. Death results from sepsis or hemorrhage.

C. Shifts the oxyhemoglobin dissociation curve to the right D. Normally constitutes about 8% of total hemoglobin E. Is primarily reduced (in vivo) by ascorbic acid 25.8. Carbon monoxide A. Shifts the oxyhemoglobin dissociation curve to the right B. Has no effect on the unbinding of oxygen at tissue sites C. Poisoning usually results from intentional exposures D. Binds to the tissue cytochromes disrupting cellular respiration E. Binding to hemoglobin is irreversible 25.9. In reference to G-6-PD deficiency A. Women are more commonly affected than men. B. Hemolysis may occur following exposure to strong reducing agents. C. As red cells age, the activity of G-6-PD increases. D. Measurement of G-6-PD activity is inaccurate following a hemolytic episode. E. It is an autosomal dominant trait. 25.10. Acquired thrombocytopenia A. B. C. D.

Is most commonly mediated by direct toxicity Has been reported following the use of quinine Most commonly involves the IgA antibody Usually occurs a week after reexposure to an inciting agent E. Demonstrates an absence of megakaryocytes on bone marrow aspiration

CHAPTER 25.6. The mature erythrocyte A. Is 90% hemoglobin by dry weight B. Carries on only aerobic metabolism C. Has no mechanism to protect itself from oxidative attack D. Can replace hemoglobin lost to senescence E. Forms 2,3-diphosphoglycerate in the red cell before the loss of the red cell nucleus 25.7. Methemoglobin A. Binds O2 more tightly than hemoglobin B. Is hemoglobin with the iron in the 3+ valence state

1869

26

ENDOCRINE PRINCIPLES 26.1. The CNS is particularly vulnerable to hypoglycemia because A. It uses a greater amount of glucose than any other individual organ. B. Brain cannot make use of free fatty acids as an energy substrate. C. Confusion resulting from hypoglycemia may cause a delay in self-treatment. D. Ketones cannot be used as an energy substrate in the initial phase of a hypoglycemic event. E. All of the above

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

26.2. Which of the following agents acts by decreasing secretion of insulin from the pancreatic islet  cells? A. B. C. D. E.

Metformin Troglitazone Acarbose Octreotide Alanine

26.3. Which of the following statements about glucagon is correct? A. Its secretion is enhanced by somatostatin. B. It inhibits the enzyme phosphorylase, thereby enhancing the breakdown of glycogen. C. It blocks the secretion of insulin for several hours after administration. D. Its structure consists of a polypeptide that readily crosses cell membranes. E. It is secreted in response to epinephrine, thereby enhancing gluconeogenesis. 26.4. Which of the following is correct with respect to hypoglycemia in diabetes? A. Glucagon is likely to be ineffective as a treatment in non-insulin-dependent diabetes (NIDDM). B. -Adrenergic antagonists often worsen the patient’s condition by causing hypokalemia. C. Patients who are on metformin as monotherapy are particularly prone to hypoglycemia. D. Observation of a patient who has sulfonamideinduced hypoglycemia is generally necessary for no more than 6 to 8 hours. E. All of the above 26.5. Which of the following combination of circumstances may predispose to hypoglycemia? A. Chronic insulin use in the setting of renal failure B. Metformin use with glyburide administration C. Alcohol intoxication with depleted glycogen stores D. Pentamidine use in the setting of renal insufficiency E. All of the above 26.6. Overdose with T4 usually becomes clinically evident in what time period? A. B. C. D. E.

Several hours 1 to 3 days 1 week 2 to 3 weeks 1 month

26.7. Hypothyroidism occurs in approximately what percentage of patients on chronic lithium therapy? A. B. C. D. E.

1.5% 15% 40% 60% 85%

26.8. Which of the following steroid hormone associations is incorrect? A. Glucocorticoid excess, insulin resistance, hyperglycemia B. Glucocorticoid hormone decrease, starvation, hypoglycemia C. Hydrocortisone depletion, acute illness, hypotension D. Glucocorticoid administration (acute), decrease in circulating neutrophils E. Glucocorticoid excess, CNS excitability, acute psychosis 26.9. Which of the following effects are not commonly associated with anabolic steroid use? A. B. C. D. E.

Testicular atrophy Decrease in LDL cholesterol Decrease in sperm production Hepatic malignancy Gynecomastia

26.10. All of the following are usually irreversible effects of anabolic steroid use by women athletes, except for A. B. C. D. E.

CHAPTER

Baldness Deepening of the voice Increase in facial hair Clitoral hypertrophy Amenorrhea

27

OPHTHALMIC PRINCIPLES 27.1. Which of the following is true of ocular irrigation after chemical exposures? A. Use of a scleral shell irrigating device such as a Morgan lens should be avoided. B. Outcome is poorer if water is used instead of other commercially available solutions. C. Regardless of the exposure, irrigation should be continued for 2 hours.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. Measurement of conjunctival pH may be an unreliable indicator of adequate irrigation. E. Prolonged irrigation is important after severe alkali burns but not severe acid burns. 27.2. Which of the following pairings is correct regarding agent-specific ocular decontamination? A. B. C. D. E.

Phenol/PEG (polyethylene glycol) 400 Calcium hydroxide (lime)/EDTA Hydrofluoric acid/calcium gluconate Phosphorus/copper sulfate All of the above

27.3. Which of the following may be indicated during the emergency management of severe alkali burns to the eye? A. Emergency needle paracentesis of the anterior chamber B. Topical corticosteroids C. Topical ascorbate and citrate D. Topical antibiotics E. All of the above 27.4. Which of the following overdoses typically causes miosis? A. B. C. D. E.

Diazepam Phenobarbital Clonidine LSD Cocaine

27.5. Which of the following is true of the ocular toxicity of methanol? A. Funduscopic abnormalities consistently precede visual changes. B. The primary site of toxicity is the retina. C. Toxicity is from formaldehyde, resulting from methanol metabolism. D. Visual changes are consistently completely reversible. E. Folate or folinic acid is not indicated once acidosis is evident.

27.7. Which of the following contributes to the risk of systemic absorption and toxicity from eye drops? A. Greater dose-to-body weight ratio in children B. Preexisting conditions in the elderly C. Lack of first-pass metabolism of drugs absorbed from the conjunctiva D. Lack of familiarity with potential adverse effects E. All of the above 27.8. Which of the following drugs may cause optic neuritis? A. B. C. D. E.

A. It only occurs after massive, acute overdose. B. It is caused by retinal vasoconstriction. C. Full recovery of vision is expected, even after complete blindness. D. It is well correlated to blood quinine concentration. E. Funduscopic abnormalities consistently precede visual changes.

Amiodarone Corticosteroids Chloroquine Ethambutol Quinine

27.9. Which of the following characteristically causes vertical nystagmus? A. B. C. D. E.

Carbamazepine Phenytoin Phencyclidine Ethanol Diazepam

27.10. Which of the following is true of ocular effects of drug abuse? A. Corneal defects have resulted from smoking “crack” cocaine. B. Cocaine intoxication causes mydriasis. C. Talc retinopathy occurs only after extensive intravenous drug use. D. Miosis from opioids results from excessive pupillary constriction rather than inhibition of dilation. E. All of the above

CHAPTER 27.6. Which of the following is true of the ocular toxicity of quinine?

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28

OTOLARYNGOLOGIC PRINCIPLES 28.1. Humans can normally detect sound in which of the following ranges? A. B. C. D. E.

200 to 40,000 Hz 100 to 40,000 Hz 20 to 40,000 Hz 20 to 20,000 Hz 100 to 20,000 Hz

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

28.2. The odor of plastic or vinyl on a patient’s breath may indicate an exposure to A. B. C. D. E.

Cyanide Methyl salicylate Turpentine Ethchlorvynol Nitrobenzene

28.3. Which of the following groups of patients is least likely to manifest tinnitus from salicylate toxicity? A. B. C. D. E.

Elderly Men Those with concomitant use of quinine Children Pregnant women

28.4. Which of the following agents is most likely to cause reversible hearing loss? A. B. C. D. E.

Cisplatin Bromates Arsenic Quinine Neomycin

28.5. In addition to stimulating the olfactory nerve, ammonia, acetone, and menthol also stimulate which other cranial nerve? A. B. C. D. E.

Facial Trigeminal Vagal Hypoglossal Glossopharyngeal

28.6. The stria vascularis of the cochlea may be susceptible to many toxins. Which of the following describes its major function? A. Regenerates hair cells of the cochlea B. Maintains the electrochemical gradient between the endolymph and the perilymph C. Conducts neural transmission to the cochlear nucleus and the inferior colliculus D. Secretes G proteins for the hair cells E. Provides negative feedback for hair cell transmissions 28.7. Which of the following toxins demonstrates the concept of rapid olfactory fatigue at concentrations exceeding 100 to 150 ppm? A. B. C. D. E.

Carbon monoxide Phosgene Cyanide Hydrogen sulfide All of the above

28.8. Noise-induced hearing impairment is most likely demonstrated by the following: A. B. C. D. E.

Testing at the 3- to 6-kHz range Testing at the 10- to 15-kHz range Testing at the 15- to 20-kHz range Testing above the 20-kHz range Testing at any range

28.9. Which of the following substances is most likely to cause tinnitus in overdose? A. B. C. D. E.

Salicylates Ibuprofen Gentamicin Haloperidol Carbamazepine

28.10. ACE inhibitors cause taste dysfunction by which of the following mechanisms? A. Inhibit adenylate cyclase at the stria vascularis B. Antagonize calcium conduction C. Decrease angiotensin II, an important protein for cochlear function D. Angioedema E. Chelate zinc at the taste receptors and the salivary proteins

CHAPTER

29

DERMATOLOGIC PRINCIPLES 29.1. Which of the following plants can cause photodermatitis? A. B. C. D. E.

Bergamot orange Wild carrot Lime Parsnip All of the above

29.2. An acute irritant contact dermatitis on the face, groin, or axilla would best be treated by which of the following? A. B. C. D. E.

Low-potency corticosteroids Medium-potency corticosteroids High-potency corticosteroids A corticosteroid ointment Topical corticosteroids under occlusion

29.3. Which is not true of hydrofluoric acid burns? A. Intense pain in the absence of significant findings may be present.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

B. With concentrations of 70% or more, the appearance of physical findings may be delayed for hours. C. Treatment includes soaking the affected area in iced solution of 25% magnesium sulfate or application of 10% calcium gluconate gel. D. 5% calcium gluconate should be injected into the affected skin if there is persistent pain. E. Hospitalization is recommended for burns larger than 5 cm2 and for those with facial involvement. 29.4. Which topical medication most frequently causes allergic contact dermatitis? A. B. C. D. E.

Bacitracin Anthralin Silver sulfadiazine Polymyxin Neomycin

29.5. Which of the following does not result from latex hypersensitivity? A. B. C. D. E.

Angioedema Asthma Contact urticaria Paronychia Death

29.6. Which of the following plants does not cause dermatitis in persons allergic to poison ivy? A. B. C. D. E.

Ginkgo tree Cashew Mango Japanese lacquer tree Bergamot orange

29.7. What is the most significant factor that determines a chemical’s percutaneous absorption? A. B. C. D. E.

Concentration Molecular size pH Lipid solubility Water solubility

A. B. C. D. E.

1873

Langerhans cell Merkel cell Mast cell Glomus cell Melanocyte

29.10. The most likely drug to produce toxic epidermal necrolysis is A. B. C. D. E.

CHAPTER

Bleomycin Phenolphthalein Allopurinol Penicillamine Ibuprofen

30

GENITOURINARY PRINCIPLES 30.1. Which of the following is a soil fumigant associated with testicular toxicity? A. B. C. D. E.

1,2-Dibromo-3-chloropropane (DBCP) Carbaryl Yohimbine Cantharidin None of the above

30.2. The effects of yohimbine include which of the following? A. B. C. D. E.

Anticholinergic activity
1-Adrenergic antagonism
2-Adrenergic agonism
2-Adrenergic antagonism 2-Adrenergic agonism

30.3. Which of the following is not considered a toxic effect of Spanish fly? A. B. C. D. E.

Gastrointestinal bleeding Hematuria Oral pain Seizures Sinus tachycardia

29.8. Which of the following is a type of eczema? A. B. C. D. E.

Allergic contact dermatitis Irritant contact dermatitis Dyshidrosis Atopic dermatitis All of the above

29.9. Which epidermal cell is responsible for inducing allergic sensitization?

30.4. A patient presents with hyperkalemia and bradycardia after the ingestion of an aphrodisiac agent. Which of the following treatments may be useful? A. B. C. D. E.

Calcium chloride DMSA Clonidine Methylene blue Digoxin-specific antibody fragments

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

30.5. Which of the following statements best describes the pharmacokinetics of nitrites? A. B. C. D. E.

Absorption occurs only after inhalation. Excretion is completely renal. A short half-life (seconds) is common. Michaelis-Menten elimination kinetics occur. None of the above

30.6. Which of the following abortifacients causes hepatotoxicity? A. B. C. D. E.

Black cohosh Cantharidin Pulegone Trichosanthin Mifepristone

30.7. All of the following statements about misoprostol are true, except A. B. C. D.

It is derived from Cajanus cajun. It is a prostaglandin analogue. It is used to treat gastric ulcers. Abortion can occur with doses just above therapeutic. E. It is commonly used as an abortifacient in Brazil.

30.8. All of the following have been used as an abortifacient, except A. B. C. D. E.

Pennyroyal oil Quinine Trichosanthins Cimetidine Mifepristone

30.9. Which of the following agents produces red urine? A. B. C. D. E.

Cascara Senna Beets Carrots Phenol

30.10. Which of the following is responsible for cyclophosphamide-induced hemorrhagic cystitis? A. B. C. D. E.

Pulegone Acrolein 1,2-Dibromo-3-chloropropane (DBCP) Cantharidin Trichosanthin

CHAPTER

31

MANAGING THE SYMPTOMATIC PATIENT WITH A POSSIBLE TOXIC EXPOSURE 31.1. A known opioid abuser is brought to the emergency department cyanotic, with a respiratory rate of 4 breaths/min. He is lethargic and combative. What is the first priority in his management? A. Opening the airway and providing bag-valvemask ventilation B. Endotracheal intubation C. 100% oxygen by nonrebreathing mask D. Administration of naloxone IM or IV E. Arterial blood gas 31.2. What is first-line therapy for a hypotensive patient with clear lungs and an unknown overdose? A. B. C. D. E.

Fluid challenge Cardiac inotrope Vasopressor Whole blood MAST trousers

31.3. Naloxone is indicated for administration in patients who A. Exhibit symptoms of meperidine neurotoxicity B. Develop nausea and vomiting following administration of morphine C. Are comatose following a benzodiazepine overdose D. Have respiratory depression of an unknown etiology E. All of the above 31.4. Which of the following is least likely to cause a seizure in a patient who presents 1 hour after a suicide attempt? A. B. C. D. E.

Carbon monoxide Isoniazid Acetaminophen Amitriptyline Propoxyphene

31.5. A patient is brought to the emergency department comatose, presumably as a result of a toxic ingestion. Physical examination reveals a GCS of 3, bilaterally dilated pupils, and an otherwise nonfocal examination. A. This patient will probably progress to brain death.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

B. CNS trauma is unlikely given the nonfocal neurologic examination. C. A brain CT is not indicated if a history of an ethanol ingestion is obtained. D. The GCS is not useful for assessing changes in the neurologic status of patients with toxicmetabolic coma. E. Complete recovery of patients with properly managed toxic-metabolic coma despite a low GCS is the rule rather than the exception. 31.6. A comatose patient has received initial stabilization of his airway, breathing, and circulation. The next consideration is A. Administration of hypertonic dextrose, thiamine, naloxone, and oxygen B. GI decontamination C. CT of brain D. Toxicology screen E. Determination of serum electrolytes and anion gap 31.7. A patient presents with severe salicylism. Immediate consideration should be given to which of the following? A. B. C. D. E.

GI decontamination Serum alkalinization Urine alkalinization Hemodialysis All of the above

31.8. Which of the following is acceptable empiric therapy for a patient with an altered mental status? A. B. C. D. E.

Analeptics including physostigmine Flumazenil Forced diuresis Urinary acidification Thiamine

31.9. Which of the following statements is correct about poison management of a patient in her third trimester of pregnancy? A. Sorbitol cannot be given with activated charcoal as it is contraindicated during pregnancy. B. Shock is easier to identify in this patient than in a nonpregnant patient. C. Hypotension may improve if the patient is turned to the right-lateral decubitus position. D. Hyperbaric oxygen should be used at lower carboxyhemoglobin levels than with nonpregnant patients. E. Naloxone should not be given, as there are limited data regarding its use in pregnancy.

1875

31.10. A comatose patient presents with a rectal temperature of 106.2°F (41.2°C) and no additional history. How should the patient’s fever be lowered? A. He should be immersed in a tepid bath. B. He should be rapidly and aggressively cooled to 101.5°F (38.6°C) either by using evaporative cooling or by immersion in an ice bath. C. A towel soaked with rubbing alcohol should be placed on his forehead and his chest. D. Rectal acetaminophen at a dose of 20 mg/kg should be administered. E. Temperature should be monitored, and if it exceeds 107°F (41.7°C), the patient should be placed in an ice bath.

CHAPTER

32

ACETAMINOPHEN 32.1. Which of the following is true of N-acetyl-p-benzoquinoneimine (NAPQI)? A. B. C. D.

It reacts readily with available electrophiles. It is formed in the liver but not in other organs. In the liver, it is mostly formed in Zone III. It is formed after acetaminophen overdose but not after recommended dosing. E. Glutathione stores must remain near normal to prevent toxicity.

32.2. Which of the following would theoretically increase the risk of acetaminophen toxicity after overdose? A. Chronic use of cimetidine B. Chronic use of ethanol and acute coingestion of ethanol C. Acute coingestion of ethanol, without chronic ethanol use D. Chronic use of ethanol without acute coingestion of ethanol E. Acute coingestion of phenobarbital 32.3. Which of the following is not a reported cause of altered mental status in a patient who took a large acetaminophen overdose? A. B. C. D. E.

Metabolic inhibition by acetaminophen Hypoglycemia Cerebral edema Opioid intoxication Dehydration

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

32.4. Which of the following is true of N-acetylcysteine? A. It is a glutathione substitute but does not lead to increased glutathione supply. B. It is a glutathione substitute and prevents the formation N-acetyl-p-benzoquinoneimine. C. It decreases the capacity for sulfation of acetaminophen. D. If administered within 8 hours of an acute acetaminophen ingestion, it can prevent hepatic failure, regardless of the serum concentration of acetaminophen. E. It interferes with the acetaminophen assay. 32.5. Which of the following is true of acetaminophen overdose in pregnancy? A. N-Acetylcysteine does not cross the human placenta. B. The fetus is incapable of producing N-acetylp-benzoquinoneimine until late in the third trimester. C. N-Acetylcysteine has been proven to protect the fetus from serious toxicity. D. In every case in which maternal outcome has been good, fetal outcome has also been good. E. In nearly all cases, both maternal and fetal outcome has been good if N-acetylcysteine was used in a timely manner. 32.6. Which of the following best characterizes the lower acetaminophen nomogram line? A. Values above the line indicate that consequential hepatotoxicity is expected. B. In most cases, values even slightly below the line indicate that no further evaluation for acetaminophen toxicity is needed. C. A value below the line indicates that all subsequent values will also be below the line. D. It is an unsafe screening tool after overdose of extended-release acetaminophen. E. The line is both highly sensitive and highly specific as an indicator of risk. 32.7. Which of the following is true of acetaminophen exposure in patients less than 5 years old? A. They have increase capacity for sulfation, providing them with protection from acetaminophen-induced hepatic injury. B. They are less likely than adults to suffer toxicity related to repeated excessive dosing (chronic overdose). C. Acute febrile illness decreases the risk of acetaminophen-induced liver injury.

D. The lower incidence of liver injury after acute acetaminophen exposure in these patients may be related to the amount of exposure, time to treatment, or decreased susceptibility. E. The acetaminophen nomogram does not apply to children. 32.8. Which of the following is true regarding renal injury after acetaminophen exposure? A. Hepatorenal syndrome is the only cause of acetaminophen induced renal injury. B. The incidence of renal injury is the same regardless of the degree of hepatic injury. C. Renal P450 metabolism of acetaminophen leads to the formation of N-acetyl-p-benzoquinoneimine. D. Pancreatic injury is more common than renal injury E. Renal injury cannot occur in the absence of hepatic injury. 32.9. Which of the following is true regarding the administration of activated charcoal after acetaminophen exposure? A. Activated charcoal does not interfere with the absorption of N-acetylcysteine. B. Activated charcoal does not decrease acetaminophen absorption. C. Interference with absorption of N-acetylcysteine is rarely a clinical concern. D. Multiple dose activated charcoal decreases the half-life of acetaminophen E. It may actually increase the absorption of acetaminophen 32.10. For which of the following cases is the acetaminophen nomogram not applicable? A. A patient who is comatose with a serum acetaminophen concentration of 20 mg/mL, and no history regarding the time of ingestion is available. B. A patient who presents with a history of single acute acetaminophen ingestion with a serum acetaminophen concentration of 20 mg/mL 28 hours after his ingestion. C. A patient who is taking 10 g of acetaminophen per day for 3 days, has a serum acetaminophen concentration of 50 mg/mL 4 hours after his last dose. D. A patient who gives a history of acute acetaminophen ingestion in a self-harm attempt presents with right upper quadrant tenderness with serum acetaminophen concentration of

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

30 mg/mL and an AST of 450 IU/mL 12 hours after his ingestion. E. All of the above.

CHAPTER

33

SALICYLATES 33.1. The most typical acid-base pattern found a few hours after a significant acute salicylate ingestion by an adult with no other medical problems and using no other medications is A. Acute respiratory alkalosis and alkalemia B. Acute respiratory acidosis and acidemia C. Acute respiratory alkalosis, metabolic acidosis and alkalemia D. Acute respiratory alkalosis, metabolic acidosis and acidemia E. Metabolic acidosis, compensatory respiratory alkalosis and acidemia 33.2. Which of the following statements best describes the effects of salicylate poisoning on glucose metabolism? A. Most patients are hyperglycemic. B. Most patients are hypoglycemic. C. The CSF glucose level is consistent with the blood glucose level. D. The rate of CSF glucose utilization exceeds the rate of supply even in the presence of a normal serum glucose. E. The CSF glucose levels are consistently high, even when serum glucose is normalor low, and this accounts for many of the CNS manifestations of salicylate poisoning. 33.3. Which of the following statements regarding salicylate-induced induced acute lung injury is true? A. It is increasingly likely to occur as the serum salicylate level rises beyond 50 mg/dL. B. It is more likely to occur after an acute salicylate ingestion. C. It reflects underlying cardiac disease, particularly CHF. D. It has never been identified in children. E. It almost always occurs in adults over 30 years of age. 33.4. Which of the following statements regarding salicylate pharmacokinetics is true? A. Salicylate absorption from the stomach is negligible.

1877

B. Salicylate absorption from the small bowel is negligible. C. The dosage form of salicylates has a negligible effect on absorption. D. After therapeutic doses, significant salicylate levels are achieved in 30 minutes and peak levels are achieved in an hour, except after an overdose, when peak levels may not be achieved for 4 to 6 hours or longer. E. After an overdose, salicylate elimination is by first-order kinetics. 33.5. Which of the following statements regarding salicylate levels is true? A. Except in rare instances, salicylate toxicity corresponds reliably with serum levels. B. A falling serum salicylate level may indicate either increased clearance or decreased tissue distribution. C. A serum salicylate level that is low or within the therapeutic range indicates that the patient can be managed appropriately without hemodialysis. D. Peak serum salicylate levels may best be reflected by the CSF salicylate level. E. Because CSF salicylate levels correlate poorly with toxicity, only serum salicylate levels should be used to determine treatment. 33.6. Which of the following signs and symptoms of salicylate poisoning always represents severe lifethreatening toxicity? A. B. C. D. E.

Tinnitus rapidly followed by deafness Vertigo Lethargy Markedly elevated temperatures Hyperventilation, hyperactivity, and agitation

33.7. Which of the following statements regarding salicylate testing is true? A. A bedside ferric chloride test indicates only salicylate use, not necessarily overdosage. B. A false-negative ferric chloride test may occur if the urine used for testing was previously used for dipstick analysis with N-Multistix or Bili Labstix. C. A positive urine ketone test means that the ferric chloride results are not reliable for salicylates. D. As in the case of an acute acetaminophen overdose, an extremely high reported serum salicylate level unaccompanied by any clinical signs of toxicity mandates rapid, aggressive

1878

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

treatment to eliminate the drug from the patient’s body. E. Ferric chloride testing is unreliable in patients with liver disease. 33.8. Which statement concerning salicylate elimination is true? A. Forced diuresis is an effective way of eliminating salicylates, but not as effective as alkaline diuresis. B. Because alkalinization of both the urine and blood is important, NaHCO3 should be used. C. Endotracheal intubation followed by hyperventilation is an effective alternative method of alkalinization for salicylate poisoning without the risk of hypernatremia or fluid overload from NaHCO3 use. D. Although a common complication of salicylate poisonings, hypokalemia does not interfere with urinary alkalinization. E. Activated charcoal is ineffective in adsorbing salicylic acid. 33.9. All of the following are indications for hemodialysis for salicylate poisoning except A. Severe fluid and electrolyte disturbances B. High (>100 mg/dL) salicylate levels regardless of the blood pH C. A patient who is unable to eliminate salicylates D. An ill patient who has ingested moderate amounts of two or more dialyzable drugs E. A patient who is experiencing deafness as a result of the overdose 33.10. Which of the following statistics regarding analgesics and salicylate poisoning is true? A. Salicylate poisoning is the most common type of analgesic-related death reported to the American Association of Poison Control Centers (AAPCC). B. The incidence of Reye syndrome continues to increase despite the decreased use of salicylates in children. C. The FDA now prohibits the use of the same name for salicylate-containing products and for acetaminophen-containing products. D. Methyl salicylate “liniments” and other externally applied salicylate products are not as toxic as ingested salicylates. E. Analgesics are responsible for more deaths annually than any other product reported to the AAPCC.

CHAPTER

34

NONSTEROIDAL AND OTHER ANTIINFLAMMATORY AGENTS 34.1. Which of the following pairs of nonsteroidal antiinflammatory (NSAID) agents are associated with the most serious toxicity? A. B. C. D. E.

Ibuprofen and naproxen Meloxicam and phenylbutazone Piroxicam and mefenamic acid Indomethacin and piroxicam Phenylbutazone and mefenamic acid

34.2. NSAIDs and corticosteroids differ in the mechanism of their antiinflammatory effects because of which of the following? A. Only NSAIDs block production of prosta glandins. B. NSAIDs are relatively more potent at the inhibition of cyclooxygenase I and II. C. NSAIDs do not affect production of arachidonic acid. D. NSAIDs do not affect production of leukotrienes. E. NSAIDs promote thromboxanes preferentially to prostacyclins, making them better anticoagulants. 34.3. Which of the following statements is true with regard to the pharmacokinetics of the NSAIDs in overdose? A. There is good evidence that the rate of absorption is significantly slower, resulting in delayed onset of toxicity. B. The drugs are primarily excreted renally, and hepatic metabolism becomes unimportant. C. The half-life stays similar to that seen with therapeutic doses. D. The NSAIDs do not penetrate the blood-brain barrier. E. The duration of toxicity is long because the NSAIDs bind irreversibly to COX-1 and COX-2 enzymes. 34.4. A patient presents with altered mental status, and a ferric chloride test performed at the bedside changes the color of the urine from yellow to a purple-brown. This indicates possible use of all of the following agents except for which one? A. Salicylates B. Phenothiazines

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Phenylbutazone D. Diflunisal E. Anthraquinones 34.5. Aplastic anemia is most commonly associated with use of which of the following NSAIDs? A. B. C. D. E.

Sulindac Phenylbutazone Naproxen Ketorolac Ibuprofen

34.6. The following statements about the clinical effects resulting from the use of NSAIDs are true, except for which of the following? A. Tinnitus indicates that the patient must also be using salicylates. B. Aseptic meningitis has been reported in patients with or without autoimmune disorders. C. Anaphylactoid reactions occur in up to 25% of adult asthmatics with nasal polyps and urticaria. D. NSAIDs may enhance toxicity from digoxin, lithium, hypoglycemics, anticoagulants, or aminoglycosides. E. Coma and metabolic acidosis commonly occur in patients with massive overdose of NSAIDs. 34.7. The following statements about the renal effects of NSAIDs are true, except for which of the following? A. NSAIDs produce renal failure but not typically in patients who are otherwise normal. B. NSAIDs account for approximately 15% of drug-induced renal failure. C. NSAIDs have been reported to produce a variety of nephropathies including interstitial nephritis, nephrotic syndrome, and papillary necrosis. D. NSAID use has been associated with hypokalemia. E. NSAID effects at the kidney may enhance lithium, digoxin, and aminoglycoside toxicity and decrease effectiveness of antihypertensives such as ACE inhibitors, -adrenergic antagonists, and diuretics. 34.8. Which of the following may be useful in treatment of the adverse affects of NSAIDs? A. B. C. D. E.

Cyclooxygenase II–selective agents Misoprostol Omeprazole Leukotriene receptor antagonists All of the above

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34.9. Although salicylates are NSAIDs, the primary differences in management of patients with NSAID toxicity compared to salicylates is best described by which of the following? A. Patients with NSAID toxicity benefit from hemodialysis but not urinary alkalinization. B. NSAIDs are not adsorbed by activated charcoal. C. Patients with NSAID toxicity benefit from urinary alkalinization but not hemodialysis. D. Patients with NSAID toxicity necessitate early gastric lavage because the drug is not removed by hemodialysis. E. Patients with NSAID toxicity benefit from neither hemodialysis nor urinary alkalinization. 34.10. Which of the following statements is correct with regard to overdoses of the COX-2–selective NSAIDs? A. They are nontoxic. B. They will likely produce toxicity similar to the other NSAIDs. C. They have a greater likelihood of producing CNS toxicity. D. They are more likely to produce gastrointestinal bleeding that the other NSAIDs. E. The COX-2 selectivity is seen in overdoses.

CHAPTER

35

ANTIHISTAMINES AND DECONGESTANTS 35.1. Which of the following H2 antagonists significantly inhibit the cytochrome P450 oxidase system? A. B. C. D. E.

Nizatidine Cimetidine Famotidine Ranitidine Fexofenadine

35.2. Which of the following antihistamines has selective peripheral antihistamine activity? A. B. C. D. E.

Pheniramine Clemastine Methdilazine Cetirizine Meclizine

35.3. Which of the following isoenzymes of the cytochrome P450 oxidase system is responsible for most of the metabolism of astemizole?

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

CYP1A2 CYP2C9 CYP2E1 CYP2D6 CYP3A4

C. Diphenhydramine D. Meclizine E. Hydroxyzine 35.10. Overdose of which of the following antihistamines has been associated with rhabdomyolysis?

35.4. Diphenhydramine is acetylated most rapidly by which of the following groups of individuals? A. B. C. D. E.

Hispanics American Indians African Americans Middle Easterners Asians

35.5. Which of the following is not a clinical sign of progressive antihistamine toxicity? A. B. C. D. E.

Increasing delirium Rising temperature Faster heart rates Falling respiratory rates Increasing blood glucose levels

35.6. During the initial assessment of a patient who has ingested excessive amounts of OTC cold syrup containing antihistamine, which of the following investigations is essential? A. B. C. D. E.

Blood acetaminophen level WBC differential Cardiac enzymes Urine specific gravity and protein Stool occult blood testing

35.7. Which of the following decongestants would be most likely to cause hypertension and bradycardia? A. B. C. D. E.

Phenylpropanolamine Pseudoephedrine Terbutaline Ephedrine Isoephedrine

35.8. Which of the following imidazoline decongestants is a histamine H2 agonist in addition to an
-adrenergic stimulant? A. B. C. D. E.

A. B. C. D. E.

Xylometazoline Naphazoline Oxymetazoline Tetrahydrozoline Neumotazoline

35.9. An acute dystonic reaction can occur from which of the following antihistamines? A. Fexofenadine B. Doxylamine

CHAPTER

Diphenhydramine Brompheniramine Doxylamine Pyrilamine Fexofenadine

36

IRON 36.1. A 20-month-old toddler is brought to the emergency department 30 minutes following potentially ingesting 100 mg/kg iron. An abdominal flat plate reveals multiple radiopaque iron fragments in the stomach. The patient is asymptomatic. Which of the following is the most rational first step in gastrointestinal decontamination? A. B. C. D. E.

Orogastric lavage with hypertonic phosphate Syrup of ipecac Orogastric lavage with deferoxamine Orogastric lavage with normal saline Whole-bowel irrigation with PEG-ELS

36.2. What is the second step in gastrointestinal decontamination for the patient in 36.1? A. B. C. D. E.

Consult surgery for emergent gastrotomy Give activated charcoal, 1g/kg Whole-bowel irrigation with PEG-ELS Syrup of ipecac Magnesium citrate by mouth

36.3. Following a significant iron ingestion, which of the following suggests that clinically consequential poisoning is not present? A. The WBC is less than 15,000/mm3 B. The serum glucose is less than 150 mg/dL C. The total iron binding capacity (TIBC) is less than the serum iron level D. The patient is asymptomatic for 6 hours in the ED E. The serum potassium is normal 36.4. A 10-kg toddler ingests ten 325-mg tablets of ferrous sulfate. The poison center is contacted and must decide the significance of the patient’s expo-

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

sure. How much iron, in elemental form, did the child ingest? A. B. C. D. E.

30 mg/kg 10 mg/kg 20 mg/kg 65 mg/kg 6.5 mg/kg

36.5. Which of the following is not an explanation for iron-induced metabolic acidosis? A. Absorption of iron and transformation of ferrous to ferric state liberates an unbuffered proton B. Iron is an acid, with a pK of 2.2 C. Iron disrupts oxidative phosphorylation D. Iron decreases cardiac output, causing hypotension and poor tissue perfusion E. Free iron is a vasodilator, causing hypotension and lactic acidosis 36.6. Which of the statements with regard to deferoxamine is correct? A. Deferoxamine is readily synthesized in the laboratory. B. Intravenous administration is the only acceptable route for deferoxamine. C. The correct dose of deferoxamine is the molar equivalent of the amount of the iron ingested. D. On a molar basis, one mole of deferoxamine binds one mole of iron. E. Deferoxamine can remove iron from hemoglobin. 36.7. Management of iron poisoning in a patient who is 10 weeks pregnant and who has vomited 10 times should not include which of the following? A. B. C. D. E.

Fluid resuscitation Whole bowel irrigation Deferoxamine Abdominal radiography The monitoring of vital signs

36.8. Which of the following is not a potential consequence of short-term deferoxamine therapy? A. B. C. D. E.

Rate-related hypotension Yersinia enterocolitis Inability to follow serum iron levels Ophthalmic toxicity Acute lung injury

36.9. Deferoxamine administration can be stopped under which of the following circumstances? A. The urine turns brownish-red

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B. The TIBC exceeds the serum iron level C. The WBC and glucose return to normal D. The anion-gap acidosis resolves, and the patient appears well E. Vomiting and diarrhea resolve 36.10. A 2-year-old was hospitalized and treated with intravenous deferoxamine for 2 days following a severe iron poisoning. His clinical improvement was dramatic, and he became asymptomatic. He once again developed a fever, followed by vomiting and diarrhea. Which of the following is a likely etiology? A. B. C. D. E.

CHAPTER

An iron bezoar Yersinia enterocolitica infection Inadequate treatment with deferoxamine Clostridium difficile infection Reingestion of iron

37

VITAMINS 37.1. Which of the following statements about vitamin A is false? A. It is a lipid-soluble vitamin. B. -Carotene is a precursor, which is rapidly converted to vitamin A. C. Approximately 90% of the total vitamin A content of the mammalian body is stored in the liver, primarily as retinyl ester. D. Hepatic reserves are often sufficient to prevent symptoms of vitamin A deficiency for several months. E. In the retina, vitamin A is required for the regeneration of the photosensitive chromoprotein rhodopsin. 37.2. Which of the following descriptions of idiopathic intracranial hypertension is true? A. It is pathognomonic for vitamin A toxicity B. It can be present despite normal CSF opening pressures C. It is best diagnosed with an MRI scan of the brain D. It is invariably accompanied by focal neurologic findings but is essentially benign E. Left untreated, it may lead to permanent visual loss. 37.3. Which of the following clinical findings is not consistent with vitamin A toxicity?

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

Prominent visual disturbances Hepatosplenomegaly Alopecia Acrodynia Abnormalities in bone growth

37.4. Hepatotoxicity from vitamin A is best described by which of the following? A. B. C. D. E.

Centrilobular necrosis Periportal necrosis Cirrhosis Kupffer cell–mediated inflammation Proliferation of bile ducts

37.5. Which of the following vitamins can interfere with coumadin therapy? A. B. C. D. E.

Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin E

37.6. Which of the following statements concerning vitamin B6 is false? A. It is a cofactor in GABA synthesis. B. It is safe in single doses as high as 75 mg/ kg/dose. C. Even low-dose therapy, used chronically, can produce toxicity. D. It is rapidly excreted. E. It causes a proximal motor neuropathy. 37.7. Which one of the following descriptions of vitamin C is true? A. It is a proven cold remedy B. It is a uricosuric agent C. It converts trivalent chromium to its less toxic hexavalent form D. It can be given as an oral or intravenous dose after acute chromium exposure E. It causes constipation at high doses 37.8. Which one of the following descriptions of vitamin D poisoning is true? A. The patient’s serum calcium is typically normal B. Milk should contain vitamin D2 because vitamin D3 is more toxic C. Vitamin D is a rapidly acting rodenticide. D. Hematopoietic toxicity is common and may be severe. E. Patients require cautious rehydration because of the risk of cardiac dysrhythmias.

37.9. Which one of the following descriptions of niacin flush is true? A. It is rare. B. It is readily prevented with aspirin. C. It represents an anticholinergic side effect of the drug. D. It occurs because of concomitant use of HMGCoA reductase inhibitors. E. It often precedes syncope. 37.10. Patients with niacin-induced hepatic toxicity have which of the following characteristics? A. Are likely to develop the niacin flush syndrome B. Have a liver biopsy demonstrating centrilobular necrosis C. Are taking sustained-release niacin preparations D. Are allergic to aspirin E. Are alcohol dependent

CHAPTER

38

DIETING AGENTS AND REGIMENS 38.1. Phentermine-fenfluramine (“phen-fen”) was a combination diet regimen withdrawn from the market for association with which of the following pathologic entities? A. B. C. D. E.

Cerebral infarction Mesenteric ischemia Cardiac valvular regurgitation Psychosis Vasculitis

38.2. Ma huang or Chinese ephedra is a “herbal” supplement used to “increase energy” and “lose weight.” This product is structurally and pharmacologically similar to which of the following drugs? A. B. C. D. E.

Caffeine Cocaine Amphetamine Nicotine Digoxin

38.3. “Starch blockers” or amylase inhibitors were promoted as diet aids that would prevent calorie absorption from ingested carbohydrates through inhibition of starch breakdown. This dieting approach was unsuccessful for which of the following reasons?

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. Adverse side effects, especially dry mouth B. High cost C. Inhibition of other vital enzymes led to hepatotoxicity D. Amylase inhibition in vivo was clinically insignificant E. Extensive muscle breakdown 38.4. Very low-calorie diets are associated with sudden death and which of the following cardiac abnormalities? A. B. C. D. E.

Atrial myxomas Atrial fibrillation First-degree AV block Torsades de pointes Ventricular fibrosis

38.9. Which one of following diet aids is not associated with primary pulmonary hypertension? A. B. C. D. E.

Mitral regurgitation Hemorrhagic stroke Primary pulmonary hypertension Atrial fibrillation Bradycardia

38.6. A 19-year-old woman develops headache and blurry vision following an overdose of phenylpropanolamine. Her pertinent vital data include a blood pressure of 180/115 mm Hg and a pulse of 58/min. An appropriate treatment for this patient might include which of the following? A. B. C. D. E.

Metoprolol Ephedrine Propranolol Phentolamine Diltiazem

38.7. Which of the following is the mechanism by which 2,4-dinitrophenol produces weight loss? A. B. C. D. E.

It blocks amylase and thus starch breakdown. It prevents glucagon release. It uncouples oxidative phosphorylation. It increases insulin release. It causes dysgeusia.

38.8. Cal-Ban 300 was a guar gum mixture used as a diet aid. Toxicity resulted from which of the following? A. B. C. D. E.

Dehydration Constipation Esophageal/intestinal obstruction Hyperthermia Nausea and bloating

Fenfluramine Aminorex Dexfenfluramine Phenylpropanolamine Phenmetrazine

38.10. Patients with eating disorders may develop skeletal or cardiac myopathy as a result of chronic abuse of which of the following? A. B. C. D. E.

38.5. Nonprescription phenylpropanolamine-containing appetite suppressants are no longer available because of risk of which of the following? A. B. C. D. E.

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CHAPTER

Syrup of ipecac Laxatives Diuretics Anorexiants Vitamin C

39

METHYLXANTHINES 39.1. Which of the following statements about the metabolism of caffeine is correct? A. Caffeine is primarily eliminated by glomerular filtration. B. In preterm infants, caffeine is metabolized in the liver to theophylline. C. Caffeine’s half-life is increased in smokers. D. Caffeine induces microsomal enzyme activity. E. Caffeine is primarily metabolized by hydroxylation. 39.2. Caffeine and theophylline exert physiologic effects at which of the following receptors? A. B. C. D. E.

Adenosine receptors Muscarinic receptors Nicotinic receptors Dopaminergic receptors Serotonergic receptors

39.3. Which of the following statements about caffeine toxicity is correct? A. Cardiac toxicity is unreported with caffeine. B. Side effects are not dose dependent. C. Caffeine causes biphasic toxicity: anxiety followed by lethargy. D. Tolerance to caffeine’s stimulatory effects occurs after several years of chronic use. E. Patients with hyperthyroidism are resistant to the stimulatory effects of caffeine.

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

39.4. Which of the following statements about caffeine and the gastrointestinal tract is correct? A. Small doses of caffeine administered each day can cause gastric erosions in animals. B. Caffeine can cause increased secretion of both pepsin and gastric acid. C. Decaffeinated coffee can be used to prevent stomach injury in patients with ulcers. D. Accumulated cyclic AMP causes an increase in secretions in the stomach. E. Caffeine is a potent inhibitor of H2 receptors in the stomach. 39.5. Which of the following statements regarding the possible side effects of caffeine is correct? A. Caffeine decreases the force of contraction of muscle. B. Caffeine increases the basal metabolic rate by 50%. C. Caffeine has inconsistent effects on lipid profiles. D. Effects of caffeine on pituitary function are not dose related. E. Habitual caffeine ingestion is associated with increased bone density. 39.6. Which of the following is considered to be the most effective technique for increasing total body clearance of theophylline or caffeine? A. B. C. D. E.

Multiple-dose activated charcoal Peritoneal dialysis Charcoal hemoperfusion Hemodialysis Single-dose activated charcoal

39.7. Which of the following laboratory abnormalities occurs most often in patients with acute theophylline poisoning? A. B. C. D. E.

Hypokalemia Respiratory acidosis Hypoglycemia Hyperchloremia Hypernatremia

39.8. Which of the following toxicities is most likely to be observed in a patient with a theophylline level of 30 µg/mL following an acute ingestion? A. Seizures and metabolic acidosis B. Ventricular tachycardia C. Coagulation disorders, bleeding, and hypotension D. Nausea, vomiting, and sinus tachycardia E. Hypotension and metabolic acidosis

39.9. Which of the following gastrointestinal decontamination techniques best reduces the absorption of theophylline and caffeine? A. B. C. D. E.

Emesis with syrup of ipecac Gastric lavage Activated charcoal Cathartics Whole-bowel irrigation

39.10. At therapeutic levels, theophylline exerts its primary pharmacologic effect by A. Inhibiting the activity of acetylcholine on cyclic AMP B. Stimulating -adrenergic receptors in the lung C. Inhibiting the activity of phosphodiesterase D. Increasing intracellular concentrations of cyclic GMP E. Antagonizing the activity of adenosine

CHAPTER

40

ANTIDIABETIC AND HYPOGLYCEMIC AGENTS 40.1. Which of the following laboratory findings is diagnostic of an exogenous insulin overdose? A. A persistent blood glucose level below 50 mg/dL B. An
1-glycoprotein level exceeding 3 mg/mL C. A C-peptide level of less than 0.2 nmol/L D. Insulin levels exceeding 6 mU/mL E. Glucagon levels less than 15 mU/mL 40.2. Which of the following antidiabetic medications causes the highest incidence of iatrogenic hypoglycemia? A. B. C. D. E.

Glyburide Rosiglitazone Acetohexamide Tolazamide Phenformin

40.3. Which of the following fruits, when unripe, has been reported to depress blood glucose levels? A. B. C. D. E.

Kiwi Grapefruit Balsam pear Ackee Star

40.4. Which of the following might be caused by an oral hypoglycemic agent overdose?

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

Bronchoconstriction Bradycardia Hemiparesis Miosis Hypoactive bowel sounds

40.5. Which of the following is the most appropriate therapy for patients with recurrent hypoglycemia following a sulfonylurea overdose? A. B. C. D. E.

Dextrose then octreotide Dextrose then diazoxide Octreotide then streptozotocin Dextrose then fructose Octreotide is first-line therapy

40.6. Which of the following oral hypoglycemic medications has the longest duration of action? A. B. C. D. E.

Tolbutamide Chlorpropamide Glyburide Tolazamide Glipizide

40.7. The biguanide metformin differs from its predecessor phenformin because it has a lower incidence of which of the following? A. B. C. D. E.

Renal toxicity Hepatic toxicity Cardiac toxicity Metabolic toxicity Treatment failures

40.8. Which of the following is associated with significant hepatic toxicity? A. B. C. D. E.

Repaglinide Troglitazone Rosiglitazone Pioglitazone Acarbose

40.9. A young child is suspected to have ingested a single sulfonylurea tablet. Which of the following is true of the initial management? A. Because the duration of action of most pills is short, brief observation should suffice. B. Hospital admission is warranted in most cases. C. Oral activated charcoal cannot adsorb sulfonylureas, so it should not be administered. D. Measurement of serial drug levels may be useful to determine the appropriate observation period. E. Prophylactic octreotide should be administered.

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40.10. Which of the following oral hypoglycemic agents would be best for use in a patient with renal impairment? A. B. C. D. E.

CHAPTER

Tolazamide Metformin Glyburide Chlorpropamide Glipizide

41

ANTICONVULSANTS 41.1. Which of the following statements with regard to phenytoin is false? A. Intravenous administration of phenytoin is associated with a rate-related incidence of hemodynamic complications. B. Serum phenytoin levels correlate with levels in the central nervous system. C. Serum phenytoin levels >30 mg/L are associated with ataxia. D. Phenytoin absorption following a single acute toxic ingestion is unpredictable. E. Multiple-dose activated charcoal reduces the elimination half-life of intravenously administered phenytoin. 41.2. Which of the following statements with regard to carbamazepine is false? A. Carbamazepine absorption following a single acute toxic ingestion is unpredictable. B. Carbamazepine levels >40 mg/L are associated with coma. C. QTc prolongation can result from carbamazepine overdose. D. The carbamazepine 10,11-epoxide metabolite is not pharmacologically active. E. Multiple-dose activated charcoal can reduce the enterohepatic circulation of carbamazepine. 41.3. Which of the following statements is false with regard to valproic acid? A. Acute valproic acid overdose is associated with delayed thrombocytopenia. B. Fatal valproic acid overdoses are associated with metabolic acidosis. C. The incidence of fatal valproic acid–induced hepatotoxicity is greater in adults than children.

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. The increasing importance of valproic acid in fatal overdose is likely related to the drug’s increased use in the management of patients with mood disorders. E. Valproic acid is a structural analogue of the neurotransmitter γ-aminobutyric acid (GABA). 41.4. Which of the following is an indication for carnitine supplementation following acute valproic acid overdose? A. B. C. D.

Seizure Metabolic acidosis Hyperammonemia Serum valproic acid level greater than twice therapeutic E. Cardiac dysrhythmia

41.5. Compared with adults, children who overdose with carbamazepine have an increased incidence of which of the following? A. B. C. D. E.

Ileus Hypoglycemia Electrocardiographic abnormalities Choreoathetosis Hyponatremia

41.9. Which of the following anticonvulsants is not metabolized and entirely renally excreted? A. B. C. D. E.

Phenytoin Lamotrigine Felbamate Vigabatrin Gabapentin

41.10. Which of the following statements is correct? A. Nonepileptic patients commonly seize following overdose with phenytoin, carbamazepine, or valproic acid. B. Patients with phenytoin ingestions are at substantial risk for cardiac dysrhythmias. C. Tremors are an uncommon occurrence following overdose. D. Vigabatrin is predictably associated with the serotonin syndrome. E. The anticonvulsant hypersensitivity syndrome is described following phenytoin, carbamazepine, and lamotrigine therapy only.

CHAPTER

42

ANTICOAGULANTS 41.6. Which of the following anticonvulsants has a metabolite almost as active as the parent compound? A. B. C. D. E.

Phenytoin Carbamazepine Gabapentin Vigabatrin Lamotrigine

41.7. All these drugs decrease phenytoin levels except which of the following? A. B. C. D. E.

Gabapentin Theophylline Rifampin Phenobarbital Carbamazepine

41.8. Which of the following anticonvulsant drugs is associated with an increased incidence of agitation in overdose? A. B. C. D. E.

Gabapentin Lamotrigine Felbamate Vigabatrin Topiramate

42.1. In evaluating a child with a known single small unintentional ingestion of a long-acting anticoagulant rodenticide, which laboratory studies would be most appropriate? A. Obtain a PT (or INR) at baseline and 24 and 48 hours after exposure. B. Obtain a PT (or INR) at 24 and 48 hours after exposure. C. Obtain a PTT at baseline and 24 and 48 hours after exposure. D. Obtain a PTT at 24 and 48 hours after exposure. E. Obtain a factor V level immediately. 42.2. A patient has a 500-mL bag containing 50,000 units of heparin unintentionally infused instead of a fluid bolus. One hour after the mistake is discovered his PTT is reported as greater than 150 seconds. The patient is asymptomatic, with normal vital signs. Which therapy would be the most appropriate? A. Infuse protamine, 500 mg IV, and repeat the PTT. B. Infuse protamine, 250 mg IV, and repeat the PTT.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Exchange transfuse the patient; no repeat PTT is needed. D. Give 2 units of FFP IV and repeat the PTT. E. Observe the patient for bleeding and repeat the PTT. 42.3. A 70-year-old man with a metal valve in the aortic position becomes confused and unintentionally doubles his warfarin dose. He presents to the hospital 7 days later and is found to have weakness, tachycardia, orthostatic hypotension, and melena with a fall in hemoglobin of 2 g/dL. His INR is reported by the laboratory as 20. Which therapeutic regimen would be the most appropriate? A. Intravenous vitamin K1 given 10 mg at a time slowly, with repeat INR in 6 hours B. Subcutaneous vitamin K1 50 mg with a repeat INR in 6 hours C. FFP 2 to 3 units as soon as available followed by subcutaneous vitamin K1, 10 mg, followed by heparin to maintain therapeutic anticoagulation when bleeding stops D. Whole blood E. Observation 42.4. Which of the following is not a proposed reason for the prolonged action of long-acting anticoagulants? A. The pellet form acts to delay and prolong absorption. B. They are highly fat soluble and concentrated in the liver. C. They are more potent inhibitors of vitamin K than warfarin. D. They follow zero-order kinetics at doses ingested. E. They are enterohepatically recirculated. 42.5. Which of the following statements is false with regard to warfarin pharmacology? A. Cimetidine can decrease warfarin metabolism by inhibiting CYP3A4. B. Allopurinol decreases anticoagulation by enhancing warfarin metabolism. C. Warfarin is highly protein bound to albumin such that other albumin-bound drugs can prolong coagulation times by displacing warfarin. D. Warfarin is a racemic mixture, with R warfarin being more active than S warfarin. E. Warfarin inhibits both vitamin K 2,3-epoxide reductase and vitamin K quinone reductase. 42.6. Low-molecular-weight heparins differ from unfractionated (conventional) heparin in all of the following ways except

1887

A. They have greater bioavailability. B. They have targeted activity against factor X. C. They achieve adequate anticoagulation with fixed dosing. D. They are not monitored by the PTT. E. They have a lower incidence of bleeding complications. 42.7. Which of the following statements about heparinassociated thrombocytopenia is false? A. Is mild and transient, occurring in 25% of patients during the first few days of therapy B. Is severe and occurs in about 1 to 5% of patients between the first and second weeks of therapy C. Is caused by antibodies to heparin–platelet factor 4 complexes D. Is produced by bone marrow depression E. Is associated with the white clot syndrome 42.8. Venom of the North American rattlesnakes produces a severe coagulopathy by which of the following mechanisms? A. Thrombin-like activity in venom activates the coagulation cascade. B. Venom constituents inhibit vitamin K–dependent coagulation factors. C. Venom binds to antithrombin III. D. Venom directly inhibits factor VIII. E. Venom inactivates platelets. 42.9. All of the following are true of hirudin except A. It was originally detected in leech saliva. B. It irreversibly blocks thrombin without the need for antithrombin III. C. Platelet factor 4 is a natural inhibitor of hirudin. D. It has a very small molecular weight and can directly enter clots. E. It has a longer half-life and enhanced bioavailability than heparin. 42.10. Which of the following therapies may not be indicated in the early management of a patient with a large intentional ingestion of long-acting anticoagulants who presents with bleeding and a high INR? A. Intravenous FFP for immediate control B. Oral or subcutaneous vitamin K1 therapy C. Whole blood if the blood loss is severe and the patient is unstable D. Phenobarbital to enhance elimination E. Multiple-dose activated charcoal

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

CHAPTER

43

ANTITUBERCULOUS AGENTS 43.1. Which of the following statements about rapid acetylators receiving isoniazid therapy is correct? A. They are at greater risk for hepatotoxicity and lower or equal risk for neurologic toxicity than are slow acetylators. B. They are at lower risk for neurologic toxicity and hepatotoxicity than are slow acetylators. C. They are at the same risk for hepatoxicity and lower risk for neurologic toxicity than are slow acetylators. D. They are at lower risk for hepatotoxicity and greater risk for neurologic toxicity than are slow acetylators. E. None of the above 43.2. Which of the following statements about hepatic toxicity from isoniazid is correct? A. About 20% of patients will show elevations in ALT with a 5% incidence of drug-induced liver disease. B. Almost all patients will have an elevation in liver enzymes with about a 10% incidence of liver disease. C. Most patients will have a transient elevation in liver function tests with about a 1% incidence of liver disease. D. Approximately 10% of patients will have an elevation in AST with about 1% of these patients going on to have clinical liver disease. E. None of the above 43.3. Which of the following adverse reactions has been associated with isoniazid therapy? A. B. C. D. E.

Liver disease Systemic lupus erythematosus Arthritis Peripheral neuropathy All of the above

43.4. Which of the following statements about isoniazid is correct? A. Isoniazid stimulates the metabolism of phenytoin. B. Pyridoxine-dependent decarboxylation and transamination reactions are stimulated by isoniazid. C. Isoniazid therapy results in an accumulation of GABA in the central nervous system.

D. The most frequent neurologic complication of isoniazid therapy is peripheral neuritis. E. None of the above 43.5. At what dose in an adult is ethambutol likely to cause optic neuropathy, visual hallucinations, abdominal pain, and confusion? A. B. C. D. E.

2g 4g 6g 8g 10 g

43.6. Usage of which of the following antituberculosis medications will make the urine orange-red? A. B. C. D. E.

Isoniazid Ethambutol Rifampin Ethionamide Pyrazinamide

43.7. Which of the following statements about rifampin overdoses is correct? A. Cardiac dysrhythmias are common. B. The red discoloration of the skin can be partially removed by washing with soap and water. C. Rifampin is primarily eliminated by renal excretion of the parent compound. D. The half-life in overdose is greater than 20 hours. E. Rifampin should be removed by charcoal hemoperfusion if the patient becomes hypotensive. 43.8. Which of the following statements about treating isoniazid toxicity is correct? A. Diazepam may worsen isoniazid-induced seizures. B. Pyridoxine should be administered as a 5 to 10% solution, infused over 3 to 6 hours. C. If the amount of isoniazid ingested is known, pyridoxine should be given in a gram-for-gram dose. D. If the amount ingested is unknown, 50 g is the usual recommended dose in adults. E. Pyridoxine should be given slowly because of its fat solubility. 43.9. Which of the following signs and symptoms would be expected to occur with an isoniazid overdose? A. Hepatic failure B. Cardiac dysrhythmias

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Seizures D. Acute renal failure E. Respiratory acidosis 43.10. Pyridoxine would not be effective as an antidote for which of the following poisonings? A. B. C. D. E.

CHAPTER

Isoniazid (isonicotinic acid hydrazide) Gyromitra esculenta Phenelzine Monomethylhydrazine None of the above

44

ANTIMALARIAL AGENTS 44.1. Which of the following statements about quinine is correct? A. Quinine is a structural analogue of acetylsalicylic acid. B. It is a very safe and effective therapy for muscle cramps. C. Intramuscular quinine administration is associated with an increased incidence of tetanus. D. It remains the standard test for detecting covert heroin use. E. Its major toxicity following overdose is renal failure. 44.2. Which of the following therapies is currently recommended for treating a patient with a quinine overdose? A. B. C. D. E.

Hemoperfusion Multiple-dose activated charcoal Stellate ganglion blockade Forced acid diuresis Peritoneal dialysis

44.3. In vitro experiments show that quinine has certain pharmacologic effects similar to which of the following classes of drugs? A. B. C. D. E.

Sulfonylureas Thiazide diuretics -Adrenergic antagonists Calcium channel blockers Phenothiazines

44.4. Serum levels similar to those noted in poisonings do not cause toxicity in patients who are severely ill with malaria because of an increase in which of the following? A. Hepatic clearance

1889

B. Renal clearance C.
1-Glycoprotein D. The volume of distribution E. The number of sickle cells 44.5. Which of the following medications can be used to treat the cardiac toxicity from the cinchona alkaloids? A. B. C. D. E.

Propranolol Disopyramide Procainamide Sodium bicarbonate Bretylium

44.6. Which of the following antimalarial agents is a dihydrofolate reductase inhibitor? A. B. C. D. E.

Chloroquine Dapsone Halofantrine Fansidar Amodiaquine

44.7. Which of the following therapies is effective in the treatment of chloroquine toxicity? A. B. C. D. E.

Atropine and sodium bicarbonate Pilocarpine and diphenhydramine Corticosteroids Diazepam and epinephrine Sodium bicarbonate and quinidine

44.8. Which cardiovascular complication has been associated with mefloquine? A. B. C. D. E.

Prolonged PR interval Increased platelet adhesion Calcium channel blockade Prolonged QTc Third-degree heart block

44.9. Which is the most significant dose-related complication of halofantrine? A. B. C. D. E.

Hypoglycemia Seizure Torsades de pointes Myocardial failure Sleep disturbance

44.10. Which manifestation has been described in children receiving artemisinins? A. B. C. D. E.

Seizures Dystonia Facial diplegia Blindness Deafness

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

CHAPTER

45

ANTIMIGRAINE AGENTS 45.1. Which of the following statements about the pharmacokinetics of ergotamine is correct? A. Ergots are well absorbed by the oral route. B. Ergots are eliminated unmetabolized in the urine. C. The volume of distribution of the ergot alkaloids is 0.2 L/kg D. The elimination half-life of the ergots is greater than 24 hours. E. Rectal bioavailability is 20 times greater than oral. 45.2. Which of the following conditions may contraindicate the use of ergotamines? A. B. C. D. E.

Gout Diabetes mellitus Hypertension Ulcerative colitis Congestive heart failure

45.3. When were the ergotamine preparations introduced for the treatment of vascular headaches? A. B. C. D. E.

1940s 1950s 1960s 1970s 1980s

45.4. Which of the following ergotamine preparations has been used in obstetric care to stimulate contraction of the uterus? A. B. C. D. E.

Ergonovine Ergotamine Ergocristine Dihydroergotamine Ergometrine

45.5. Which of the following medications should not be used to treat ergot-induced vasoconstriction? A. B. C. D. E.

Phentolamine Captopril Propranolol Prazosin Nifedipine

45.6. Following oral administration, peak ergotamine levels will occur at A. 1 hour

B. C. D. E.

2 hours 3 hours 4 hours 6 hours

45.7. Which of the following cardiac dysrhythmias would most likely be found in a patient with an exposure to ergot? A. B. C. D. E.

Sinus tachycardia Sinus bradycardia Atrioventricular block Premature ventricular contractions Ventricular tachycardia

45.8. Which of the following ergot medications would be most likely to cause retroperitoneal fibrosis? A. B. C. D. E.

Ergotamine Ergonovine Bromocriptine Dihydroergotamine Methysergide

45.9. Ergots were discovered when they were found to be contaminating A. B. C. D. E.

Peach trees Rye grain Corn Tomato plants Potato plants

45.10. The maximum quantity of ergotamine that should be taken daily and weekly is A. B. C. D. E.

CHAPTER

2 mg in 1 day, 6 mg in 1 week 4 mg in 1 day, 20 mg in 1 week 6 mg in 1 day, 10 mg in 1 week 8 mg in 1 day, 16 mg in 1 week 12 mg in 1 day, 24 mg in 1 week

46

ANTIBIOTICS 46.1. After an anaphylactic (IgE-mediated) reaction to penicillin, the risk for anaphylaxis to a cephalosporin is A. B. C. D. E.

Twice the general population risk (0.04%) 10 times the general population risk (1%) No increased risk 50 times the general population risk (10%) 1000 times the population risk (20%)

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

46.2. Risk factors that have been identified for imipenem-induced seizures include A. B. C. D. E.

Pregnancy Cardiovascular disease Concurrent antibiotics Renal insufficiency Hepatic insufficiency

46.3. All of the following are risk factors for the development of aminoglycoside-induced nephrotoxicity except A. B. C. D. E.

High trough levels Large total dose Genetic predisposition Presence of a renal infection Previous aminoglycoside therapy

46.4. Chloramphenicol overdose causes the following: A. B. C. D.

Gastrointestinal upset only Seizures and gastrointestinal upset only Tinnitus, seizures, and gastrointestinal upset Gastrointestinal upset, metabolic acidosis, and cardiovascular collapse E. Acute hepatic failure

46.5. Risk factors for the development of “gray baby syndrome” include all of the following except A. Elevated serum chloramphenicol concentration B. Age 3 to 6 months C. Inability to excrete chloramphenicol D. High doses of chloramphenicol E. Inability to conjugate chloramphenicol 46.6. Toxic effects after fluoroquinolone exposure include all of the following except A. B. C. D. E.

Renal failure Seizures Acute psychosis Hepatotoxicity Gastrointestinal upset

46.7. Erythromycin is involved in many drug interactions through its ability to inhibit A. B. C. D. E.

CYP1A2 CYP2D6 CYP3A4 CYP2D16 CYP2D18

46.8. Risk factors for the development of the vancomycin-related “red man syndrome” include all of the following except

A. B. C. D. E.

1891

Rapid infusion rates Increased concentrations Prior exposure Use of prophylactic techniques None; all are true

46.9. All of the following are considered to have drug interactions with ketoconazole except A. B. C. D. E.

Terfenadine Cimetidine Astemizole Cisapride Verapamil

46.10. Which antibiotics have not been reported to cause seizures in humans or animals? A. B. C. D. E.

CHAPTER

Penicillins Cephalosporins Fluoroquinolones Aminoglycosides None of the above

47

ANTINEOPLASTIC AGENTS 47.1. Which of the following is the mechanism responsible for methotrexate-induced renal failure? A. Dihydrofolate reductase inhibition B. Thymidylate synthetase inhibition C. Precipitation of polyglutamate metabolites of methotrexate D. Precipitation of 7-hydroxy metabolites of methotrexate E. Deposition of immune complexes 47.2. Methotrexate inhibition of dihydrofolate reductase activity results in which of the following toxic manifestations? A. B. C. D. E.

Bone marrow suppression Renal failure Seizures Hepatitis Peripheral neuropathy

47.3. The extravasation of which agent is associated with an increased incidence of tissue necrosis? A. B. C. D. E.

Doxorubicin Methotrexate Carboplatin Bleomycin Cytarabine

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

47.4. The administration of repeat-dose activated charcoal increases the elimination of which agent? A. B. C. D. E.

Mechlorethamine Vincristine Doxorubicin Carboplatin Methotrexate

47.5. Inappropriate secretion of antidiuretic hormone (SIADH) is a toxic manifestation of which of the following agents? A. B. C. D. E.

Methotrexate Cisplatin Vincristine Daunorubicin Mitoxantrone

47.6. Which of the following cardiac manifestations is a dose-dependent response of doxorubicin? A. B. C. D. E.

Dysrhythmias Repolarization abnormalities on the ECG Pericarditis Myocarditis Cardiomyopathy

47.7. Color disturbance and high-frequency hearing loss are the toxic effects of which agent? A. B. C. D. E.

Methotrexate Cisplatin Daunorubicin Vincristine Cyclophosphamide

47.8. Which of the following has not been shown to lower the cerebrospinal fluid (CSF) methotrexate level after an intrathecal (IT) overdose? A. B. C. D. E.

CSF drainage CSF perfusion Intrathecal leucovorin Intrathecal carboxypeptidase G class enzymes CSF exchange

47.9. Which of the following is a factor associated with an increased incidence of extravasation during IV antineoplastic agent therapy? A. Concentration of the antineoplastic agent B. Placement of the IV over the dorsum of the hand C. Use of antineoplastic agents with vesicant properties. D. Administration by an inexperienced healthcare provider E. Rate of infusion of the solution

47.10. Which of the following antineoplastic agents has MAOI activity? A. B. C. D. E.

CHAPTER

Doxorubicin Procarbazine Carboplatin Vinblastine Chlorambucil

48

CARDIAC GLYCOSIDES 48.1. Which of the following statements about digoxin is correct? A. B. C. D.

Digoxin decreases cardiac excitability. Digoxin decreases automaticity. Digoxin increases cardiac refractoriness. Digoxin decreases cardiac conduction velocity. E. Digoxin increases atrioventricular conduction.

48.2. Which of the following statements about digoxinspecific Fab fragments is incorrect? A. The antibodies are produced in sheep and then are enzymatically cleaved, separating the Fab and Fc fragments. B. Digoxin-specific Fab fragments will correct digoxin-induced hyperkalemia. C. Digoxin Fab fragments will reverse digoxin toxicity within minutes of administration. D. Serum digoxin levels will increase dramatically following administration of the Fab fragments. E. Patients with renal failure who receive digoxin-specific Fab require hemodialysis for removal of the antibody–antigen complex. 48.3. A potassium serum level of greater than _____ has been associated with a high probability of death in digoxin-poisoned patients. A. B. C. D. E.

2.0 mEq/L 2.5 mEq/L 4.0 mEq/L 4.5 mEq/L 5.5 mEq/L

48.4. One of the early symptoms of digoxin toxicity is A. B. C. D. E.

Hypertension Bradycardia Wide QRS complex Wide QTc interval Atrial fibrillation

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

48.5. The elevation of serum potassium levels following toxic administration of digitalis has been attributed to A. Acidemia B. Increased gastrointestinal absorption C. The inhibition of uptake of potassium by muscle D. Increased renal tubular reabsorption E. Inhibition of chloride channels 48.6. In a comparison of digoxin and digitoxin, which of the following statements is correct? A. Digoxin is more highly bound to plasma proteins than is digitoxin. B. Digitoxin is cleared by renal mechanisms only. C. Digoxin is cleared primarily by the kidney. D. Gastrointestinal absorption of digoxin is more complete than is that of digitoxin. E. The duration of effect of digoxin is much greater than that of digitoxin. 48.7. Which of the following plants contains a cardiac glycoside with the ability to cause a digoxin-like poisoning? A. B. C. D. E.

Jimson weed Lily of the valley Yew Bleeding heart Glory lily

48.8. A 60-kg patient with with chronic digoxin toxicity (digoxin level 3 ng/mL), second-degree heart block, and a heart rate of 45 should receive how many vials of digoxin-specific Fab? A. B. C. D. E.

1 vial 2 vials 5 vials 10 vials 15 vials

48.9. Which of the following therapeutic interventions is considered safest in the setting of acute digoxin toxicity? A. B. C. D. E.

Calcium gluconate Quinidine Verapamil Lidocaine Cardioversion

48.10. One standard vial of Digibind (containing 38 mg) will bind to how much digoxin? A. 0.5 mg B. 1.2 mg

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C. 1.8 mg D. 2.4 mg E. 3 mg

CHAPTER

49


-ADRENERGIC ANTAGONISTS 49.1. Propranolol is more toxic than the other beta adrenergic antagonists. Which property is most responsible for this? A. Potassium channel blockade causing prolonged QT interval and ventricular dysrhythmias. B. Sodium channel blockade causing ventricular dysrhythmias and seizures. C. Intrinsic sympathomimetic activity. D. High lipid solubility. E. Peripheral vasodilation resulting in profound hypotension. 49.2. What is unique about sotalol overdose? A. Sodium channel blockade causing prolonged QT interval and predisposing to torsades de pointes. B. Sodium channel blockade causing prolonged QRS duration and predisposing to ventricular dysrhythmias. C. Potassium channel blockade causing prolonged QT interval and predisposing to torsades de pointes. D. Potassium channel blockade causing prolonged QRS duration and predisposing to ventricular dysrhythmias. E. Nitric oxide release resulting in peripheral vasodilation. 49.3. What features of -adrenergic antagonist ingestion are most closely associated with a fatal outcome? A. Ingestions of more than 1 g. B. Ingestions of sustained-release products. C. Ingestion of -adrenergic antagonists with membrane-stabilizing effect. D. Coingestion of other cardioactive toxins. E. Ingestion of sotalol. 49.4. Which statement concerning the role of phosphodiesterase inhibitors (PDIs) in the management of -adrenergic antagonist overdose is true? A. PDIs typically increase the blood pressure without improving cardiac output.

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

B. PDIs have been shown in animal models to act in synergy with glucagon. C. PDIs typically increase cardiac output without increasing blood pressure. D. There is no evidence that PDIs are of benefit in -adrenergic antagonist toxicity. E. PDIs are easy to titrate because of a short halflife. 49.5. A 28-year-old previously healthy woman has taken 4 g of propranolol in a suicide attempt. Despite therapy with maximal doses of glucagon, highdose insulin, epinephrine, isoproterenol, and milrinone, she remains profoundly hypotensive and bradycardic. Which of the following therapies is most indicated? A. B. C. D. E.

Hemodialysis. Hemoperfusion. High-dose calcium and atropine. Ventricular pacing. Intraaortic balloon pump.

49.6. A patient being treated for sotalol overdose suddenly develops ventricular tachycardia. Which management step is least likely to be effective? A. B. C. D. E.

Hypertonic sodium bicarbonate Correction of hypomagnesemia Overdrive pacing Lidocaine Cardioversion

49.7. Which of the following statements concerning the use of vasopressors in -adrenergic antagonist toxicity is false? A. Glucagon infusions may cause vomiting. B. Epinephrine may cause hypertension. C. Isoproterenol infusions may cause hypotension. D. Norepinephrine may cause pulmonary edema. E. Amrinone may cause hypertension. 49.8. Asymptomatic patients who have ingested a -adrenergic antagonist require a period of observation. Which of the following minimum observation periods is true? A. B. C. D.

4 hours for an atenolol overdose. 6 hours for a propranolol overdose. 9 hours for a sotalol overdose. 12 hours for a sustained release metoprolol overdose. E. 6 hours for an overdose of propranolol and diphenhydramine.

49.9. What agent, taken in overdose, is most likely to cause the following clinical scenario? The patient is conscious with the following vital signs: pulse 60/min and systolic blood pressure 60 mm Hg. Serum glucose is 300 mg/dL. The electrocardiogram shows a sinus rhythm with narrow complexes. A. B. C. D. E.

Propranolol Digoxin Diltiazem Amitriptyline Heroin

49.10. What agent, taken in overdose is most likely to cause the following clinical scenario? The patient is unconscious following a seizure and has the following vital signs: pulse 40/min; blood pressure 80/50 mm Hg; and respirations 12/min. Serum potassium is 5 mEq/L, and serum glucose is 60 mg/dL. The electrocardiogram shows sinus bradycardia with a QRS interval duration of 130 milliseconds. A. B. C. D. E.

CHAPTER

Propranolol Digoxin Diltiazem Amitriptyline Heroin

50

CALCIUM CHANNEL BLOCKERS 50.1. In therapeutic dosing, which of the following channels do calcium channel blockers antagonize? A. B. C. D. E.

Voltage-sensitive L-type channels Voltage-sensitive T-type channels Receptor-activated S-type channels Receptor-activated T-type channels Naloxone-sensitive calcium channels

50.2. Which of the following proteins is involved in excitation/contraction coupling within the cardiac muscle cell? A. B. C. D. E.

Tropomyosin Actin Calmodulin Myosin light-chain kinase Myoglobin

50.3. Which of the following calcium channel blockers has the least affinity for myocardial tissue?

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

Verapamil Diltiazem Nifedipine Bepridil All have equal affinity for the myocardium

50.4. Following a calcium channel blocker overdose, which of the following findings is the patient unlikely to manifest? A. B. C. D. E.

Idioventricular junctional escape rhythm Hypotension Hyperglycemia Acute lung injury Seizures

50.5. A 50-year-old man presents 6 hours after ingesting 20 sustained release verapamil tablets. He is asymptomatic, and his physical examination is notable for a heart rate of 70 and a blood pressure of 130/85 mm Hg. Which of the following strategies for gastrointestinal decontamination is the most appropriate? A. Emesis induced by syrup of ipecac, multipledose activated charcoal B. Multiple-dose activated charcoal, whole-bowel irrigation C. Orogastric lavage, whole-bowel irrigation D. Multiple-dose activated charcoal alone E. Orogastric lavage, single-dose activated charcoal 50.6. Which of the following therapeutic agents is correctly paired with its mechanism of action? A. B. C. D. E.

Calcium—enhances release of catecholamines Glucagon—direct-acting -adrenergic agonist Dopamine—direct-acting -adrenergic agonist Amrinone—inhibits phosphodiesterase III 4-Aminopyridine—causes release of insulin

50.7. Insulin is a current therapy for patients with calcium channel blocker poisoning. Which of the following is true of insulin therapy? A. Insulin works by increasing central autonomic outflow. B. Insulin therapy for calcium channel blocker poisoning should never be administered intravenously because of the risk of hypoglycemia. C. Insulin should always be administered concomitantly with a norepinephrine infusion. D. It is administered as a bolus of 0.1 U/kg of insulin and 25 to 50 g of dextrose followed by an infusion of 0.2 to 0.3 U/h of insulin and 0.5 g/kg/h of dextrose.

1895

E. It is administered at the same dose as for patients with diabetic ketoacidosis. 50.8. Which of these descriptions of salvage therapy following pharmacotherapeutic failure is correct? A. External pacemakers are almost always effective at capturing the myocardium. B. Although internal pacemakers do not improve inotropy, they may be beneficial by raising the heart rate. C. Intraaortic balloon pump therapy is a poor choice because of the potential need for its long-term use. D. Hyperbaric oxygen therapy improves inotropy by raising the patient’s oxygen carrying capacity. E. Extracorporeal membrane oxygenation has produced excellent results in calcium channel blocker–poisoned patients. 50.9. A patient presents to the emergency department with profound hypotension and bradycardia following the overdose of his antihypertensive medications. By which of the following findings can calcium channel blocker or -adrenergic antagonist overdose be differentiated? A. Calcium channel blocker–poisoned patients are typically more profoundly bradycardic. B. A high serum glucose is a reliable marker for calcium channel blocker poisoning. C. A normal mental status in this patient would suggest calcium channel blocker poisoning. D. Calcium channel blocker–poisoned patients should have an elevated serum calcium. E. The electrocardiogram findings are completely different. 50.10. Which of the following dispositions is most appropriate for a 2-year-old child who ingested one or two diltiazem tablets 2 hours before assessment? The patient is asymptomatic and has a normal physical examination. A. Close monitoring in the emergency department for 4 to 6 hours, and if the child remains clinically stable, discharge home with parents B. Admission to the intensive care unit for continuous cardiac monitoring for 24 hours C. Home management with close poison center contact D. Admission to the pediatric ward for 24-hour observation E. None of the above

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

CHAPTER

51

MISCELLANEOUS ANTIHYPERTENSIVES 51.1. Angioedema is commonly associated with which of the following antihypertensive agents? A. B. C. D. E.

Clonidine Hydralazine Captopril Reserpine Bepredil

51.2. Naloxone may be an effective therapy for the reversal of clonidine poisoning. In which other antihypertensive agent poisoning may naloxone also be effective? A. B. C. D. E.

Prazosin Angiotensin-converting enzyme inhibitors Reserpine Minoxidil Verapamil

51.3. Clonidine exerts its hypotensive effect by acting as which of the following? A. B. C. D. E.

Central α1 agonist Central α2 agonist Central α1 antagonist Central α2 antagonist Peripheral
1 agonist

51.4. Which of the following clinical findings is not expected in a patient with a large clonidine overdose? A. B. C. D. E.

Hypertension Hypotension Hypothermia Miosis Dysrhythmia

51.5. Which of the following agents is not considered, by physiologic effect, as being a sympatholytic agent? A. B. C. D. E.

Guanabenz Terazosin Guanethidine Diazoxide Trimethaphan

51.6. Concerning clonidine, which is theoretically correct? A. Clonidine is a benzodiazepine. B. Clonidine is metabolized primarily by the liver. C. Yohimbine should be given to patients with clonidine overdose.

D. Clonidine is activated by demethylation to dopamine by monoamine oxidase. E. Abrupt cessation of clonidine is associated with seizures. 51.7. A 56-year-old woman with a history of hypertension has just recovered from an episode of angioedema after beginning captopril for her hypertension. All of the following antihypertensive agents would be acceptable alternative medications except for which agent? A. B. C. D. E.

Atenolol Fosinopril Losartan Diltiazem All are acceptable

51.8. The mechanism of action of losartan is which of the following? A. B. C. D. E.

Peripheral
1 antagonist Angiotensin-converting enzyme inhibitor Angiotensin II receptor antagonist Direct vasodilator Potassium-sparing diuretic

51.9. Which of the following antihypertensive agents and a potential adverse effect is incorrectly paired? A. B. C. D. E.

Diazoxide—hypoglycemia Reserpine—depression Hydralazine—lupuslike syndrome Sodium nitroprusside—cyanide toxicity Methyldopa—hemolytic anemia

51.10. Angioedema secondary to angiotensin-converting enzyme inhibitor use occurs after which of the following? A. B. C. D. E.

CHAPTER

1 to 2 days 2 to 2 weeks 1 to 2 months 1 to 2 years None of the above

52

ANTIDYSRHYTHMIC AGENTS 52.1. Conduction disturbances associated with flecainide, quinidine, and procainamide toxicity have been successfully treated with A. Tocainide B. Magnesium sulfate

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Dobutamine D. Sodium bicarbonate E. Lidocaine 52.2. In the animal model of severe lidocaine toxicity, which therapeutic intervention has resulted in survival? A. Cardiopulmonary resuscitation with or without mechanical chest compression B. Charcoal hemoperfusion C. Administration of magnesium sulfate followed by sodium bicarbonate D. Administration of amiodarone E. External pacing 52.3. Lidocaine is an aminoacyl amide that is a synthetic derivative of which of the following topical anesthetics? A. B. C. D. E.

Benzocaine Cocaine Tetracaine Procaine Dibucaine

52.4. If a patient with congestive heart failure (CHF) requires lidocaine for ventricular dysrhythmias, the pharmacokinetics will differ from a patient without CHF in what way? A. B. C. D. E.

CHF will decrease the hepatic clearance. CHF will decrease the renal clearance. CHF will increase the volume of distribution. CHF will decrease the protein binding. CHF will increase the fraction of ionized drug.

52.5. Which of the following statements about N-acetylprocainamide (NAPA) is correct? A. NAPA is a prodrug of procainamide. B. NAPA plasma concentrations are not clinically relevant. C. NAPA and procainamide can be removed by hemodialysis. D. NAPA toxicity should be considered in patients who have a prolonged PR interval. E. NAPA differs from procainamide because it does not cause drug-induced lupus erythematosus. 52.6. Which of the following is inconsistent with a diagnosis of quinidine overdose? A. B. C. D. E.

Torsades de pointes Tachycardia Hyperkalemia Hypotension Acute lung injury

1897

52.7. If a patient with a tocainide overdose is alkalinized with intravenous sodium bicarbonate to a pH of 7.50, what alteration in pharmacokinetics can occur? A. B. C. D. E.

Increased clearance Decreased clearance Increased protein binding Decreased protein binding Increased volume of distribution

52.8. The primary difference between tocainide and lidocaine is that A. Tocainide is highly protein bound. B. Tocainide is ineffective for treating atrial dysrhythmias. C. Tocainide’s half-life is much shorter than that of lidocaine. D. Tocainide is absorbed following oral administration. E. Tocainide does not undergo extensive firstpass metabolism. 52.9. Marked QRS and PR interval changes associated with minimal QTc prolongation are noted with toxicity of which antidysrhythmic drug? A. B. C. D. E.

Quinidine Procainamide Flecainide Lidocaine Tocainide

52.10. Which of the following antidysrhythmics is a class IC analogue of lysergic acid with 5 to 10 times the antidysrhythmic potency of procainamide? The drug has been demonstrated to induce dysrhythmias and result in sudden cardiac death. A. B. C. D. E.

CHAPTER

Propafenone Bretylium Encainide Tocainide Mexiletine

53

INHALATIONAL ANESTHETICS 53.1. Which clinical finding is not secondary to a direct toxic effect of nitrous oxide? A. Megaloblastic anemia B. Subacute combined degeneration of the spinal cord

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STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Irreversible brain damage D. Increased risk for spontaneous abortion E. Reduced fertility 53.2. Which statement regarding abuse of halogenated volatile anesthetics is true? A. Ingestion is associated with gastrointestinal symptoms but without hemodynamic or CNS findings because these agents are not well absorbed via the enteral route. B. Hospital personnel have been involved in most reported cases. C. Topical application to mucous membranes has not been associated with toxicity. D. The acrid smell of halothane aids in making the diagnosis. E. Tonic-clonic seizures usually occur. 53.3. Which of the following are risk factors for lifethreatening hepatitis following halothane exposure? A. B. C. D. E.

Multiple exposures Thin body habitus Male gender White race Coadministration with agents

other

inhalational

Halothane Isoflurane Methoxyflurane Enflurane Diethyl ether

53.5. Intraoperative carbon monoxide poisoning as a complication of closed-circuit anesthesia is most likely to occur when? A. B. C. D. E.

CHAPTER

A. B. C. D. E.

Critical illness polyneuropathy Rapacuronium metabolite Acute necrotizing myopathy Homozygous atypical plasma cholinesterase Previously undiagnosed hepatic insufficiency

54.2. Which of the following is true with regard to critical illness polyneuropathy? A. It is caused by residual nondepolarizing neuromuscular block. B. It is associated with long-term nondepolarizing neuromuscular block. C. It is associated with multiple organ failure. D. It is caused by long-term glucocorticoid use. E. It is irreversible. 54.3. Which of the following is correct with regard to succinylcholine?

53.4. Which of the following inhalational anesthetics is most associated with diabetes insipidus? A. B. C. D. E.

thetic. Anesthesia was induced with O2, N2O, thiopental, fentanyl, and succinylcholine and maintained for the 4-hour procedure with O2, N2O, isoflurane, fentanyl, and rapacuronium infusion. Which of the following is the most likely cause of weakness?

At the end of a long day of cases At the end of a long week of cases In the middle of the day On the first case after a weekend When soda lime is used instead of baralyme

54

NEUROMUSCULAR BLOCKING AGENTS 54.1. You are called to evaluate a patient with chronic renal failure who has persistent respiratory failure and quadriparesis 1 hour following a general anes-

A. It is appropriate for use in the emergency difficult pediatric airway. B. It is eliminated primarily by the kidney. C. It should not be used on the day of an acute spinal cord injury. D. Neuromuscular block is augmented by pretreatment with a nondepolarizing neuromuscular blocker. E. It can cause succinic acid intoxication. 54.4. Which of the following statements is correct? A. Pancuronium causes tachycardia by blocking parasympathetic ganglia. B. Chronic phenytoin therapy does not affect pancuronium metabolism. C. Renal failure does not affect the duration of tubocurarine. D. Chronic phenytoin therapy does not affect mivacurium metabolism. E. When the ratio of the fourth to the first twitch on a supramaximal train of four electrical nerve stimuli is >0.7, the neuromuscular blocker effect is reversed enough so that a patient will not experience weakness. 54.5. Which of the following statements is correct with regard to general anesthesia? A. The pupillary light reflex is unaffected while under general anesthesia, even when neuromuscular blockers are used.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

B. Benzodiazepines before anesthesia decrease explicit recall following anesthesia. C. The atracurium metabolite laudanosine can cause seizures in otherwise normal adults. D. Pancuronium enhances morphine analgesia. E. The incidence of awareness is increased when neuromuscular blockers are used. 54.6. Which of the following statements is correct with regard to malignant hyperthermia (MH) in adults? A. Hyperpyrexia is an early sign of MH. B. MH can be triggered by some nondepolarizing neuromuscular blockers. C. Hyperkalemia and cardiac arrest can occur shortly after the onset of MH. D. Like hyperthyroidism, MH is treated with -adrenergic antagonists. E. Tachycardia should be treated with IV calcium channel blockers. 54.7. Which of the following statements is correct with regard to succinylcholine-induced severe hyperkalemia? A. It occurs in patients with renal failure. B. It can occur following acute hemorrhagic shock. C. It is prevented by pretreatment with a small dose of a nondepolarizing neuromuscular blocker. D. It is prevented by pretreatment with a small dose of a depolarizing neuromuscular blocker. E. It is caused by proliferation of presynaptic ACh receptors. 54.8. Pancuronium is the only commonly used NMB with which of the following characteristics? A. It decreases heart rate and decreases arterial blood pressure. B. It decreases heart rate and increases arterial blood pressure. C. It increases heart rate and decreases arterial blood pressure. D. It increases heart rate and increases arterial blood pressure. E. It causes significant dose-dependent histamine release. 54.9. Sensitivity to pancuronium neuromuscular block is enhanced by which of the following? A. Chronic phenytoin therapy B. Long-term pancuronium therapy in a critically ill patient C. Myasthenia gravis

1899

D. Acute sepsis E. Prior administration of neostigmine 54.10. Under which circumstance is the duration of succinylcholine effect more than doubled? A. B. C. D. E.

CHAPTER

In hepatic insufficiency Following chronic echothiophate eye drops After systemic thermal burn injury Following 2 units of fresh frozen plasma IV When the dibucaine number is >70%

55

LOCAL ANESTHETICS 55.1. Which of the following statements regarding lidocaine toxicity is not correct? A. Patients may develop seizures secondary to block of the cerebral inhibitory pathways. B. Patients may develop coma secondary to block of cerebral excitatory pathways. C. When lidocaine is used for nerve blocks, lifethreatening toxicity does not occur. D. Hypoxia and respiratory and metabolic acidosis all can increase the CNS and cardiovascular toxicity of lidocaine. E. Toxic effects usually correlate with plasma concentrations. 55.2. Which of the following statements about the pharmacokinetics of local anesthetics is correct? A. Only the ionized form can penetrate the nervous system. B. The speed of onset is determined by the drug’s pKa. C. The dose administered does not influence the time to onset of block. D. Agents with greater protein binding have a shorter duration of effect. E. Most of the local anesthetics are strong acids. 55.3. Which of the following is not a proposed mechanism of toxicity of the local anesthetic agents? A. B. C. D. E.

Uncoupling of oxidative phosphorylation Sodium channel blockade GABA antagonism NMDA agonism Altered sarcoplasmic release of calcium ions

55.4. Which of the following statements about local anesthetic allergies is correct?

1900

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. Patients allergic to an amide agent could generally safely receive a preservative-free preparation of the same drug. B. Allergy to local anesthetics is very common. C. Most true local anesthetic allergies are to the amide agents. D. Patients allergic to amide agents should never receive ester agents. E. Patients allergic to one ester agent could safely receive a different ester agent. 55.5. Which of the following local anesthetics is an ester? A. B. C. D. E.

Cocaine Mepivacaine Bupivacaine Lidocaine Ropivacaine

55.6. Which of the following local anesthetic agents most frequently causes methemoglobinemia? A. B. C. D. E.

Lidocaine Benzocaine Cocaine Prilocaine Procaine

55.7. Following an inadvertent bolus of an excessive amount of lidocaine, which of the following should be expected to occur first? A. B. C. D. E.

Headache Paralysis Vomiting Seizure Asystole

55.8. A patient in the ICU on a lidocaine infusion for ventricular dysrhythmias is suspected of developing early lidocaine toxicity. What clinical findings did the healthcare provider likely notice to suggest this syndrome? A. B. C. D. E.

A plasma lidocaine level of 4 µg/mL Hepatitis Worsening ventricular tachycardia Coma Tremor

55.9. Which of the following statements regarding the treatment of local anesthetic poisoning is true? A. The initial treatment for lidocaine toxicity is cardiopulmonary resuscitation. B. The initial therapy for bupivacaine cardiotoxicity is lidocaine.

C. Regardless of the treatment adminstered, lidocaine poisoning is almost always fatal. D. Hemodialysis, once the patient is stabilized, is highly efficacious in removing most local anesthetic agents. E. The performance of CPR is not important in patients with bupivacaine poisoning. 55.10. Which of the following statements regarding lidocaine is correct? A. Lidocaine is nontoxic orally because of poor bioavailability. B. The metabolites of lidocaine, MEGX and GX, are pharmacologically inactive. C. If lidocaine and prilocaine are combined, the lidocaine becomes able to penetrate skin. D. Lidocaine is administered in doses up to 55 mg/kg during tumescent anesthesia. E. Lidocaine routinely crossreacts with the cocaine drug-of-abuse assay.

CHAPTER

56

PHARMACEUTIC ADDITIVES 56.1. Propylene glycol is metabolized hepatically by alcohol dehydrogenase to A. B. C. D. E.

Polyethylene glycol Ethylene glycol Lactate Methanol Oxalate

56.2. Polyethylene glycol 200 (PEG 200) has been associated with what organ toxicity? A. B. C. D. E.

Renal tubular necrosis Acute pancreatitis Central lobular hepatic necrosis Cardiac myopathy Pneumoconiosis

56.3. The “gasping” syndrome described in neonates is believed to result from A. A decreased ability to metabolize benzyl alcohol B. A decreased ability to metabolize benzoic acid C. A glucose-6-phosphate dehydrogenase (G-6-PD) deficiency D. Sterile water for injection E. Methanol

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

56.4. Chlorobutanol has a chemical structure similar to that of A. B. C. D. E.

Trichloroethanol Perchloroethylene Vinyl chloride Trifluoroperazine Polyvinyl chloride

56.5. Thimerosal is a(n) _________________ mercury compound widely employed as a pharmaceutical preservative. A. B. C. D. E.

Elemental Organic Inorganic Pentavalent Trivalent

56.6. Benzalkonium chloride is the most widely used ____________ preservative in the United States. A. B. C. D. E.

Parenteral Topical Otic Ophthalmic Oral

56.7. The pharmaceutical additive(s) found most often in medications (except water) is/are A. B. C. D. E.

Glycerin Thimerosal Benzalkonium chloride Phenol Parabens

56.8. Acute renal failure from adulterated acetaminophen has been associated with which pharmaceutical additive? A. B. C. D. E.

Diethylene glycol Polyethylene glycol Benzyl alcohol Propylene glycol Sorbitol

56.9. Thrombocytopenia, hepatomegaly, renal dysfunction, and distal tubular crystal deposition were all manifested with what medication? A. B. C. D. E.

Sulfanilamide Bacteriostatic water Adulterated acetaminophen E-Ferol Thimerosal-containing vaccinations

56.10. Which hereditary syndrome predisposes patients to adverse effects from sorbitol?

A. B. C. D. E.

CHAPTER

1901

Bruton disease Turner syndrome Tay-Sachs disease Hurler syndrome Hereditary fructose intolerance

57

CYCLIC ANTIDEPRESSANTS 57.1. Which of the following therapeutic interventions is the most effective in narrowing the QRS complex in patients with cyclic antidepressant toxicity? A. B. C. D. E.

Acetazolamide Intravenous hypertonic saline Intravenous hypertonic sodium bicarbonate Hyperventilation Intravenous lidocaine

57.2. Following a tricyclic antidepressant overdose, how soon after arrival in the emergency department will seizures, hypotension, or cardiac dysrhythmias occur? A. B. C. D. E.

1 hour 2 hours 4 hours 6 hours 8 hours

57.3. Amoxapine differs from the other cyclic antidepressants in that it causes a higher incidence of which of the following in overdose? A. B. C. D. E.

Sinus tachycardia Ventricular tachycardia Respiratory depression Seizures Coma

57.4. Which of the following cyclic antidepressants causes a dose-related increase in systolic blood pressure? A. B. C. D. E.

Bupropion Maprotiline Trazodone Venlafaxine Amoxapine

57.5. Which of the following statements about the pharmacokinetics of the cyclic antidepressants is correct? A. The volume of distribution is 2 to 5 L/kg.

1902

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

B. The cyclic antidepressants are 60% protein bound. C. They do not partition well into fat. D. A very small percentage of the ingested dose is excreted unchanged in the urine. E. The cyclic antidepressants bind to albumin.

CHAPTER

58

SEROTONIN REUPTAKE INHIBITORS AND ATYPICAL ANTIDEPRESSANTS 58.1. Which of the following is not a SSRI?

57.6. Which of the following cyclic antidepressants is the most potent inhibitor of dopamine reuptake? A. B. C. D. E.

Amoxapine Venlafaxine Doxepin Imipramine Desipramine

57.7. Which of the following cyclic antidepressants does not inhibit the reuptake of either serotonin or norepinephrine? A. B. C. D. E.

Amitriptyline Desipramine Nortriptyline Doxepin Bupropion

57.8. Which of the following ECG changes is believed to be highly predictive of seizures and dysrhythmias in patients with first-generation tricyclic antidepressant toxicity? A. B. C. D. E.

Right bundle branch block Prolonged PR interval Decreased conduction velocity A QRS complex >100 milliseconds An S wave in leads I and aVL

57.9. Which of the following cyclic antidepressants has the most anticholinergic activity? A. B. C. D. E.

Amitriptyline Doxepin Fluoxetine Maprotiline Amoxapine

57.10. Which of the following antidysrhythmics can be safely used in patients with cyclic antidepressant toxicity? A. B. C. D. E.

Quinidine Bretylium Propranolol Disopyramide Lidocaine

A. B. C. D. E.

Paroxetine Sertraline Citalopram Venlafaxine Fluoxetine

58.2. Which finding on physical examination is seen more commonly in serotonin syndrome than in neuroleptic malignant syndrome? A. B. C. D. E.

Fever Altered mental status Hyperreflexia Autonomic instability Mydriasis

58.3. Serotonin syndrome involves overstimulation of which serotonin receptor? A. B. C. D. E.

5-HT1 5-HT2 5-HT3 5-HT4 5-HT5

58.4. SSRIs have been used to treat which of the following disorders? A. B. C. D. E.

Obesity Attention deficit disorder Dysrhythmias Seizures Hypersalivation

58.5. Which antidepressant does not inhibit the reuptake of serotonin? A. B. C. D. E.

Fluoxetine Venlafaxine Citalopram Nefazodone Mirtazapine

58.6. Which of the following effects has not been reported after an isolated overdose of SSRIs? A. B. C. D. E.

Seizures Tachycardia Mental status depression Hyperthermia Nausea and vomiting

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

58.7. Which therapy is not a treatment for serotonin syndrome? A. B. C. D. E.

Antipyretics Active cooling Benzodiazepines Cyproheptadine Supportive care

58.8. SSRIs cause drug interactions by inhibiting which cytochrome P450 isoenzyme system? A. B. C. D. E.

CYP2E1 CYP2D6 CYP1A2 CYP3A4 CYP2A10

58.9. Which of the following are requirements of the serotonin syndrome? A. Two dopaminergic drugs must be administered. B. Two serotonergic drugs must be administered. C. A serotonergic and a dopaminergic drug must be administered. D. A single serotonergic drug is administered. E. A single dopaminergic drug is administered. 58.10. The SSRI that is reported to cause seizures and dysrhythmias after overdose is A. B. C. D. E.

Fluoxetine Sertraline Citalopram Nefazodone Mirtazapine

1903

59.2. Optimum antipsychotic effects of the phenothiazines will not occur until the patient has received the medication for approximately A. B. C. D. E.

1 week 2 weeks 1 month 2 months 6 months

59.3. If a patient receiving thioxanthene or loxapine develops hyperthermia, muscle rigidity, autonomic dysfunction, and an altered level of consciousness, the patient is most likely experiencing A. B. C. D. E.

An allergic reaction Tardive dyskinesia Drug toxicity from an excessive dose Neuroleptic malignant syndrome (NMS) An extrapyramidal reaction

59.4. If neuroleptic malignant syndrome (NMS) occurs, it is recommended to discontinue the antipsychotic, but if an antipsychotic is necessary, what should be done? A. If NMS occurs, no additional neuroleptics should be given. B. Treat with bromocriptine or dantrolene and restart therapy with the same neuroleptic. C. Discontinue the neuroleptic for 2 weeks and restart on another neuroleptic from a different class. D. Add benztropine to prevent the development of NMS. E. Add a benzodiazepine to prevent the development of NMS. 59.5. What is the most common extrapyramidal effect of antipsychotic therapy?

CHAPTER

59

ANTIPSYCHOTICS 59.1. A patient receiving chlorpromazine who is started on cimetidine may require a higher dose of chlorpromazine because A. Cimetidine increases the renal clearance of chlorpromazine. B. Chlorpromazine absorption is pH dependent. C. Chlorpromazine has substantial first-pass metabolism. D. Cimetidine increases the hepatic clearance of chlorpromazine. E. Cimetidine increases the distributive volume of chlorpromazine.

A. B. C. D. E.

Parkinsonism Dystonia Akathisia Tardive dyskinesia Malignant hyperthermia

59.6. What is the most serious central nervous system toxic effect of antipsychotic therapy? A. B. C. D. E.

Parkinsonism Seizure disorders Akathisia Tardive dyskinesia Akinesia

59.7. Which treatment has been shown to be beneficial in tardive dyskinesia?

1904

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

Cholinergic stimulation Anticholinergics Cyclobenzaprine Clozapine Lithium carbonate

59.8. Antipsychotics, when taken alone, are usually quite safe even when taken in significant overdose. The antipsychotic most frequently associated with causing death when taken as an overdose is A. B. C. D. E.

Haloperidol Thioridazine Chlorpromazine Loxapine Prochlorperazine

59.9. Which of the following dysrhythmias most commonly occurs in a patient with a mesoridazine overdose? A. B. C. D. E.

Bradycardia Torsades de pointes Increased QT and QRS intervals Decreased PR interval Atrial fibrillation

59.10. Phenothiazine metabolites are lipophilic and have large volumes of distribution. A qualitative analysis for phenothiazines in the urine from a patient who has taken a phenothiazine may remain positive for A. B. C. D. E.

CHAPTER

24 hours 48 hours 7 to 10 days 21 days Greater than 1 month

60

MONOAMINE OXIDASE INHIBITORS

60.2. Severe hypertension in a MAO inhibitor–poisoned patient is best treated with the use of which of the following? A. B. C. D. E.

-Adrenergic antagonists
-Adrenergic antagonists Calcium channel blockers Labetalol Nitroprusside

60.3. Monoamine oxidase metabolizes all of the following agents except for which one? A. B. C. D. E.

Dietary monoamines Norepinephrine Adenosine Serotonin Epinephrine

60.4. MAOI use results in which of the following? A. B. C. D. E.

Expanded storage pool of norepinephrine Decreased urinary excretion of catecholamine Decreased production of catecholamine Increased production of 5-hydroxytryptamine Increased secretion of catechols from the adrenal medulla

60.5. MAOI overdose may be best characterized by which of the following? A. B. C. D. E.

Delayed onset of symptoms Hypothermia Pinpoint pupils Anticholinergic syndrome Respiratory depression

60.6. Which of these drugs can safely be used with MAOIs without risking drug interactions? A. B. C. D. E.

Ephedrine Phenylpropanolamine Norepinephrine Cocaine Amphetamine

60.1. Which of the following is true regarding the MAO isozymes?

60.7. Tyramine may precipitate a hypertensive crisis in patients on MAOIs by which mechanism?

A. MAO-A is found only in the gastrointestinal tract. B. The preferred substrate for MAO-A is serotonin. C. MAO-B inhibition is responsible for tyramine sensitivity. D. Selegiline is a selective MAO-A inhibitor. E. All currently available MAO-A inhibitors are reversible, whereas the currently available MAO-B inhibitors are irreversible.

A. Inhibiting the metabolism of endogenous catecholamines B. Direct binding to postsynaptic
receptors C. Blockade of -adrenergic receptors producing unopposed
-adrenergic effects D. Release of stored norepinephrine E. Blocks catechol-O-methyltransferase 60.8. Which drug may be given to a patient taking MAOIs without a potential interaction?

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

61.3. Which of the following is false?

Albuterol Meperidine Fluoxetine Barbiturates Sulfonylureas

60.9. The serotonin syndrome can be avoided when using MAOIs in combination with which of the following agents? A. B. C. D. E.

Dextromethorphan Imipramine Clomipramine Meperidine Morphine

60.10. The newer MAOIs such as moclobemide are thought to be safer because of which of the following characteristics? A. B. C. D. E.

CHAPTER

Reversible Irreversible MAO-A isoenzyme selective MAO-B isoenzyme selective Covalently bound to MAO

61

LITHIUM 61.1. In a patient with normal renal function, which is the least effective treatment for acute lithium poisoning? A. Continuous arteriovenous (CAVH) B. Hemodialysis C. Peritoneal dialysis D. Maximizing GFR E. Continuous arterioarterial (CAAH)

1905

hemofiltration

hemofiltration

61.2. Which of following concerning extracorporeal removal of lithium is not true? A. The small size aids in its ability to be removed via hemodialysis. B. Its small volume of distribution is similar to that of total body water at 0.6 to 0.9 L/kg. C. Hemodialysis is a better modality than hemoperfusion for lithium removal because lithium does not bind well to charcoal. D. It is well bound to proteins, especially albumin. E. Its clearance via hemodialysis is mainly dependent on blood flow.

A. Malignant cardiac disturbances are common in lithium toxicity. B. Patients with lithium poisoning and mental status changes should undergo peritoneal dialysis immediately. C. Patients with renal failure and lithium toxicity should be managed with aggressive decontamination and hemodialysis. D. Cardiac changes such as ST and T wave changes may be noted in lithium toxicity and need not be treated aggressively. E. Lithium is not bound to activated charcoal well. 61.4. All of the following statements regarding lithium clearance are true except A. Patients who undergo hemodialysis will frequently develop a “rebound” and need to be redialyzed. B. Hemodialysis effectively lowers both the serum and the central nervous system lithium concentration. C. When trying to determine an accurate tissue level of lithium, the best time to check is 1 hour after dialysis. D. An asymptomatic patient with a lithium level of 5.0 mEq/L should undergo dialysis. E. A patient with chronic lithium poisoning and altered mental status should undergo hemodialysis. 61.5. The following pharmacokinetic statements regarding lithium are all true except A. The volume of distribution is similar to total body water. B. The vast majority is excreted by the kidneys. C. Dehydration may lead to increase toxicity. D. Lithium readily crosses cellular membranes of the kidney, liver, and CNS, leading to rapid onset of effects. E. Lithium is rapidly absorbed and has a rapid peak serum level. 61.6. Which of the following statements regarding CAVH or CAAH is false? A. They may be alternatives to hemodialysis in patients with lithium toxicity. B. Their clearance per hour is less than that of hemodialysis. C. Unlike hemodialysis, they do not demonstrate a “rebound” in lithium concentration.

1906

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. They have the benefit of not requiring specialized personnel to perform. E. They are better at preventing permanent neurologic deficits than hemodialysis.

C. As a prophylactic treatment for patients with muscle tension headaches D. As a salt substitute in patients with hypertension E. As a constituent of the soft drink 7-Up.

61.7. Which of the following statements concerning decontamination and treatment of the acutely poisoned lithium patient is false? A. Numerous studies in humans have shown sodium polystyrene sulfonate (SPS) to be beneficial in clearing lithium from the body. B. Repeat doses of activated charcoal play no role in decontamination of patients poisoned with lithium. C. Elimination of lithium can be increased by ensuring good GFR with a sodium-containing electrolyte solution. D. Lithium is handled by the kidney in a manner similar to sodium. E. Lithium’s small size makes it amenable to hemodialysis. 61.8. All the following regarding lithium and its interactions are true except A. Lithium shares the same valence as sodium and potassium. B. It has an ionic radius that is similar to that of manganese. C. Some of lithium’s actions may involve the inhibition of inositol monophosphate. D. cAMP function via norepinephrine is altered by lithium. E. Lithium’s interaction with numerous enzymes, neurotransmitters, and ions may explain its diverse actions. 61.9. Which statement regarding signs and symptoms of lithium toxicity is true? A. Most patients will have nausea and vomiting after an acute ingestion. B. Dehydration may play a significant role in toxicity with chronic overdose. C. Subtle neurologic changes may be the presenting symptoms in a patient with chronic lithium toxicity. D. Patients with acute toxicity usually develop dysarthria as the presenting neurologic finding. E. Seizures are a sign of severe neurologic complications of lithium toxicity. 61.10. Lithium has not been used A. To treat manic-depressive disorder B. As a cell stimulator in neutropenic patients

CHAPTER

62

OPIOIDS 62.1. Which is not true concerning opioid receptors? A. There may be an endogenous ligand that is identical to morphine. B. Under the new system of opioid nomenclature, the opioid receptors are renamed OP. C. The µ receptor is most closely associated with respiratory depression. D. When stimulated, a κ receptor subtype (κ2) may produce dysphoria. E. All opioids bind to µ receptors better than they bind to κ receptors. 62.2. Which of the following is not true concerning the currently accepted or proven signal transduction mechanism through which opioid agonists produce their opioidlike clinical effects? A. Some receptors inhibit adenylate cyclase activity through inhibitory G proteins. B. Opioid receptors may enhance GABA binding on the chloride channel. C. Several opioid agonists increase conductance through a potassium channel. D. Closure of N-type calcium channels via a G protein is an accepted mechanism. E. Any receptor subtype may utilize several different signal transduction mechanisms, depending on location. 62.3. Which statement is false regarding the clinical pharmacology and toxicology of opioid agonists? A. Hypoventilation may result from hypopnea or bradypnea. B. Support of ventilation and oxygenation is the primary mode of therapy. C. It is not important to know the exact opioid agent to which the patient was exposed to provide adequate care. D. The presence of small pupils in a person known to use illicit substances is sufficient evidence for opioid poisoning. E. It is better to start with low doses of naloxone and proceed upward than to give a large initial dose.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

62.4. Which of the following findings is not expected in patients following a suicidal opioid overdose? A. B. C. D. E.

Altered mental status Respiratory depression Miosis Methemoglobinemia Abdominal distension

62.5. Which of these is not expected to occur in a patient with severe acute opioid toxicity after a singleagent opioid overdose? A. B. C. D. E.

Seizures Apnea Pulmonary edema Cardiac dysrhythmias Acute hypertension

62.6. Which is true concerning naloxone? A. Naloxone is unconditionally safe and should be used liberally in patients with altered mental status regardless of historical or clinical factors. B. Because of enhanced receptor specificity, the dose of naloxone needed to reverse opioid intoxication may be higher in patients exposed to naturally occurring opiates than synthetic opioids. C. After administration of naloxone and reversal of opioid toxicity, the patient is considered cured and may be discharged home safely. D. Meperidine-induced seizures typically respond to naloxone. E. Naloxone may have a role in patients manifesting clonidine toxicity. 62.7. Concerning “body packers,” which of the following is true? A. Body packers ingest illicit substances before arrest to avoid discovery of their drugs by police. B. It is usually impossible to differentiate cocaine body packers from heroin body packers without toxicology analysis. C. Patients may be asymptomatic for hours or days before developing toxicity. D. Opioid toxicity is an absolute indication for surgical removal of the packets. E. Patients not demonstrating toxicity should receive cascara or other potent irritant cathartics. 62.8. Which of the following is false concerning fentanyl and its analogues?

1907

A. Fentanyl and its illicit analogues are prevalent drugs of abuse among street users and physicians. B. Epidemic death rates in heroin abusers are occasionally related to fentanyl substitution. C. Fentanyl-induced rigidity may prevent adequate chest wall function. D. Fentanyl-induced seizures are probably better classified as a movement disorder. E. Fentanyl induces massive histamine release, which is commonly related to intraoperative death. 62.9. Which is false concerning the utilization of the laboratory? A. Naloxone, despite its structural similarity with morphine, does not crossreact with the morphine immunoassay. B. Fentanyl is often difficult to detect because of its high potency. C. Patients who eat poppy seeds may have positive assays for heroin. D. Patients who eat poppy seeds may have positive assays for morphine. E. Patients using therapeutic doses of codeine will have a positive morphine assay. 62. 10. Which of the following is true concerning methadone? A. Methadone poisoning is identical to that from other opioids except that the duration of effect of methadone is very prolonged. B. Acute, severe parkinsonian symptoms have resulted from MPTP (1-methyl-4-phenyl1,2,3,6-tetrahydropyridine) contamination of illicit methadone synthesis. C. Patients are generally given high therapeutic doses of methadone to prevent withdrawal. D. levo-
-Acetylmethadol (LAAM, Orlaam) is a slightly shorter-acting opioid agent than methadone. E. Nalmefene is useful in the outpatient management of methadone-overdose patients.

CHAPTER

63

SEDATIVE-HYPNOTIC AGENTS 63.1. Alkalinization of the urine with sodium bicarbonate will enhance urinary excretion of which of the following barbiturates? A. Amobarbital

1908

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

B. C. D. E.

Butabarbital Secobarbital Phenobarbital Pentobarbital

63.2. The amount of drug that will be present in the blood compartment following an oral phenobarbital overdose depends on which of the following? A. B. C. D. E.

Rate constant of absorption Volume of distribution Quantity of drug ingested Dissolution rate of the tablet All of the above

63.3. Which of the following benzodiazepines has the shortest duration of action? A. B. C. D. E.

Triazolam Diazepam Oxazepam Lorazepam Alprazolam

63.4. Which of the following sedative-hypnotic agents is most likely to cause ventricular dysrhythmias? A. B. C. D. E.

Meprobamate Ethchlorvynol Glutethimide Chloral hydrate Methaqualone

63.5. Which of the following agents binds to benzodiazepine receptors and can be reversed with flumazenil? A. B. C. D. E.

Meprobamate Ethchlorvynol Glutethimide Chloral hydrate Zolpidem

63.6. Which of the following statements about bromides is correct? A. Bromides interfere with the measurement of sodium. B. The half-life of bromide may be as long as 12 days. C. Bromide is eliminated primarily in the bile. D. The administration of potassium will hasten the elimination of bromide. E. Bromide tablets are radiopaque. 63.7. Anticholinergic symptomatology would be expected with which of the following sedativehypnotics in overdose?

A. B. C. D. E.

Ethchlorvynol Glutethimide Temazepam Meprobamate Clorazepate dipotassium

63.8. Which of the following statements about glutethimide is correct? A. Elimination is primarily renal. B. The half-life decreases in overdose. C. An active metabolite may be responsible for the long duration of effects. D. Toxicity is equivalent to that of the benzodiazepines. E. Absorption is rapid and complete. 63.9. Which of the following statements about meprobamate is correct? A. It is largely protein bound. B. Volume of distribution is 0.75 L/kg. C. Withdrawal symptoms respond well to methadone. D. Elimination is primarily renal. E. All of the above 63.10. Which of the following sedative-hypnotic agents would not result in a drug interaction in a patient concomitantly taking warfarin? A. B. C. D. E.

CHAPTER

Chloral hydrate Triazolam Phenobarbital Meprobamate None of the above

64

ETHANOL 64.1. Which one of the following statements relating to ethanol metabolism is correct? A. Acetate is converted to acetoacetate, which enters the Krebs (citric acid) cycle. B. Gluconeogenesis is impaired by the conversion of pyruvate to lactate. C. MEOS system (CYP2E1) is the main pathway for ethanol metabolism. D. Oxidation of ethanol to acetaldehyde by ADH requires NADP+. E. Pyridoxine (vitamin B6) is essential for the oxidation of acetaldehyde to acetate.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

64.2. An 80-kg man ingests 100 mL of 80-proof whisky (Vd of 0.5 L/kg). Assuming instantaneous and complete absorption and no distribution or metabolism, what is the serum ethanol concentration? A. B. C. D. E.

50 mg/dL. 100 mg/dL. 200 mg/dL. 400 mg/dL. 800 mg/dL.

64.3. Which one of the following is correct regarding alcoholic ketoacidosis (AKA)? A. B. C. D. E.

The serum lactate is generally negative. Cellular redox state is low (reduced). Nitroprusside test is strongly positive. Normal anion metabolic acidosis. Serum glucose exceeds 300 mg/dL (16.67 mmol/L).

64.4. Which one of the following occurs in the development of ethanol tolerance? A.
-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor up-regulation. B. γ-Aminobutyric acidA (GABAA) receptor upregulation. C. Kainate receptor up-regulation. D. Metabotropic glutamate (mGluR) receptor upregulation. E. N-Methyl-D-aspartate (NMDA) receptor upregulation. 64.5. Which one of the following is an essential cofactor for transketolase, pyruvate dehydrogenase, and
-ketoglutarate dehydrogenase? A. B. C. D. E.

Folate Niacin Pyridoxine Riboflavin Thiamine

64.6. Which one of the following is the major contributor to the increased anion gap metabolic acidosis in alcoholic ketoacidosis (AKA)? A. B. C. D. E.

Acetate. Acetoacetate. -Hydroxybutyrate. Lactate. Pyruvate.

64.7. In a thiamine-deficient state, which one of the following is the rate-limiting step in the Krebs cycle? A. Oxaloacetate to citrate. B. Citrate to isocitrate.

1909

C. Isocitrate to
-ketoglutarate. D.
-Ketoglutarate to succinate. E. Succinate to fumarate. 64.8. Which one of the following will most likely interact with ethanol to result in a disulfiramlike reaction? A. B. C. D. E.

Chloral hydrate. Griseofulvin. Isoniazid. Niacin. Ranitidine.

64.9. In which one of the following situations will the nitroprusside test be strongly positive? A. B. C. D. E.

Methanol intoxication. Ethanol intoxication. Ethylene glycol intoxication. Isopropanol intoxication. Phenol intoxication.

64.10. Which one of the following concerning ethanol ingestion is correct? A. In certain people, cimetidine may result in mildly elevated ethanol levels. B. Ethanol-induced hypoglycemia is more common in adults than children. C. Fomepizole does not inhibit the metabolism of ethanol. D. The facial flushing syndrome that occurs in some patients after ethanol ingestion is caused by an overactive ADH and an underactive aldehyde dehydrogenase. E. Fortification of ethanol products with thiamine would eliminate Wernicke encephalopathy.

CHAPTER

65

DISULFIRAM AND DISULFIRAMLIKE REACTIONS 65.1. In which one of the following industries would an occupational exposure to disulfiram most likely occur? A. B. C. D. E.

Dye manufacturing Jewelry manufacturing Plexiglas manufacturing Rubber manufacturing Wood manufacturing

65.2. Which one of the following enzymes is inhibited by disulfiram?

1910

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

Alcohol dehydrogenase Dopamine -hydroxylase Monoamine oxidase Tryptophan 5-hydroxylase Tyrosine hydroxylase

65.3. Why is the inhibitory effect of disulfiram on aldehyde dehydrogenase prolonged? A. There are active metabolites. B. Half-life of the parent compound that is longer than most drugs. C. Irreversible inhibition of aldehyde dehydrogenase. D. Large volume of distribution and slow release from tissue stores. E. Prolonged enterohepatic circulation. 65.4. How long following cessation of disulfiram therapy are most patients at risk for a developing a disulfiram-ethanol reaction? A. B. C. D. E.

24 hours 1 to 2 days 5 to 7 days 1 to 2 weeks 2 to 3 weeks

65.5. A patient exposed to which one of the following chemicals would be expected to develop a disulfiramlike reaction on exposure to ethanol? A. B. C. D. E.

Acrylamide Calcium carbimide Cobalt Isopropyl alcohol Nickel

65.6. Ingestion of which one of the following mushrooms would be expected to cause a disulfiramlike reaction on exposure to ethanol? A. B. C. D. E.

Amanita pantherina Chlorophyllum molybdites Coprinus atramentarius Cortinarius orellanus Galerina autumnalis

65.7. Which one of the following subfamilies of the cytochrome P450 mixed-function oxidase system does disulfiram predominantly inhibit? A. B. C. D. E.

CYP2E1 CYP2C9 CYP2D6 CYP3A4 CYP3E1

65.8 For which one of the following exposures would diethyldithiocarbamate, a disulfiram metabolite, be a potential antidote? A. B. C. D. E.

Elemental nickel Nickel acetate tetrahydrate Nickel-beryllium alloy Nickel carbonate Nickel carbonyl

65.9 Which one of the following is caused by chronic disulfiram therapy? A. Decreased serum cholesterol B. Decreased concentration of nickel in body fluids C. Halitosis D. Hypotension E. Pancreatitis 65.10. Which of the following substrates is required by both alcohol dehydrogenase and aldehyde dehydrogenase? A. B. C. D. E.

CHAPTER

ATP GTP NAD+ NADP+ Thiamine

66

TOXIC ALCOHOLS 66.1. Diagnostic clues that a patient may be poisoned with ethylene glycol (antifreeze) include which of the following? A. B. C. D. E.

Ketonuria Fluorescent urine Hypokalemia Radiopaque density in stomach Hyperemic optic discs

66.2. The retinal toxicity observed following methanol poisonings results from A. B. C. D. E.

Hyperosmolarity Elevated lactic acid levels Metabolism of methanol to formaldehyde Metabolism of methanol to formic acid Destruction of the retinal phospholipid membrane

66.3. Which of the following is considered to be an appropriate therapeutic intervention for a patient with ethylene glycol poisoning given IV ethanol who is

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

unstable and is at a health care facility unable to perform hemodialysis? A. B. C. D. E.

Multiple-dose activated charcoal Charcoal hemoperfusion Forced alkaline diuresis Peritoneal dialysis Continuous arteriovenous hemofiltration

66.4. Ethylene glycol is metabolized to oxalic acid by which of the following enzymes? A. B. C. D. E.

Cytochrome P450 isozyme CYP3A4 Glutamic acid decarboxylase Alcohol dehydrogenase Pyruvic acid dehydrogenase Reduced nicotinic acid dehydrogenase

66.5. Which of the following is characteristic of a severe isopropanol exposure? A. B. C. D. E.

Crystalluria A high anion gap Ocular toxicity Ketonuria Metabolic acidosis

66.6. Which of the following alcohols has the greatest percentage of renal clearance? A. B. C. D. E.

Ethanol Methanol Isopropanol Ethylene glycol Benzyl alcohol

1911

66.9. Which of the following electrocardiographic abnormalities may be found with an ethylene glycol overdose? A. B. C. D. E.

Long PR interval Short QTc interval Wide QRS complex Long QTc interval Peaked T waves

66.10. Calcium oxalate monohydrate crystals can be confused with which of the following crystals? A. B. C. D. E.

CHAPTER

Sodium urate crystals Struvite crystals Calcium oxalate dihydrate crystals Calcium pyrophosphate crystals Hippurate crystals

67

COCAINE 67.1. In an animal model of cocaine toxicity, reversal of which of the following parameters is best associated with survival? A. B. C. D. E.

Hypertension Tachycardia Hyperthermia Hyperventilation Acidosis

66.7. Which of the following statements is correct about ethanol therapy for ethylene glycol or methanol overdoses?

67.2. Which of the following mechanisms explains cocaine-induced myocardial ischemia?

A. Ethanol cannot be given orally. B. The loading dose is 1.8 g ethanol/kg body weight. C. The maintenance dose is usually 230 mg/kg/h. D. Intravenous ethanol should be given as a 5 to 10% solution. E. Ethanol therapy should result in a blood ethanol level of 50 mg/dL.

A. Increased myocardial oxygen demand from hypertension and tachycardia B. Coronary artery spasm from
-adrenergic effects C. Platelet aggregation and impaired thrombolysis D. Increased atherogenesis E. All of the above

66.8. Which of the following substances has caused central nervous system toxicity, respiratory distress, hypotension, and renal and hepatic failure in the neonate?

67.3. A young man is brought to the hospital by customs agents because of suspected gastrointestinal drug smuggling. He has normal vital signs and a normal examination. Which of the following would be the most appropriate therapy?

A. B. C. D. E.

Bacteriostatic sodium chloride Propylene glycol (diluent) Sterile water for injection Ringer’s lactate Dextrose 10% solution

A. Immediate surgical removal B. Keeping the patient NPO in the ICU pending evaluation C. Oral bulk laxative therapy in the ICU

1912

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. Oral activated charcoal and whole-bowel irrigation E. Single-dose activated charcoal without a cathartic 67.4. Genetically engineered mice that lack the dopamine reuptake pump have which of the following psychomotor responses to cocaine? A. No response B. A heightened initial response with shorter duration C. A heightened initial response with longer duration D. A normal response E. An attenuated response with longer duration 67.5. Haloperidol is contraindicated following cocaine use for which of the following reasons? A. B. C. D.

It exacerbates seizures in animal models. It increases lethality in animal models. It may increase the risk of torsades de pointes. It blocks presynaptic dopamine receptors, thus enhancing catecholamine effects. E. All of the above

67.6. Which of the following therapies is contraindicated in a patient with cocaine-induced myocardial ischemia? A. B. C. D. E.

Nitroglycerin Phentolamine Metoprolol Aspirin Thrombolysis

67.7. Cocaine’s direct effect on the heart is best described as that of a A. B. C. D. E.

Positive inotrope and chronotrope Type IA and IC antidysrhythmic agent Type II antidysrhythmic agent Type IB antidysrhythmic agent Type IV antidysrhythmic agent

67.8. Which of the following will not prolong the metabolism of cocaine? A. B. C. D. E.

Mivacurium Succinylcholine Pancuronium Tetracaine Bupivacaine

67.9. Which of the following is required to produce rhabdomyolysis in the setting of cocaine use? A. Hyperthermia

B. C. D. E.

Psychomotor agitation Hypertension Tachycardia None of the above

67.10. Which of the following is not commonly found as a cocaine adulterant? A. B. C. D. E.

CHAPTER

Starches Thallium Local anesthetics Sympathomimetics Sugars

68

AMPHETAMINES 68.1. Which of the following has been consistently demonstrated in animal models following the chronic administration of 3,4-methylenedioxymethamphetamine (MDMA)? A. B. C. D. E.

Basal ganglia damage Diffuse white-matter atrophy Serotonergic neuron damage Neurofibrillary tangles None of the above

68.2. Chronic use of diet medications such as fenfluramine has been associated with A. B. C. D. E.

Schizophrenia Renal tubular acidosis Acute dystonia Primary pulmonary hypertension Myocarditis

68.3. Intravenous methamphetamine use is associated with which of the following? A. B. C. D. E.

Lead toxicity Thallium toxicity Arsenic toxicity Cobalt toxicity Phosphine toxicity

68.4. Which of the following regarding “ice” is false? A. It is more stereoisomerically pure than methamphetamine in the 1970s. B. It has higher purity than methamphetamine in the 1970s. C. It is a different salt form than methamphetamine in the 1970s.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. It has larger macroscopic crystals than methamphetamine in the 1970s. E. It is more likely to be synthesized from ephedrine than methamphetamine in the 1970s. 68.5. Necrotizing vasculitis from amphetamine use may affect the following organ system: A. B. C. D. E.

Central nervous system Coronary arteries Kidneys Pancreas All of the above

68.6. Which of the following statements concerning khat is false? A. Adrenergic complications are less frequent than with amphetamine abuse. B. The fresh leaves are less potent than the dried leaves. C. Khat is commonly used in eastern and central Africa. D. The primary active substance is cathinone. E. Cathinone may be converted to cathine spontaneously. 68.7. Which of the following statements is false? A. Neuroleptic agents such as haloperidol may be superior to diazepam in the treatment of amphetamine toxicity in animal models. B. Benzodiazepines are not efficacious in the clinical management of amphetamine toxicity. C. Benzodiazepines are more efficacious than neuroleptic agents in the management of ethanol withdrawal. D. Benzodiazepines are more efficacious than neuroleptic agents in the management of acute cocaine toxicity. E. Agitation from cocaine, amphetamine, phencyclidine, or ethanol withdrawal may be similar. 68.8. Acidification of the urine for amphetamine intoxication is not recommended because A. Acidification will increase amphetamine elimination in the urine. B. Acidification will decrease oxygen unloading to the tissues. C. Acidification may cause a heatstrokelike syndrome. D. Acidification will worsen hypokalemia. E. Acidification will increase precipitation of myoglobin in the renal tubules.

1913

68.9. Which of the following symptoms is not likely to be observed in a patient with amphetamine intoxication? A. B. C. D. E.

Urinary retention Mydriasis Tachycardia Hypertension Hyperthermia

68.10. Amphetamine toxicity is not expected to result in mortality from which of the following? A. B. C. D. E.

CHAPTER

Intracranial hemorrhage Dysrhythmias Hypothermia Aortic dissection Agitation

69

PHENCYCLIDINE AND KETAMINE 69.1. Phencyclidine and ketamine antagonize the effects of glutamate at which receptor site? A. B. C. D. E.

GABAA receptor Kainate receptor Quisqualate receptor N-Methyl-D-aspartate receptor Postsynaptic glycine receptor

69.2. Which of the following clinical symptoms is not mediated by ketamine’s effect on the NMDA receptor? A. B. C. D. E.

Analgesia Anesthesia Psychosis Bronchodilation Cognitive deficits

69.3. Which of the following statements about the clinical pharmacology of ketamine is incorrect? A. Ketamine has approximately one tenth the potency of PCP. B. Recovery time after a therapeutic intravenous dose averages 3 hours. C. It is extensively metabolized by the cytochrome P450 liver isozymes. D. Norketamine, a major metabolite, has onethird the anesthetic potency of ketamine. E. The D(+)-isomer of ketamine is a more effective anesthetic.

1914

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

69.4. Which of the following substances does not produce a false-positive test for phencyclidine? A. B. C. D. E.

PHP PCE Dextrorphan Dextromethorphan MDMA

69.5. Which neuropsychiatric disorder does PCP and ketamine intoxication most closely mimic? A. B. C. D. E.

Dementia Depression Schizophrenia Mania Obsessive-compulsive disorder

69.6. Which of the following is correct about the clinical presentation of a phencyclidine overdose? A. B. C. D. E.

Patients may have rotatory nystagmus. Patients often have absent bowel sounds. Patients often have dry mucous membranes. There is often a metabolic alkalosis. Cardiac dysrhythmias are common.

69.7. NMDA receptors modulate all of the following actions except A. B. C. D. E.

Appetite Seizure activity Cognition and memory Neuronal development Sensory perception

69.8. Animal models suggest that NMDA antagonists are protective in which disease processes? A. B. C. D. E.

Cerebrovascular accidents Headache Depression Mania Schizophrenia.

69.9. Which of the following statements about the clinical pharmacology of phencyclidine is correct? A. B. C. D.

It is not lipid soluble. It is distributed primarily to extracellular fluid. It is extensively protein bound. Nine percent is excreted unchanged in the urine. E. Renal excretion is increased with alkalinization.

69.10. Which of the following therapeutic interventions is effective in a patient with a phencyclidine overdose?

A. B. C. D. E.

CHAPTER

Emesis with syrup of ipecac Activated charcoal Gastric lavage Sorbitol catharsis Whole-bowel irrigation

70

LYSERGIC ACID DIETHYLAMIDE AND OTHER HALLUCINOGENS 70.1. Which of the following medications is the initial choice to treat anxiety and hypertension associated with hallucinogen use? A. B. C. D. E.

Propranolol Phenylephrine Diazepam Labetalol Haloperidol

70.2. Which of the following statements about hallucinations is true? A. Hallucinogens alter and distort perception, thought, and mood. B. Patients with drug-induced hallucinations cannot typically identify their surroundings. C. The first use of hallucinogenic drugs was in the counterculture movements of the 1960s. D. An illusion is identical to a hallucination but is not drug induced. E. Because of their lack of sufficient prior life experiences, hallucinations cannot occur in children. 70.3. Which of the following best describes the role of the neurotransmitter serotonin in producing hallucinations? A. Neuronal serotonin release is the primary mechanism by which LSD causes hallucinations. B. The 5-HT2 receptor subtype is responsible for hallucinations. C. Antagonism of endogenous serotonin at several 5-HT receptor subtypes causes hallucinations. D. Because of its role as a serotonin agonist, LSD is frequently implicated in the serotonin syndrome. E. Although formerly believed to be serotonin mediated, most recent evidence suggests that acetylcholine agonism is the cause of the hallucinations.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

70.4. Which of the following findings is a common physiologic response to hallucinogenic drugs? A. B. C. D. E.

Diarrhea Tachycardia Miosis Hypothermia Respiratory depression

70.5. Which one of these plants and mushrooms contains lysergic acid hydroxyethylamide? A. B. C. D. E.

Datura stramonium Ipomoea violacea Lophophora williamsii Amanita muscaria Psilocybe cubenis

1915

B. N,N-Dimethyltryptamine (DMT) is a potent, long-acting hallucinogen with good gastrointestinal tract absorption. C. Bufotenine is derived from Bufo sp., a large toad, and ingestion may be lethal. D. Mescaline is found in Lophophora williamsii, the sea cucumber. E. LSD still has several important clinical utilities. 70.10. Which of the following psychological parameters is affected by LSD? A. B. C. D. E.

Arousal Emotion Perception Thought process All of the above

70.6. Which of the following statements about lysergic acid diethylamide is true? A. LSD has an easily recognized taste and smell. B. LSD interferes with glucose utilization in the cerebral cortex C. LSD is hepatically metabolized with an elimination half-life of about 2.5 hours D. LSD is poorly absorbed by the gastrointestinal tract, which is why it must be smoked. E. LSD remains legal in certain states. 70.7. Which of these structural classes is not a hallucinogen? A. B. C. D. E.

Lysergamides Indolealkyamines Methylxanthines Phenylethylamine Cannabinols

70.8. Which of the following statements about Lophophora williamsii is true? A. Peyote (Lophophora williamsii) is a small black-brown spineless cactus. B. Mescaline is the active hallucinogenic alkaloid. C. Peyote buttons are aromatic and sweet. D. There is delayed absorption of peyote from the GI tract. E. The Native American Church is banned from peyote use. 70.9. Which of the following statements about hallucinogens is true? A. Methylenedioxymethamphetamine (MDMA) produces clinical effects analogous to LSD.

CHAPTER

71

MARIJUANA 71.1. Naturally occuring cannabinoid receptors are identified in association with which of the following? A. B. C. D. E.

Chronic marijuana users only Normal humans and laboratory animals Mice exposed to marijuana extract Liver carcinoma Pregnant women

71.2. Possible medical indications for marijuana include all of the following except which condition? A. B. C. D. E.

Glaucoma Anorexia Diabetes Nausea Asthma

71.3. Which of the following is the most psychoactive substance in marijuana? A. B. C. D. E.

Cannabidiol 9-Tetrahydrocannabinol Cannabichromene Dronabinol 6-Tricannabinol

71.4. Which of the following physical findings is not consistent with marijuana intoxication? A. Conjunctival injection B. Tachycardia C. Lethargy

1916

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. Nystagmus E. Confusion 71.5. Which of the following is probably true of chronic marijuana usage? A. Smokers develop medical problems similar to those of chronic cigarette smokers. B. Female smokers have an increased incidence of breast cancer. C. Male offspring of users have an increased incidence of learning disabilities. D. Smokers have an increased risk for pulmonary embolus. E. Men have increased sperm motility. 71.6. Which of the following is correct with respect to the detection of THC metabolites in urine? A. B. C. D. E.

Not routinely done on drug abuse screens Confirmed by immunoassay techniques Positive at levels of 5 ng/mL Dependent on patterns of individual usage Blocked by high levels of vitamin C

71.7. Common intentional adulterants to marijuana include which of the following? A. B. C. D. E.

MDMA and fentanyl Propoxyphene and codeine PCP and cocaine Morphine and gluthethimide Paraquat and diquat

71.8. Which of the following is true with regard to passive inhalation of marijuana? A. Cannot cause a positive urine test B. Cannot cause psychological responses C. Can cause a positive screening test but negative confirmatory test D. Consistently causes positive test results E. Is not associated with physiologic responses 71.9. Prenatal use of marijuana can cause which of the following? A. A withdrawal syndrome in the neonate B. Complications similar to those associated with alcohol use C. Consistent low birth weight D. Neurobehavioral problems in the child E. No measurable changes in male offspring 71.10. Which of the following is true with regard to the psychoactive compound in marijuana? A. Concentrates in human breast milk and may be transferred to the newborn.

B. C. D. E.

CHAPTER

Does not have a specific receptor in the brain Is excreted unchanged in the urine Is distributed primarily in the body water Is found in high concentration in the CSF

72

SUBSTANCE WITHDRAWAL 72.1. Which of the following increases mortality in patients with alcohol withdrawal? A. B. C. D. E.

Chlordiazepoxide Dextrose-containing fluids Chlorpromazine Intravenous thiamine Magnesium

72.2. Baclofen withdrawal and baclofen overdose share which of the following features? A. B. C. D. E.

Anxiety Somnolence Diaphoresis Tremor Seizures

72.3. Opioid withdrawal shares which of the following characteristics with ethanol withdrawal? A. B. C. D. E.

High rate of concurrent infections Fever Altered mental status Tachycardia High mortality rate

72.4. Which one of the following is true concerning alcohol withdrawal seizures? A. They are usually partial complex in nature. B. They are characteristically followed by a prolonged postictal phase. C. More than a single seizure should suggest another diagnosis. D. They are generally self-limited and do not require anticonvulsant therapy. E. Always are accompanied by other signs of withdrawal. 72.5. Morbidity and mortality for alcohol withdrawal are not determined by which of the following? A. B. C. D. E.

Presence of concurrent illness Occult infection Ethanol level at the time of withdrawal Subtherapeutic phenytoin levels Volume status

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

72.6. Which one statement accurately characterizes patients with benzodiazepine withdrawal? A. Withdrawal occurs several days after cessation of benzodiazepines B. The patients typically do not respond to barbiturates C. They manifest seizures, miosis, tachycardia, piloerection, and agitation D. They always have concomitant thiamine deficiency E. Intravenous magnesium salts produces excellent symptom relief 72.7. Which one of the following regarding clonidine withdrawal is correct? A. It is more likely if doses greater than 1.2 mg/d are used B. It is best treated by therapy with a -adrenergic antagonist C. It never includes CNS manifestations such as hallucinations or agitation D. It occurs most frequently following use of a clonidine patch E. Patients should be treated with naloxone 72.8. Which one of the following is false with regard to clonidine, naloxone, and opioids? A. B. C. D.

Clonidine is used to treat opioid withdrawal. Naloxone is used to treat clonidine toxicity. Naloxone is used to treat opioid toxicity. Rapid detoxification programs use regimens that include both naloxone and clonidine. E. Opioids are used to treat clonidine withdrawal.

72.9. Which of the following is false with regard to opioid withdrawal seizures in neonates? A. They are associated with maternal methadone use. B. They are rarely associated with maternal heroin use. C. They never occur in adults. D. They do not occur for several weeks. E. They are best prevented with paregoric. 72.10. Which one of the following statements about γ-hydroxybutyrate withdrawal is correct? A. It is a phenomenon mediated by serotonin receptors. B. Patients should be treated with the pharmaceutical preparation sodium oxybate (γ-hydroxybutyrate). C. Is not generally a concern in those who use the drug exclusively at parties.

1917

D. It should not result from γ-butyrolactone abuse. E. It is treated with 1,4-butanediol in some experimental models.

CHAPTER

73

NICOTINE AND TOBACCO PREPARATIONS 73.1. At “usual” doses achieved through smoking, nicotine can be expected to produce all of the following physiologic effects except A. B. C. D. E.

Nausea Muscle tremor Increased lower esophageal sphincter tone Improved memory Increased neurohumoral production

73.2. Nicotine is least well absorbed from which site? A. B. C. D. E.

Oral mucosa Lung Small intestine Skin Stomach

73.3. Which of the following statements about nicotine metabolism is most correct? A. 80 to 90% of a dose is excreted unchanged in urine. B. Excretion can be enhanced by urinary acidification. C. The volume of distribution is approximately 10 L/kg. D. The half-life of cotinine is 1 to 4 hours. E. Drugs metabolized by the P450 system have their metabolism induced by nicotine. 73.4. All the following can be early signs of acute nicotine poisoning except A. B. C. D. E.

Erythema Hypertension Vomiting Seizures Atrial fibrillation

73.5. As nicotine poisoning progresses from the early phase to the late phase, which of the following changes is likely to occur? A. Muscle fasciculation to muscle paralysis B. CNS stimulation to CNS depression C. Tachycardia to bradycardia

1918

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

D. Hypertension to hypotension E. All of the above 73.6. Which of the following statements regarding the management of nicotine poisoning is the most appropriate? A. Almost all exposures require immediate medical evaluation. B. A serum level above 10 ng/mL predicts serious toxicity. C. Mecamylamine is the best antidote for seizure control. D. Syrup of ipecac should be used in pediatric cases only. E. Fluid repletion and maintenance of hydration is preferable to urinary acidification as a method of enhancing elimination. 73.7. Which statement about tobacco sources is most correct? A. Most cigarettes are manufactured from Nicotiana rustica. B. Kreteks are derived from Indian tobacco. C. Turkish tobacco is made from the Lobelia inflata plant. D. Chewing tobacco is packaged in “twists” and “plugs.” E. Snuff is usually inhaled through the nose. 73.8. All the following nicotine-replacement therapies have been shown to reduce withdrawal symptoms except A. B. C. D. E.

Smokeless cigarettes Exchange-resin gum Transdermal patches Nasal spray Metered-dose oral inhalers

73.9. Which of the following is a manifestation of nicotine withdrawal? A. B. C. D. E.

Diarrhea Depression Increased heart rate Muscle relaxation Anorexia

73.10. Which statement about smoking-cessation treatment is correct? A. Nicotine replacement therapy (NRT) eliminates craving for cigarettes. B. NRT does not control weight gain.

C. Transdermal nicotine patches (TNP) are more effective than nicotine gum in producing abstinence. D. NRT is not effective unless accompanied by a counseling or behavior modification program. E. After 1 year the abstinence rate of TNP users is equivalent to the abstinence rate among spontaneous quitters.

CHAPTER

74

FOOD POISONING 74.1. What toxin causes paralytic shellfish poisoning? A. B. C. D. E.

Brevitoxin Saxitoxin Domoic acid Tetrodotoxin Ciguatoxin

74.2. Which food poisoning has the highest fatality/case rate in the United States? A. B. C. D. E.

C. botulinum Salmonella Mushrooms E. coli O157:H7 Scombroid

74.3. Which cause of food poisoning is not characterized by a rapid onset of symptoms after exposure (500 rem results in death within 2 weeks in most exposed persons. E. Exposure to >5000 rem results in death and fulminant cardiovascular collapse within a 24- to 72-hour period.

CHAPTER

1939

94

METHEMOGLOBINEMIA 94.1. Which of the following compounds has a metabolite responsible for its toxicity? A. B. C. D. E.

Lidocaine Benzocaine Dapsone Nitroglycerin Nitrates

94.2. A 6-week-old infant presents with tachypnea, tachycardia, cyanosis, and fever. The infant becomes less cyanotic with oxygen therapy. Because the child lives on a farm, you analyze the arterial blood on a CO-oximeter and find a methemoglobin level of 7%. What would be the appropriate next step? A. Consider methylene blue use because of the obvious stress that the infant is exhibiting. B. Continue high-flow oxygen therapy because the infant responded well to the treatment and continue the workup for other causes of cyanosis. C. Contact your nearest hyperbaric chamber. D. Check the infant’s G6PD level. E. Place the infant on a monitor and evaluate the electrocardiogram. 94.3. Methemoglobinemia occurs when oxidant stress A. Causes the globin portion of hemoglobin to change its configuration B. Causes the porphyrin ring to destabilize C. Causes the iron in the center of the porphyrin ring to lose an electron D. Causes the denaturation of protein in the red cell membrane with subsequent hemolysis E. Causes individuals with G6PD deficiency to undergo hemolysis 94.4. A cyanotic patient is brought to the emergency department from a house fire. Which of the following is least likely to be the cause of cyanosis? A. Hypoxia from upper airway edema caused by thermal injury B. Hypoxia from pulmonary injury caused by smoke inhalation C. Hypoxia from carbon monoxide toxicity D. Methemoglobinemia from inhaled smoke toxins E. Hypoxia caused by bronchospasm

1940

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

94.5. Which of the following has been associated with methemoglobinemia in young children? A. B. C. D. E.

Diaper ointments with tetracaine Ingestion of naphthalene mothballs High nitrate concentrations from well water Diapers labeled with aniline dye All of the above

94.6. Which of the following symptoms is expected to occur at a methemoglobin concentration of 15% in an otherwise healthy patient? A. B. C. D. E.

Shortness of breath at rest Cyanosis Dizziness and fatigue Coma or asystole Headache and confusion

94.7. Which of the following substances has been associated with the development of both methemoglobinemia and sulfhemoglobinemia? A. B. C. D. E.

Naphthalene Metoclopramide Thiazide diuretics Lidocaine Phenazopyridine

94.8. At what age do children develop full NADH methemoglobin reductase activity? A. B. C. D. E.

2 months 4 months 6 months 1 year 2 years

94.9. Which amount of hemoglobin must exist in the Fe3+ state for a detectable cyanosis to be present? A. B. C. D. E.

0.5 g/dL 3 g/dL 1.5 g/dL 10 g/dL None of the above

94.10. The red cell uses which of the following compounds as an electron donor to reduce methemoglobin and maintain the methemoglobin level at less than 1%? A. B. C. D. E.

NADH NADPH Ascorbic acid Reduced glutathione All of the above

CHAPTER

95

SIMPLE ASPHYXIANTS AND PULMONARY IRRITANTS 95.1. Which of the following statements is correct? A. Acute lung injury (ALI) occurs commonly during myocardial infarctions (MI). B. Development of ALI is commonly a preterminal event. C. The diagnosis of the acute respiratory distress syndrome (ARDS) requires demonstration of extremely poor oxygenating ability in patients with an appropriate history. D. ARDS is most commonly caused by inhalation of chlorine gas. E. The increasing water solubility of a gas correlates directly with the potential of that gas to produce ALI. 95.2. Which is correct about simple asphyxiant gases? A. Simple asphyxiants never produce measurable laboratory abnormalities. B. Certain simple asphyxiant gases mediate physiologic changes in addition to hypoxia. C. They vary in their ability to produce hypoxia. D. Typical symptoms include shortness of breath and frothy, blood-tinged sputum. E. It is impossible to succumb to simple asphyxiants outdoors. 95.3. The clinical presentation after exposure to a highly water-soluble irritant gas may include all of the following except A. Drooling, cough, or stridor B. Conjunctival and oropharyngeal mucosal erythema C. Normal arterial blood gas measurement D. Symptom onset delayed 24 hours E. Improvement with nebulized 2% sodium bicarbonate 95.4. Which of the following concerning irritant gases is not correct? A. Mixing sodium hypochlorite and ammonia may generate chloramine gas. B. Burning plastic may liberate phosgene. C. Silo-filler disease is related to excessive exposure to sulfur dioxide. D. Burning nitrocellulose (radiographic film) is expected to generate nitrogen dioxide. E. Inhalational hydrogen fluoride toxicity is predominantly related to its systemic absorption.

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

95.5. Reactive airways dysfunction syndrome (RADS) is unlikely after exposure to which toxic gas? A. B. C. D. E.

Helium Chlorine Methylisocyanate Ammonia Capsaicin

95.10. All of the following describe toxic mechanisms of pulmonary irritants except A. B. C. D. E.

95.6. Management of patients with irritant gas exposure should include which of the following? A. High-dose corticosteroid therapy to limit the immunologic response B. Nebulized 8.4% sodium bicarbonate to neutralize the acid-forming gases C. Hyperbaric oxygenation to limit hypoxic pulmonary damage D. Supplemental oxygen only as necessary to maintain an adequate PO2 E. Transtracheal instillation of surfactant 95.7. Which of the following describes phosgene? A. Phosgene poisoning no longer occurs since its use as a war gas was banned by the Geneva Convention. B. Prolonged exposure is unlikely because of its foul odor. C. Dissolution in the mucosal water is rapid, but the onset of toxicity is delayed. D. Once it has dissolved, the acidic products generate an influx of inflammatory cells. E. Pulmonary toxicity can be completely averted with N-acetylcysteine (NAC). 95.8. Which of the following is used as a riot-control agent? A. B. C. D. E.

Cyanide Methylisocyanate Acrolein Chloroacetophenone Ozone

95.9. Which of the following statements best describes metal fume fever? A. Direct pulmonary toxicity occurs, and serum metal levels are elevated. B. It is a recurrent flulike syndrome that develops shortly after exposure to metal oxide fumes generated during welding, galvanizing, or smelting. C. Exacerbation of symptoms during the workweek is typical. D. The drug of choice in management is BAL. E. Chest radiography during the episode usually reveals patchy pulmonary infiltrates.

1941

CHAPTER

NH4+ + HOCl → H+ + H2O + NH2Cl Cl2 + H2O → 2 HCl + {O} N2 + 3 H2O → H2NO3 + 2 H2 O2 + Fe2+ → Fe3+ + O2 SO2 + H2O → H2SO3

96

SMOKE INHALATION 96.1. What percentage of fire-related deaths are from smoke inhalation? A. B. C. D. E.

Less than 10% 10 to 30% 50 to 80% Greater than 90% None of the above

96.2. Which of the following toxic gases is formed by combustion of plastics? A. B. C. D. E.

Styrene Cyanide Sulfur dioxide Hydrogen fluoride Hydrogen sulfide

96.3. Which of the following toxic gases is formed by the combustion of polyvinyl chloride? A. B. C. D. E.

Carbon monoxide Hydrogen chloride Phosgene Chlorine All of the above

96.4. Which of the following is the most important physical property of a toxin within smoke that determines the location of lung injury? A. B. C. D. E.

pH Molecular weight Particle size Water solubility Charge

96.5. Which of the following is not an irritant toxin? A. B. C. D. E.

Isocyanates Ammonia Acrolein Cyanide Chlorine

1942

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

96.6. Which of the following is not a chemical asphyxiant? A. B. C. D. E.

Cyanide Hydrogen sulfide Acrolein Carbon monoxide Oxides of nitrogen

96.7. Which of the following is not an indication for early endotracheal intubation in smoke inhalation victims? A. B. C. D.

Coma Stridor Full-thickness circumferential neck burns Edematous oropharynx with carbonaceous sputum E. Wheezing

96.8. The level of the respiratory tract at which an irritant in smoke causes injury is dependent on which of the following? A. B. C. D. E.

Water solubility of the toxin Concentration of the inhaled toxin Duration of exposure to the toxin Particle size of the toxin All of the above

96.9. Which of the following mechanisms does not increase airways resistance in the tracheobronchial tree following smoke inhalation? A. B. C. D. E.

Intraluminal debris Bronchiolar mucosal edema Inspissated secretions Acute bronchospasm Thermal Injury

96.10. In the smoke inhalation victim, lactic acidosis may be caused by which of the following? A. B. C. D. E.

CHAPTER

Carbon monoxide Cyanide Hypoxemia Hypoperfusion All of the above

97

CARBON MONOXIDE 97.1. Carbon monoxide poisoning may occur from which of the following exposures? A. Propane

B. C. D. E.

Trichloroethylene Trichloroethane Methylene chloride All of the above

97.2. Which of the following is not true about carbon monoxide? A. It has an affinity of 200 to 250 times greater than oxygen for hemoglobin. B. It has an affinity 40 times greater than oxygen for myoglobin. C. It is a product of heme degradation. D. It binds to cytochrome oxidase. E. It causes a rightward shift in the oxyhemoglobin dissociation curve. 97.3. Which of the following can reliably be used to confirm CO exposure in an ethanol-inebriated patient before obtaining an arterial COHb level? A. Depression of pulse oximetry B. Cherry red discoloration of the skin C. Breath sampling for carbon monoxide concentration D. Oxygen saturation from arterial blood gas E. Venous carboxyhemoglobin level 97.4. Delayed or persistent neuropsychological sequelae after CO poisoning have included A. B. C. D. E.

Memory and learning problems Cortical blindness Parkinsonism Incontinence All of the above

97.5. All of the following fetal outcomes have been associated with serious exposure to carbon monoxide during pregnancy except A. B. C. D. E.

Stillbirth Mental retardation Cerebral palsy Normal infant Placental abruption

97.6. All of the following statements are true about carbon monoxide except A. B. C. D. E.

It is more dense than air. It is nonirritating. It is colorless. It is odorless. It binds to myoglobin.

97.7. Which of the following is associated with central neurologic injury in animal models of CO poisoning?

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. B. C. D. E.

Leukocyte adherence Lysosomal degeneration Hypertensive episode Carboxyhemoglobin level no less than 50% Decrease in cerebral adenosine

97.8. In addition to low densities in cerebral white matter, the other common abnormal area on magnetic resonance imaging (MRI) associated with severe CO poisoning and neurologic sequelae is the A. B. C. D. E.

Substantia nigra Pineal gland Hypothalamus Globus pallidus Cerebellum

97.9. The elimination half-life of carboxyhemoglobin with 100% oxygen at room pressure is closest to A. B. C. D. E.

5 hours 4 hours 2 hours 1 hour 15 minutes

97.10. Which of the following is reliably associated with potential neuropsychological sequelae from carbon monoxide poisoning? A. B. C. D. E.

CHAPTER

Syncope Headache COHb >20% Metabolic alkalosis None of the above

98

CYANIDE AND HYDROGEN SULFIDE 98.1. The antidotal effect of nitrite in cyanide poisoning results in part from which of the following? A. B. C. D. E.

Formation of carboxyhemoglobin Nitric oxide–induced vasodilation Myocardial relaxation Reduction in cerebrovascular autoregulation Binding to cyanide and excretion of the complex

98.2. Adverse effects of nitrite administration include which of the following? A. Rhabdomyolysis B. Hair loss C. Diminished PO2

1943

D. Hypotension E. Red, flushed skin 98.3. What is the most likely clinical manifestation following exposure to cyanide gas? A. B. C. D. E.

Ventricular tachycardia Hematemesis Convulsions Abdominal pain Cyanosis

98.4. Which of the following is not an accepted mechanism for cyanide toxicity? A. B. C. D. E.

Lipid peroxidation Histotoxic hypoxia NMDA receptor activation Hypoxemia Methemoglobinemia

98.5. A person survives severe cyanide poisoning, but over a period of several days the patient develops bradykinesia and a tremor. What area of the brain is likely to be abnormal on CT imaging of this patient? A. B. C. D. E.

Vermis of cerebellum Basal ganglia Reticular activating system Frontal lobes of the cerebral cortex Temporal lobes of the cerebral cortex

98.6. Which of the following physiological manifestations is consistent with cyanide poisoning? A. B. C. D. E.

Lowered central venous oxygen saturation Nongap metabolic acidosis Hypoglycemia Hypophosphatemia Elevated blood lactate

98.7. Which of the following is not a source of cyanide poisoning? A. Incomplete combustion of nitrogen-containing organic compounds B. Ingestion of nitriles C. Apricot seed ingestion D. Nitroprusside therapy E. Burning of wood 98.8. Rescuers of hydrogen sulfide poisoning victims often become victims themselves because of olfactory fatigue and failure to smell the rotten egg odor. At what atmospheric concentration does olfactory fatigue occur? A. 1 ppm B. 10 ppm

1944

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. 100 ppm D. 1000 ppm E. 10,000 ppm 98.9. Which of the following is not a common clinical manifestation of hydrogen sulfide poisoning? A. B. C. D. E.

Ocular pain Diarrhea Pulmonary edema Respiratory paralysis Metabolic acidosis

98.10. Which of the following is a source of hydrogen sulfide? A. B. C. D. E.

CHAPTER

Decomposition of grain in silos Incomplete combustion of silk Combination of ammonia and hypochlorite Sewer gas Mercury refining

99

RADIATION 99.1. A criticality event occurs when which of the following occurs? A. An individual receives a lethal amount of radiation B. A mass casualty event occurs with radiation C. A cell mutates into a neoplasm D. A chain reaction of fissions occurs releasing nuclear energy E. A critical number of cells die, and ARS begins 99.2. The amount of radiation exposed in the Goiânia incident was equivalent to which of the following? A. A million times that administered for a thallium stress test B. As much as exists in a smoke detector C. Three times more than from a chest radiograph D. A billion times that released after the Chernobyl incident E. A thousand times less than that released following detonation of a fission bomb. 99.3. Cell phones, televisions, and metal detectors are not considered to be radiation hazards to humans because their signals consist of which of the following? A. High-energy photons B. Low-energy photons

C. High-energy electrons D. Low-energy electrons E. Low-energy
particles 99.4. Which of the following particles may cause an irradiated object to become radioactive? A. B. C. D. E.


particle  particle Neutron Photon Positron

99.5. In general, radiosensitivity of cells varies according to which of the following relationships? A. Directly with the rate of proliferation and directly with degree of differentiation B. Directly with the rate of proliferation and inversely with degree of differentiation C. Inversely with the rate of proliferation and directly with degree of differentiation D. Inversely with the rate of proliferation and inversely with degree of differentiation E. Independent of rate of proliferation or degree of differentiation 99.6. Which of the following is the most common effect when ionizing radiation enters cells? A. B. C. D. E.

Alter DNA Ionize water Form peroxides Alter the structure of organic molecules Alter RNA

99.7. Residential radon exposure is associated with which of the following malignancies? A. B. C. D. E.

Bone Breast Lung Hematologic Intestinal

99.8. Survivors of the atomic bomb blast in Nagasaki who had higher levels of radiation exposure tended to have which of the following? A. B. C. D. E.

A higher incidence of thyroid disease A higher incidence of pancreatic carcinoma A higher incidence of lung carcinoma A higher incidence of osteogenic sarcoma No significant increase in disease

99.9. Which of the following is true of children born to survivors of atomic bombings at Hiroshima and

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

Nagasaki who were not exposed to radiation in utero in comparison with a control population? A. B. C. D. E.

A higher incidence of leukemia A higher incidence of thyroid disease A higher incidence of mental retardation A higher incidence of microcephaly No discernible increase in disease

99.10. At which of the following doses is a single, wholebody irradiation likely to be immediately fatal? A. B. C. D. E.

CHAPTER

10 rad 100 rad 500 rad 10 Gy 100 Gy

100

CHEMICAL AND BIOLOGICAL WEAPONS 100.1. Which of the following chemical agents is least volatile and demonstrates the greatest environmental persistence? A. B. C. D. E.

Phosgene Sarin Soman Tabun VX

100.2. Which of the following produces painful skin vesicles within hours of contact? A. B. C. D. E.

Botulinum toxin GD Sulfur mustard T-2 toxin VX

100.3. High doses of atropine, sometimes in excess of 1000 mg, may be required to effectively treat the toxicity caused by which of the following? A. B. C. D. E.

Parathion Sarin Soman Tabun Phosgene

100.4. Inhalation of which of the following CBW agents is least likely to produce a pulmonary syndrome? A. Bacillus anthracis spores B. Botulinum toxin C. Coxiella burnetti

1945

D. Phosgene E. Yersinia pestis 100.5. Treating victims exposed to which of the following CBW agents poses the greatest overall risk of contaminating healthcare facilities and personnel? A. B. C. D. E.

Anthrax spores Sarin Soman Sulfur mustard VX

100.6. A mass-casualty event where victims collapse with respiratory failure is least consistent with exposure to which of the following CBW agents? A. B. C. D. E.

Botulinum toxin Cyanogen chloride Lewisite Tabun VX

100.7. Complaints of eye pain, lacrimation, rhinorrhea, cough, nausea, and vomiting are least likely to occur from exposure to which of the following CBW agents? A. B. C. D. E.

Adamsite Chloroacetophenone Hydrogen cyanide Sarin Sulfur mustard

100.8. Which of the following CBW agents is not generally intended to be temporarily incapacitating? A. B. C. D. E.

Botulinum toxin Capsaicin Q fever 3-Quinuclidinyl benzilate Staphylococcal enterotoxin B

100.9. Soman toxicity would respond most favorably to treatment with which of the following agents/ drugs? A. B. C. D. E.

2,3-Dimercaprol 4-Dimethylaminophenol Pyridostigmine bromide 3-Quinuclidinyl benzilate Sodium nitrite

100.10. Which characteristic physical/chemical property is incorrectly associated with its corresponding CW agent(s)? A. Density less than air—Hydrogen cyanide B. Odor like garlic—Nerve agents

1946

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Odor like geraniums—Lewisite D. Odor like hay—Phosgene E. Volatility like water—Sarin

CHAPTER

101

SNAKES AND OTHER REPTILES 101.1. Antivenom most consistently reverses what pathology in a Crotaline envenomation? A. B. C. D. E.

Pain at the bite site Edema and ecchymosis at the bite site Coagulopathy Secondary infection Seizures

101.2. A significant coagulopathy is most commonly associated with the bite of which of the following snakes? A. B. C. D. E.

Western diamondback rattlesnake Sonoran coral snake Mojave rattlesnake Eastern coral snake Black rat snake

101.3. The dose of equine-based Crotaline antivenom required to treat a pit viper bite A. B. . D. E.

Is based on clinical presentation and response Is initially two vials every 2 hours Is limited to 20 vials Is based on the size of the snake Is based on the number of fang marks

101.4. Which of the following abnormalities is most difficult to correct with antivenom? A. B. C. D. E.

Altered mental status Thrombocytopenia RBC hemolysis Cardiovascular instability Gastrointestinal dysfunction

101.5. Systemic effects of a western diamondback rattlesnake envenomation would most likely include A. B. C. D. E.

Headache and fever Bloody diarrhea and abdominal cramps Muscle fasciculations, nausea, and weakness Confusion and diplopia Seizures and bradycardia

101.6. Which of the following is true concerning local effects of eastern diamondback rattlesnake bites? A. Pain is the most common symptom. B. Tissue necrosis is common in copperhead bites. C. Compartment syndrome occurs in 30% of bites. D. Fangs commonly penetrate 2 to 4 cm. E. Soft tissue swelling is maximum at 2 to 4 hours. 101.7. Allergic reactions to antivenom: A. Do not occur in patients with negative skin tests B. Are related to the number of vials given and rapidity of administration C. Can be prevented by administering steroids D. Are an absolute contraindication to its use E. Are seen only in patients with prior antivenom exposure 101.8. Signs and symptoms of coral snake bite would most likely include A. B. C. D. E.

Significant swelling and pain Early coagulopathy Metallic taste and tongue edema Diplopia and weakness Chest pain and shortness of breath

101.9. Gila monster (Heloderma suspectum) bites A. B. C. D. E.

Are best treated with antivenin Are associated with renal failure Cause severe pain and moderate edema Are commonly fatal Are associated with a coagulopathy

101.10. A patient with a very serious systemic effects from a western diamondback rattlesnake bite is being given large doses of antivenom and develops dyspnea, hypotension, urticaria, and wheezing. What is the most appropriate next step? A. Initially stop antivenom, treat for anaphylaxis, and restart antivenom B. Send blood for type and crossmatch and administer platelets and cryoprecipitate C. Stop antivenom altogether and proceed with surgical excision of envenomated tissue D. Stop antivenom altogether and administer fluids, furosemide, high-dose steroids, and methotrexate E. Increase antivenom and consider this a sign of ARDS and progressive envenomation

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

CHAPTER

102

ARTHROPODS 102.1. Which of the following statements about black widow spider bites is correct? A. Only the male spider is capable of envenomating its victim. B. There is usually a severe local reaction. C. Severe muscle cramps, nausea, weakness, and tremor can develop within several hours. D. The antivenom should be administered to patients with mild to moderate symptoms. E. The spider can be identified by the violin markings on the spider’s black abdomen. 102.2. Which of the following statements about the brown recluse spider is correct? A. Brown recluse bites occur year round in farm workers in most parts of the United States. B. The location of the bite is initially very painful. C. Within 1 hour the bite blisters and becomes necrotic. D. Antivenom should be administered at the first sign of tissue necrosis. E. The victim may develop fever, arthralgias, hemolysis, and DIC. 102.3. Which of the following statements about a sting from a Centruroides scorpion is correct? A. Stings occur predominantly in the northwestern United States. B. Mortality is approximately 25% in children. C. Mannitol relieves the intense muscle cramps. D. Victims may develop muscle fasciculations and cramps, seizures, renal failure, and cardiovascular collapse. E. None of the above 102.4. Which of the following statements about tick paralysis is correct? A. Improvement is often seen after the entire tick is removed from the skin. B. The tick must be on the skin for 2 to 3 hours before disease will develop. C. Absent deep tendon reflexes at 6 hours is characteristic. D. Calcium gluconate will effectively reverse muscle weakness. E. Boys get tick paralysis more commonly than girls.

1947

102.5. Which of the following statements about hymenoptera stings is correct? A. The venoms produced by wasps, hornets, and yellow jackets are almost identical. B. Subcutaneous epinephrine 0.3 mL of 1:100,000 may be used to treat bronchospasm. C. A delayed reaction of fever, malaise, headache, polyarthritis, and lymphadenopathy may occur 1 to 2 days after a sting. D. Anaphylaxis associated with multiple bee stings is IgG mediated. E. Patients who have a history of severe reactions to bee stings should be provided a prefilled autoinjector syringe containing diphenhydramine 50 mg. 102.6. Which of the following statements about the funnel web spider is correct? A. The venom of the female spider is more toxic than that of the male spider. B. Envenomations can be treated effectively with cimetidine. C. They are found in Queensland, New South Wales, Tasmania, and Victoria. D. Fatalities have not been reported from this spider. E. The toxin of the funnel web spider is
-bungarotoxin. 102.7. Which of the following is not found in the venom of fire ants? A. B. C. D. E.

Phospholipase Hyaluronidase N-Acetyl--glucosamidase Piperidine Cyanide

102.8. Which of the following arthropods is most likely to cause a necrotic lesion? A. B. C. D. E.

Apis mellifera Dugesiella henzi Atrax robusta Latrodectus mactans Tegenaria agrestis

102.9. Which of the following is a true statement regarding an encounter with a tarantula? A. Most bite wounds are very painful and develop into large necrotic lesions. B. Hypotension is prominent and results from toxin-mediated myocardial dysfunction.

1948

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

C. Eye exposure to urticating hairs is the predominant complaint. D. An effective antivenom exists and is available through the zoo-venom network. E. Myoglobinuric renal failure is the major concern following envenomation. 102.10. Which of the following may be the most beneficial therapeutic intervention for patients with severe pain from a black widow spider bite? A. B. C. D. E.

CHAPTER

Loxosceles antivenom Morphine Calcium gluconate Amitriptyline Hyperbaric oxygen

103

MARINE ENVENOMATIONS 103.1. Which of the following statements about Scorpaenidae envenomations is correct? A. The lionfish will normally not attack man unless cornered. B. The most common symptoms are nausea, vomiting, and diaphoresis. C. The venom is a complex hemolytic toxin. D. The lionfish is the most dangerous of the species. E. Home aquarium injuries are a common cause of stonefish envenomations. 103.2. Which of the following Scorpaenidae envenomations would be most likely to be fatal? A. B. C. D. E.

Lionfish Stonefish Turkeyfish Zebrafish Tigerfish

103.3. An antivenom is available for which of the following aquatic envenomations? A. B. C. D. E.

Sea wasp Stingray Man-of-war jellyfish Cone shell Sea urchin

103.4. A patient who presents with a rash confined to the genital area 1 day after swimming in the ocean may have been exposed to which of the following?

A. B. C. D. E.

Hydroids Sea anemones Box jellyfish Fire coral Thimble jellyfish

103.5. Which of the following fish have dorsal spines that are sharp enough and powerful enough to be thrust through a leather boot? A. B. C. D. E.

Stingray Weeverfish Lionfish Starfish Tigerfish

103.6. Which antibiotics should be selected for treating infected wounds from exposure to marine animals, sea water, and ocean sediment? A. B. C. D. E.

Aminoglycosides Ampicillin Third-generation cephalosporins Fluoroquinolones Chloramphenicol

103.7. Which of the following statements about the tentacles of the Portuguese man-of-war is correct? A. They may be several hundred feet long. B. Each man-of-war may have several hundred tentacles. C. Once detached, tentacles are no longer capable of stinging. D. The tentacles contain nematocysts that can deliver a neurotoxic venom. E. They are found only in the Pacific Ocean. 103.8. Which of the following starfish is venomous? A. B. C. D. E.

Sea star Ivory star Crown-of-thorns Flower star Canterbury star

103.9. An envenomation from which of the following is most likely to result in the patient having spines embedded in the affected limb? A. B. C. D. E.

Stingray Lionfish Portuguese man-of-war Sea urchin Weeverfish

103.10. Which of the following statements about the venom isolated from the sea snake is correct?

STUDY QUESTIONS FOR GOLDFRANK’S TOXICOLOGIC EMERGENCIES, SEVENTH EDITION

A. It inhibits the reuptake of calcium into the sarcoplasmic reticulum. B. It interferes with Na+-K+-ATPase activity. C. It inhibits the slow calcium channels. D. It causes direct stimulation of postsynaptic glycine receptors. E